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Gut microbiota and physical exercise in obesity and diabetes – A systematic review

Published:January 26, 2022DOI:https://doi.org/10.1016/j.numecd.2022.01.023

      Highlights

      • Physical exercise as a beneficial gut microbiota modulator in metabolic diseases.
      • Physical exercise as an alternative therapy for metabolic diseases via gut microbiota.
      • Physical exercise may modulate the gut bacteria diversity and abundance in obesity.
      • Physical exercise may reduce metabolic endotoxemia markers in type 2 diabetes.
      • The benefits of exercise on gut microbiota need to be proved by well-designed trials.

      Abstract

      Background and aim

      The gut microbiota (GM) plays an essential role in maintaining health, and imbalance in its composition is associated with the physiopathogenesis of metabolic diseases, such as obesity and type 2 diabetes mellitus (T2DM). Diet and antibiotics are known modulators of GM, but the influence of physical exercise in modulating the diversity and abundance of hindgut bacteria is still poorly understood. The aim of this systematic review was to investigate the scientific evidence about the effect of physical exercise on GM modulation in subjects with obesity and T2DM.

      Methods and results

      A search in PubMed, Web of Science, Scopus, Cochrane and Embase databases using keywords related to gut microbiota, physical exercise and metabolic diseases was performed. Eight clinical studies met the inclusion criteria, six in subjects with obesity and two in individuals with T2DM. In three studies carried out in individuals with obesity, exercise was able to positively modulate the diversity of GM and the abundance of some species of bacteria, mostly by increasing the Bifidobacteriaceae family, and the Bacteroides and Akkermansia genera, and by decreasing the Proteobacteria phylum. The studies in subjects with T2DM found that physical exercise may reduce metabolic endotoxemia markers.

      Conclusions

      Physical exercise may be a beneficial modulation strategy of GM composition in metabolic diseases, specifically aerobic exercises carried out for at least 6 weeks with moderate or high intensity. Nevertheless, well-designed clinical trials are needed to clarify the role of physical exercise on GM in subjects with obesity and T2DM.

      Keywords

      1. Introduction

      The non-communicable chronic diseases have been growing exponentially in recent decades. According to the World Health Organization (WHO) [
      WHO - World Health Organization
      Health topics - obesity [Internet].
      ], the prevalence of overweight or obese children and adolescents between 5 and 19 years old increased more than four times in the period from 1975 to 2016, and the world forecast for 2025 is that 2.3 billion overweight adults, with 700 million individuals with obesity. Diabetes mellitus (types 1 and 2), in turn, is one of the fastest growing global health emergencies of the 21st century. In 2019, the prevalence of people with diabetes in the world was of 463 million [
      • Aschner P.
      • Karuranga S.
      • James S.
      • Simmons D.
      • Basit A.
      • Shaw J.
      The International Diabetes Federation's guide for diabetes epidemiological studies.
      ]. The projection for 2030 is 578 million people, and in 2045 will be 700 million people with diabetes worldwide, with 90% of them with type 2 diabetes (T2DM) [
      • Aschner P.
      • Karuranga S.
      • James S.
      • Simmons D.
      • Basit A.
      • Shaw J.
      The International Diabetes Federation's guide for diabetes epidemiological studies.
      ,
      • Saeedi P.
      • Petersohn I.
      • Salpea P.
      • Malanda B.
      • Karuranga S.
      • Unwin N.
      • et al.
      Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition.
      ].
      Unhealthy changes in diet, and sedentary lifestyle have been identified as the main risk factors for the emergence of metabolic diseases, especially obesity and T2DM [
      WHO - World Health Organization
      Health topics - obesity [Internet].
      ,
      • Aschner P.
      • Karuranga S.
      • James S.
      • Simmons D.
      • Basit A.
      • Shaw J.
      The International Diabetes Federation's guide for diabetes epidemiological studies.
      ]. Individuals affected by these diseases usually present an imbalance in the composition of their gut microbiota (GM), termed dysbiosis [
      • Singer-Englar T.
      • Barlow G.
      • Mathur R.
      Obesity, diabetes, and the gut microbiome: an updated review.
      ]. GM is currently considered an important endocrine organ involved in complex functions related to the maintenance of energy homeostasis, inflammatory status and immunity of the host [
      • Fan Y.
      • Pedersen O.
      Gut microbiota in human metabolic health and disease.
      ]. Changes in the composition and abundance of hindgut beneficial bacteria and in the intestinal homeostasis may result in deleterious changes related to insulin sensitivity [
      • Gurung M.
      • Li Z.
      • You H.
      • Rodrigues R.
      • Jump D.B.
      • Morgun A.
      • et al.
      Role of gut microbiota in type 2 diabetes pathophysiology.
      ], accumulation of body fat, and systemic inflammation [
      • Gomes A.C.
      • Hoffmann C.
      • Mota J.F.
      The human gut microbiota: metabolism and perspective in obesity.
      ]. These metabolic changes denote an important role of dysbiosis in the trigger and evolution of metabolic diseases, acting in a two-way pathway in the pathophysiogenesis and in the harmful metabolic changes of obesity [
      • Singer-Englar T.
      • Barlow G.
      • Mathur R.
      Obesity, diabetes, and the gut microbiome: an updated review.
      ,
      • Fan Y.
      • Pedersen O.
      Gut microbiota in human metabolic health and disease.
      ,
      • Gomes A.C.
      • Hoffmann C.
      • Mota J.F.
      The human gut microbiota: metabolism and perspective in obesity.
      ,
      • Castaner O.
      • Goday A.
      • Park Y.M.
      • Lee S.H.
      • Magkos F.
      • Shiow S.
      • et al.
      The gut microbiome profile in obesity: a systematic review.
      ] and T2DM [
      • Singer-Englar T.
      • Barlow G.
      • Mathur R.
      Obesity, diabetes, and the gut microbiome: an updated review.
      ,
      • Gurung M.
      • Li Z.
      • You H.
      • Rodrigues R.
      • Jump D.B.
      • Morgun A.
      • et al.
      Role of gut microbiota in type 2 diabetes pathophysiology.
      ]. Thus, the positive modulation of GM may contribute to the prevention and treatment of these diseases.
      Diet is one of the main modulating agents of GM, particularly in individuals with T2DM [
      • Houghton D.
      • Hardy T.
      • Stewart C.
      • Errington L.
      • Day C.P.
      • Trenell M.I.
      • et al.
      Systematic review assessing the effectiveness of dietary intervention on gut microbiota in adults with type 2 diabetes.
      ], and exercise seems to contribute to improving the composition of gut bacterial communities, regardless of diet [
      • Dorelli B.
      • Gallè F.
      • De Vito C.
      • Duranti G.
      • Iachini M.
      • Zaccarin M.
      • et al.
      Can physical activity influence human gut microbiota composition independently of diet? a systematic review.
      ]. The plausible positive effect that exercise practice has on bowel physiology and GM composition has been postulated as one of the mechanisms by which physical exercise acts to improve metabolic health [
      • Mailing L.J.
      • Allen J.M.
      • Buford T.W.
      • Fields C.J.
      • Woods J.A.
      Exercise and the gut microbiome: a review of the evidence, potential mechanisms, and implications for human health.
      ,
      • Aya V.
      • Flórez A.
      • Perez L.
      • Ramírez J.D.
      Association between physical activity and changes in intestinal microbiota composition: a systematic review.
      ]. In addition, changes promoted by physical exercise in GM composition may influence performance and mood in elite athletes [
      • Clark A.
      • Mach N.
      Exercise-induced stress behavior, gut-microbiota-brain axis and diet: a systematic review for athletes.
      ]. Physical exercise promotes changes in bowel motility [
      • Oettlé G.J.
      Effect of moderate exercise on bowel habit.
      ,
      • Dainese R.
      • Serra J.
      • Azpiroz F.
      • Malagelada J.R.
      Effects of physical activity on intestinal gas transit and evacuation in healthy subjects.
      ], increases the concentrations of fecal bile acids [
      • Hagio M.
      • Matsumoto M.
      • Yajima T.
      • Hara H.
      • Ishizuka S.
      Voluntary wheel running exercise and dietary lactose concomitantly reduce proportion of secondary bile acids in rat feces.
      ,
      • Meissner M.
      • Lombardo E.
      • Havinga R.
      • Tietge U.J.F.
      • Kuipers F.
      • Groen A.K.
      Voluntary wheel running increases bile acid as well as cholesterol excretion and decreases atherosclerosis in hypercholesterolemic mice.
      ], changes the temperature and distribution of gut blood flow [
      • Mailing L.J.
      • Allen J.M.
      • Buford T.W.
      • Fields C.J.
      • Woods J.A.
      Exercise and the gut microbiome: a review of the evidence, potential mechanisms, and implications for human health.
      ,
      • Rowell L.B.
      • Brengelmann G.L.
      • Blackmon J.R.
      • Twiss R.D.
      • Kusumi F.
      Splanchnic blood flow and metabolism in heat-stressed man.
      ], and positively modulates the functioning of immune system cells that are close to the gut mucosa [
      • Packer N.
      • Hoffman-Goetz L.
      Exercise training reduces inflammatory mediators in the intestinal tract of healthy older adult mice.
      ,
      • Hoffman-Goetz L.
      • Pervaiz N.
      • Guan J.
      Voluntary exercise training in mice increases the expression of antioxidant enzymes and decreases the expression of TNF-α in intestinal lymphocytes.
      ]. These effects promote a series of stimuli related to improved gut barrier integrity [
      • Campbell S.C.
      • Wisniewski P.J.
      • Noji M.
      • McGuinness L.R.
      • Haeggblom M.M.
      • Lightfoot S.A.
      • et al.
      The effect of diet and exercise on intestinal integrity and microbial diversity in mice.
      ,
      • Lira F.S.
      • Rosa J.C.
      • Pimentel G.D.
      • Souza H.A.
      • Caperuto E.C.
      • Carnevali L.C.
      • et al.
      Endotoxin levels correlate positively with a sedentary lifestyle and negatively with highly trained subjects.
      ], reduced chronic low-intensity inflammation [
      • Lira F.S.
      • Rosa J.C.
      • Pimentel G.D.
      • Souza H.A.
      • Caperuto E.C.
      • Carnevali L.C.
      • et al.
      Endotoxin levels correlate positively with a sedentary lifestyle and negatively with highly trained subjects.
      ] and insulin resistance [
      • Sohail M.U.
      • Yassine H.M.
      • Sohail A.
      • Al Thani A.A.
      Impact of physical exercise on gut microbiome, inflammation, and the pathobiology of metabolic disorders.
      ], and possible increased abundance of beneficial bacteria in the hindgut [
      • Bressa C.
      • Bailen-Andrino M.
      • Perez-Santiago J.
      • Gonzalez-Soltero R.
      • Perez M.
      • Gregoria Montalvo-Lominchar M.
      • et al.
      Differences in gut microbiota profile between women with active lifestyle and sedentary women.
      ,
      • Clarke S.F.
      • Murphy E.F.
      • O’Sullivan O.
      • Lucey A.J.
      • Humphreys M.
      • Hogan A.
      • et al.
      Exercise and associated dietary extremes impact on gut microbial diversity.
      ].
      Current scientific evidence points to a potentially beneficial association between physical exercise and GM, according to five systematic reviews published on the topic [
      • Dorelli B.
      • Gallè F.
      • De Vito C.
      • Duranti G.
      • Iachini M.
      • Zaccarin M.
      • et al.
      Can physical activity influence human gut microbiota composition independently of diet? a systematic review.
      ,
      • Aya V.
      • Flórez A.
      • Perez L.
      • Ramírez J.D.
      Association between physical activity and changes in intestinal microbiota composition: a systematic review.
      ,
      • Shahar R.T.
      • Koren O.
      • Matarasso S.
      • Shochat T.
      • Magzal F.
      • Agmon M.
      Attributes of physical activity and gut microbiome in adults: a systematic review.
      ,
      • Mitchell C.M.
      • Davy B.M.
      • Hulver M.W.
      • Neilson A.P.
      • Bennett B.J.
      • Davy K.P.
      Does exercise alter gut microbial composition? a systematic review.
      ,
      • Ortiz-Alvarez L.
      • Xu H.
      • Martinez-Tellez B.
      Influence of exercise on the human gut microbiota of healthy adults: a systematic review.
      ]. The results of these reviews indicate that, despite the low scientific quality and the great heterogeneity of the included studies, physical exercise might positively modulate the diversity and abundance of the gut beneficial bacteria, and the production of metabolites associated with GM. None of these reviews, however, evaluated the effect of physical exercise on GM in individuals with metabolic diseases, such as obesity and T2DM. Considering that these diseases are commonly associated with harmful changes in the composition of the host GM [
      • Singer-Englar T.
      • Barlow G.
      • Mathur R.
      Obesity, diabetes, and the gut microbiome: an updated review.
      ,
      • Gurung M.
      • Li Z.
      • You H.
      • Rodrigues R.
      • Jump D.B.
      • Morgun A.
      • et al.
      Role of gut microbiota in type 2 diabetes pathophysiology.
      ,
      • Gomes A.C.
      • Hoffmann C.
      • Mota J.F.
      The human gut microbiota: metabolism and perspective in obesity.
      ], the aim of this review was to investigate the scientific evidence on the effect of physical exercise on the modulation of GM in subjects with obesity or T2DM.

      2. Methods

      2.1 Study strategy

      The study was recorded in the International Prospective Register of Systematic Review (PROSPERO) – CRD 42021241379 [
      • Booth A.
      • Clarke M.
      • Dooley G.
      • Ghersi D.
      • Moher D.
      • Petticrew M.
      • et al.
      The nuts and bolts of PROSPERO: an international prospective register of systematic reviews.
      ]. The results of this systematic review were reported according to the statement Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) [
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • Boutron I.
      • Hoffmann T.C.
      • Mulrow C.D.
      • et al.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      ]. A literature search was performed in the PubMed, Web of Science, Scopus, Cochrane and Embase databases up to March 11, 2021, by two authors (JSCS and CSS). There were no restrictions on the publication period. Articles were retrieved from databases matching the following words: (exercise OR physical activity OR physical exercise OR resistance training OR aerobic exercise) AND (gut microbiota OR gut microbiome OR dysbiosis OR endotoxemia OR bifidobacterium OR lactobacillus OR eubacterium OR faecalibacterium OR akkermansia OR short-chain fatty acids [SCFA] OR butyrates) AND (type 2 diabetes mellitus OR diabetes OR diabetes mellitus OR obesity OR overweight OR body mass index) (see supplementary material). Firstly, titles and abstracts of the studies were checked according to their relevance, by two authors (JSCS and CSS). Abstracts that met the criteria were independently reviewed by the same two authors (JSCS and CSS), and the full text of potentially eligible studies was analyzed. Any disagreement between authors regarding the inclusion of a study was solved by a third author (MMVN).

      2.2 Inclusion and exclusion criteria

      The Population, Intervention, Comparison, Outcomes and Survey (PICOS) model was used to define the eligibility criteria of the studies [
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • Boutron I.
      • Hoffmann T.C.
      • Mulrow C.D.
      • et al.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      ]. The inclusion criteria for records found in the literature were: (a) intervention study in humans (clinical trials, randomized clinical trials, crossover studies, uncontrolled and/or non-randomized clinical trials [Survey]) on the effect of any type of physical exercise [Intervention] on the modulation of GM (types of bacteria, diversity, abundance, and metabolites associated with beneficial gut bacteria [Outcomes]); (b) studies carried out with individuals with overweight/obesity and/or type 2 diabetes mellitus without age restriction [Population]; (c) studies published in English. The exclusion criteria adopted were: (a) observational studies (descriptive and analytical), reviews, meta-analyses, comments, and opinion articles; (b) preclinical studies (in animal model). There was no limitation for the year of publication.

      2.3 Data extraction

      Data were extracted from the studies by two authors (JSCS and CSS) using a standard form that included: (a) author's name and bibliographic reference; (b) study design; (c) primary objective of the study; (d) sample characteristics (sample size, mean age, sex and comorbidities); (e) results of the study on the gut microbiota; (f) diet and food consumption assessment; (g) features of the physical exercise intervention; (h) fecal sample collection; and (i) technique used to analyze the microbiota composition. After extraction, all data were summarized into two tables.

      2.4 Quality assessment and risk of bias

      The quality of the studies was independently assessed by two authors (JSCS and CSS), according to the Physiotherapy Evidence Database (PEDro) scale [
      • Morton N.A.
      The PEDro scale is a valid measure of the methodological quality of clinical trials: a demographic study.
      ]. The PEDro scale is composed of 11 items that assess the methodological quality, internal and external validity and risk of bias in randomized clinical trials, classifying them with a final score from 0 to 10, as the first item is inherent to all included studies (eligibility criteria). The final score of the PEDro scale classifies the studies in the following categories: ≤ 3 points = low methodological quality; 4–5 points = reasonable quality study; 6–8 points = good quality study; ≥ 9 points = excellent methodological quality. Only studies considered of reasonable methodological quality or upper were included.

      3. Results

      3.1 Retrieved and eligible studies

      The initial search retrieved 1747 studies, of which 412 were excluded because they were duplicates, adding up 1335 articles for screening. After reading the title and abstract, 35 articles were considered relevant and selected for full reading of the text. After applying the inclusion/exclusion criteria, 27 articles were excluded for different reasons: sample composed of individuals without obesity or T2DM (n = 10); only abstract was published (n = 6); analytical observational study (n = 4); no intervention with exercise (n = 4); did not assess the microbiota composition (n = 2); study considered of low methodological quality (n = 1). Finally, eight articles were considered eligible for this review, of which six were carried out in individuals with obesity, and two were performed in subjects with T2DM (Fig. 1).

      3.2 Sample characteristics

      One study carried out in individuals with T2DM [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ] was considered of good quality, and the others were classified as of reasonable methodological quality [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ,
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ,
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ,
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ,
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ,
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ] by the PEDro scale [
      • Morton N.A.
      The PEDro scale is a valid measure of the methodological quality of clinical trials: a demographic study.
      ] (Table 1).
      Table 1Evaluation of the methodological quality of clinical trials by the PEDro scale.
      Study, year1234567891011Score
      Obesity
      Allen et al., 2018 [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ]
      YNNYNNNYYNY4
      Huang et al., 2020 [
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ]
      YNNYNNNYNYY4
      Kern et al., 2020 [
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ]
      YYYYNNNNNYY5
      Munukka et al., 2018 [
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ]
      YNNYNNNYYNY4
      Quiroga et al., 2020 [
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ]
      YYYYNNNNNYY5
      Rettedal et al., 2020 [
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ]
      YNNYNNNYYNY4
      Type 2 diabetes mellitus
      Motiani et al., 2020 [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ]
      YYYYNNNYNYY6
      Pasini et al., 2019 [
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ]
      YNNYNNNYYNY4
      Criteria: 1- eligibility criteria; 2- randomly allocated individuals; 3- allocation of secret subjects; 4- comparability at baseline; 5- “blind” subjects; 6- “blind” therapists; 7- “blind” evaluators; 8- results >85% of participants; 9- data analyzed by “intention to treat”; 10- statistical comparisons between groups; 11- point measures and measures of variation. Y: yes; N; no.
      The sample size of the included studies ranged from 19 [
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ] to 88 [
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ] subjects with obesity, and from 26 [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ] to 30 [
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ] volunteers with T2DM. Regarding the gender, four studies were performed with men and women [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ,
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ,
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ], one with men [
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ] and one with women [
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ] affected by obesity. In studies with T2DM subjects, one study was carried out with men and women [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ], and the other, with men [
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ]. In addition, four studies were performed with adults [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ,
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ,
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ] and two with children/adolescents [
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ,
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ] with obesity, whereas among T2DM subjects, the studies were carried out with adults [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ] or elderly [
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ]. Moreover, four studies were with individuals affected by obesity [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ,
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ,
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ], and two studies included individuals with overweight and/or obesity [
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ,
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ]. Concerning the studies in T2DM, one adopted as an inclusion criterion the diagnosis of the disease at least 2 years ago [
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ], and another included individuals with pre-diabetes and T2DM [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ] (Table 2).
      Table 2Design and main results of studies that evaluated the effect of physical exercise on the gut microbiota modulation in subjects with obesity or type 2 diabetes mellitus.
      ReferenceStudy designPrimary objectiveSample characteristicsInterventionMain results
      Measurements of microbiota and metabolite compositionTaxonomic changes
      Subjects with obesity
      Allen et al., 2018 [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ]
      Non-controlled and non-randomized clinical trial (study of a single group)Assess the impact of exercise on gut microbiota composition, functional capacity and metabolic production in eutrophic and obese adultsn = 32 (eutrophic n = 18, obese n = 14); sedentary

      Eutrophic: M = 9; age = 25.10 ± 6.52 years; BMI = 22.21 ± 2.76

      Obese: M = 3; age = 31.14 ± 8.57 years; BMI = 35.71 ± 5
      6 weeks of aerobic exercise↔ α-diversity

      ↔ β-diversity

      ↑ SCFA (acetate, propionate and butyrate), greater increase in eutrophics
      Eutrophic

      Phylum Bacteroidetes:

      bacteroides

      Phylum Firmicutes:

      ↑ faecalibacterium

      ↑ lachnospira

      Obese

      Phylum Bacteroidetes:

      ↑ bacteroides

      Phylum Firmicutes:

      ↓ fecalibacterium
      Huang et al., 2020 [
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ]
      Non-controlled and non-randomized clinical trial (study of a single G)Evaluate the effects of a combination of exercise and calorie-restricted diet on hemodynamic parameters and gut microbiota composition in adolescents with obesityn = 24 (M = 15), age = 12.88 ± 0.41 years (6–16 years); BMI = 31.02 ± 0.946 weeks of aerobic exercise combined with strength training↑ α-diversity

      ↔ β-diversity

      ↓ Ratio Fimicutes:Bacteroidetes
      Phylum Firmicutes:

      Lactobacillales

      ↓ Bacilli

      ↓ Streptococcaceae,

      ↓ Streptococcus

      ↓ Veillonella

      ↑ Christensenellaceae

      Phylum Bacteroidetes:

      ↑Butyricimonas

      Phylum Lentisphaerae:

      ↑ Lentisphaeria

      ↑ Victivallales,

      ↑ Victivallaceae

      ↑ Victivallis
      Kern et al., 2020 [
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ]
      Randomized controlled clinical trialAssess whether physical exercise alters the diversity, composition and functional potential of gut microbiota in overweight or obese humans in a context of daily activitiesn = 88 (M = 51%); age = 36 (30–41) years; BMI = 29.7 (27.9; 31.4); sedentary

      Control G: n = 14 (M = 57%), Age = 38 (30–42); BMI = 29.9 (27.6; 32.2)

      Bicycle G: n = 19 (M = 42%); Age = 35 (28–43) years; BMI = 30.0 (28.3; 33.9)

      Moderate G: n = 21 (M = 55%), Age = 33 (27–38) years; BMI = 29.3 (27.4; 30.5)

      Vigorous G: n = 24 (M = 50%), Age = 39 (33–42) years; BMI = 29.9 (28.2; 32.1)
      6 months of physical activity↑ α-diversity of Vigorous G in month 3

      β-diversity in Bicycle G, Moderate G and Vigorous G compared to Control G
      There was no change in the composition of bacterial phyla
      Munukka et al., 2018 [
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ]
      Uncontrolled and non-randomized clinical trial (study of a single G)Determine the effects of exercise on gut microbiota composition and function in overweight or obese womenn = 19 women; age 36.8 ± 3.9 years; BMI = 31.8 ± 4.4; sedentary6 weeks of aerobic exercise↔ α-diversity

      ↔ β-diversity (Bray–Curtis dissimilarity)

      β-diversity (Jaccard distance)

      ↔ Ratio Fimicutes:Bacteroidetes
      Phylum Firmicutes:

      ↑ Dorea

      ↑ Anaerofilum

      Phylum Bacteroidetes:

      ↓ Porphyromonadaceae

      ↓ Odoribacter

      Phylum Verrucomicrobia:

      ↑ Verrucomicrobia

      ↑ Verrucomicrobiaceae

      ↑ Akkermansia

      Phylum Actinobacteria:

      ↑ Bifidobacteriaceae

      Phylum Proteobacteria:

      ↓ Proteobacteria

      Desulfovibrionaceae

      Enterobacteriaceae
      Quiroga et al., 2020 [
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ]
      Randomized controlled clinical trialDetermine whether exercise can favorably alter the functionality and composition of gut microbiota and the inflammatory status of obese childrenn = 39; age = 7–15 years

      Healthy control G: n = 14; (M = 7); age = 9.5 ± 0.4 years; eutrophic weight

      Control obese G: n = 14 (M = 7); age 10.5 ± 0.5 years

      Trained obese G: n = 25 (M = 13); age 11.0 ± 0.4 years
      12 weeks of aerobic exercise combined with strength trainingα-diversity e β-diversity not evaluated↓ Proteobacteria

      ↓Gammaproteobacteria
      Rettedal et al., 2020 [
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ]
      Non-controlled and non-randomized clinical trial (study of a single G)Investigate whether HIIT alters the gut microbiota composition and diversity of eutrophic and obese individualsn = 32 men (eutrophic n = 14, obese n = 15); age = 20–45 years

      Eutrophic: age = 29 ± 2 years; % fat = 21 ± 2%

      Obese: age = 31 ± 2 years; % fat = 33 ± 2%
      3 weeks of HIIT↔ α-diversity

      ↔ β-diversity

      ↔ Ratio Firmicutes:Bacteriodetes
      There was no change in the composition of bacterial phyla
      Subjects with type 2 diabetes mellitus
      Motiani et al., 2020 [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ]
      Uncontrolled randomized clinical trialEvaluate the effects of SIT and MICT training on metabolism, gut microbiota composition and insulin resistance in individuals with pre-diabetes or TT2DMn = 26 (M = 16, prediabetic n = 9, T2DM n = 17); age = 49 SIT G: n = 10 (M = 7); BMI = 29.3 [27.5–31.0]

      MICT G: n = 8 (M = 6); BMI = 30.7 [28.9–32.6]
      2 weeks of SIT or MICT↔ α-diversity

      ↔ β-diversity

      ↓ Ratio Firmicutes:Bacteriodetes

      ↓ LBP
      ↑ Bacteroidetes

      Phylum Firmicutes:

      ↓ Clostridium spp.

      ↓ Blautia spp.

      ↑ Lachnospira (SIT G)

      ↑ Veillonella (MICT G)

      Faecalibacterium (MICT G)
      Pasini et al.,

      2019 [
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ]
      Non-randomized and uncontrolled clinical trial (study of a single G)Evaluate the effect of exercise on gut microbiota composition and intestinal permeability in T2DM patientsn = 30 men; age = 70 ± 2.3 years; BMI = 29.8 ± 3.7; T2DM diagnosis >2 years; sedentary6 months of aerobic exercise combined with strength and flexibility training↔ α-diversity

      ↔ β-diversity

      ↓ zonulin
      ↓Candida albicans

      ↓Mycetes spp.

      ↔ Lactobacillus spp.

      ↔ Bifidobacterium spp.

      ↔ Enterococcus spp.

      ↔ Streptococcus spp.

      ↔ Bacteroides spp.

      ↔ Escherichia coli

      ↔ Campylobacter spp.

      ↔ Clostridium difficile

      ↔ Salmonella spp.

      ↔ Shigella spp.

      ↔ Yersinia enterocolitica
      M: men; BMI: body mass index; SCFA: short-chain fatty acids; G: group; HIIT: high intensity interval training; SIT: sprint interval training; MICT: moderate-intensity continuous training; T2DM: type 2 diabetes mellitus; LBP: lipopolysaccharide binding protein; ↑: increase; ↓: reduction; ↔: no change.

      3.3 Features of the interventions and body weight changes

      Interventions with physical exercise lasted from 3 weeks [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ] to 6 [
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ] months in individuals with obesity, and from 2 weeks [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ] to 6 [
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ] months in subjects with T2DM. The exercise volume ranged from 2 [
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ,
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ] to 6 [
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ] weekly sessions. Different supervised training protocols were performed: three studies in individuals with obesity [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ,
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ] and one study in individuals with T2DM [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ] applied an aerobic training protocol; one study with individuals with obesity [
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ] and one study with subjects affected by T2DM [
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ] carried out a combination of aerobic training and strength training; one study in T2DM volunteers performed a combination of leisure activities, aerobic training and strength training [
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ]; and one study adopted monitored intervention, but unsupervised, with counseling for the practice of physical activity within a context of daily habits of participants with obesity [
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ]. Regarding the duration and intensity of the training session, two studies carried out interval protocols of short duration (20–30 min) at high intensity [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ,
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ], two studies performed training longer than 60 min at moderate or high intensity [
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ,
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ], and the others applied training lasting from 35 to 60 min at moderate or high intensity [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ,
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ,
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ] (Table 3).
      Table 3Characteristics of the intervention with physical exercise and fecal analysis of studies that evaluated the effect of physical exercise on the gut microbiota modulation in subjects with obesity or type 2 diabetes mellitus.
      ReferenceIntervention with exerciseDietControl groupFecal sampleMicrobiota analysis technique
      Type of exerciseDose, frequency and intensity
      Subjects with obesity
      Allen et al., 2018 [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ]
      Continuous supervised aerobic exercise of moderate to vigorous intensity on the treadmill6 weeks; 3 times/week; 30–60 min/session

      Week 1: 30 min

      Weeks 2 and 3: 45 min

      Weeks 4, 5 and 6: 60 min

      Intensity: 60% HHR (weeks 1–3) up to 75% HHR (5% increase per week during weeks 4–6)
      Standardized diet for 3 days before collection. No food intervention during the exercise intervention

      Food consumption assessment: 7-day food record before and after the intervention
      No control groupStored for a maximum of 30 min after defecation at −80 °C16S rRNA sequencing: (PowerLyzer PowerSoil DNA Isolation)

      SCFA (concentrations by gas chromatography)
      Huang et al., 2020 [
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ]
      Aerobic exercise (cycling, walking, running, dancing, and playing ball) of moderate to high intensity, combined with strength training6 weeks; 6 times/week; 5 h/day; estimated energy expenditure = 1500–2500 kcal/day

      Aerobic training: moderate-high intensity (70%–85% HRmax) or high intensity (∼90% HRmax) alternating with low intensity (∼60% HRmax). Monitored by heart rate monitor.

      Strength training: 2–3 sets of 12–15 reps at 40–50% of maximum strength with 2–3 min rest between sets
      Food intervention: calorie restricted diet (60% carbohydrate, 20% protein and 20% fat). All meals were prepared and supervised by a nutritionistNo control groupThe sample was frozen in liquid nitrogen and stored in 5 mL tubes immediately after defecation16S rRNA sequencing (Bioanalyzer 2100 system)
      Kern et al., 2020 [
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ]
      Leisure physical activity of moderate or vigorous intensity and active cycling6 months; 5 times/week; estimated energy expenditure = 1600 kcal/week for women and 2100 kcal/week for men.

      Bike G: intensity = ∼60% Vo2peak.

      Moderate G: 150 min/week; intensity = 50% VO2peak

      Vigorous G: intensity = 70% VO2peak
      Guidance to maintain the usual dietary pattern

      Food consumption assessment: 3-day pre- and post-intervention food recall
      Individuals who have maintained their usual lifestyleSample stored at −18 °C in the participants' homes after collection and later stored at −80 °C until the period of analysis16S rRNA sequencing (NucleoSpinSoil kit)
      Munukka et al., 2018 [
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ]
      Supervised aerobic exercise at moderate intensity on an exercise bike6 months; 3 times/week; 40–60 min/session

      Week 1–2: 40 min continuous at low intensity (below aerobic threshold). Weeks 3–4: 8 min warm-up and 3 blocks of 10 min at moderate intensity (between aerobic and anaerobic threshold) with a recovery interval of 4 min (50 min total). Weeks 5–6: 7 min warm-up and 4 blocks of 10 min at moderate intensity (between aerobic and anaerobic threshold) with a recovery interval of 3 min (60 min total)
      Guidance to maintain the usual dietary pattern.

      Food consumption assessment: 3-day food recall before and after intervention
      No control groupSample immediately stored at −20 °C after collection and later stored at −80 °C16S rRNA sequencing (GTX stool kit)
      Quiroga et al., 2020 [
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ]
      Supervised interval aerobic exercise on an exercise bike combined with strength training12 weeks; 2 times/week; 45 min/session

      Initial aerobic training: 7 min of warm-up; interval training (4 maximum 30″ shots with 3 min interval)

      Strength training: 4 exercises with 3 sets of 8–12 repetitions with an interval of 30–60 s at 30%–70% of 1RM

      Final aerobic training: 7 min (4 min with low load and 3 min with high load)
      Nutritional advice for a healthy and balanced diet.

      Food consumption: not assessed
      Healthy control G and Obese control G maintained their usual daily routineSamples homogenized after collection and stored at −80 °C until the period of analysis16S rRNA sequencing (QIAamp DNA Stool Mini kit)
      Rettedal et al., 2020 [
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ]
      HIIT supervised on exercise bike3 weeks; 2 times/week

      9-12 shots of 60 s at 100% VO2peak with 75 s interval
      Guidance to maintain the usual dietary pattern

      Food consumption assessment: food frequency questionnaire
      No control groupStool samples collected and immediately suspended in a solution (DNA/RNA Shield™) and stored at −80 °C16S rRNA sequencing (Fecal/Soil Microbe Microprep kit)
      Subjects with diabetes mellitus tipo 2
      Motiani et al., 2020 [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ]
      Moderate to high intensity supervised aerobic exercise (SIT or MICT) on an exercise bike3 weeks; 3 times/sessions

      SIT = 4–6 maximum 30 s shots with 4 min rest interval between each shot (Winggate Protocol)

      MICT = 40–60 min of continuous exercise of moderate intensity (60% Vo2peak)
      Guidance to maintain the usual dietary pattern

      Food consumption: not assessed
      No control groupStored at −80 °C until the period of analysis16S rRNA sequencing (Nextera

      XT Index Kit)
      Pasini et al.,

      2019 [
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ]
      Combination of aerobic exercise on the stationary bike with strength and flexibility training6 months; 3 times/week; 90 min/session

      Aerobic training: 15–35 min monitored by heart rate (3 first months at −5 bpm LCTG, from the third month onwards the rate was increased not exceeding RCT).

      Strength training: performed with free weights and elastics with exercises for large muscle groups (3 sets of 8–15 repetitions)
      Food intervention: Mediterranean-type calorie restriction diet 40–60% carbohydrate, 30% fat and 10–20% protein, 1900 kcal/day).

      Food consumption: not assessed
      No control groupUninformedSelective agar culture measured after 48 h of incubation
      HRR: heart rate reserve; HRmax: maximum heart rate; VO2peak: peak oxygen consumption; G: group; RM: maximum repetition; HIIT: high intensity interval training; BPM: beat per minute; SIT: sprint interval training; MICT: moderate-intensity continuous training; LCTG: cardiac gas exchange threshold; RCT: respiratory compensation threshold; SCFA: short-chain fatty acids.
      Considering the relevant role of the diet on the modulation of the GM, this variable was analyzed in this review. In individuals with obesity, two studies performed dietary intervention [
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ,
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ], and the others guided the participants to keep their usual dietary pattern during the intervention period [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ,
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ,
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ]. In individuals with T2DM, one study carried out dietary intervention through a calorie-restricted diet [
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ]. In addition, three studies included in this review did not assessed the food consumption [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ,
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ,
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ] (Table 3). Another variable that should be considered when evaluating GM modulation is body composition, since changes in GM related to physical exercise may be due to changes in body composition [
      • Mailing L.J.
      • Allen J.M.
      • Buford T.W.
      • Fields C.J.
      • Woods J.A.
      Exercise and the gut microbiome: a review of the evidence, potential mechanisms, and implications for human health.
      ]. Allen et al. [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ] suggested that the improvement in GM after intervention with physical exercise may be dependent on the body mass index (BMI), as the SCFA production enhanced only in eutrophic individuals, and specific bacteria like Bacteroides increased in subjects with obesity. However, Huang et al. [
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ] found a reduction in body composition and beneficial change in the GM after physical exercise intervention, in both adolescents with eutrophic and obese BMI.

      3.4 Changes related to the gut microbiota

      3.4.1 Studies in subjects with obesity

      The α-diversity and β-diversity of GM were evaluated by most studies, except for the study by Quiroga et al. [
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ] (Table 2). Two studies observed an increase in α-diversity: Huang et al. [
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ] reported an increase in α-diversity after six weeks of intervention with aerobic exercise, whereas Kern et al. [
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ] found an improvement in α-diversity after three months of vigorous physical exercise. The other studies did not observe significant changes in α-diversity [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ,
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ]. In turn, Kern et al. [
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ], by the Bray–Curtis Dissimilarity statistical method, and Munukka et al. [
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ], by the Jaccard Distance Similarity Coefficient, reported an increase in β-diversity after intervention.
      All studies evaluated the gut bacterial abundance [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ,
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ,
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ,
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ,
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ,
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ,
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ], and most of them showed significant changes in GM composition [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ,
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ,
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ]. One study also analyzed metabolites related to GM [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ] (Table 2). Intervention with aerobic exercise for six weeks increased the abundance of Bacteroides in sedentary adults with obesity, and increased the fecal concentrations of propionate, acetate and butyrate in the group of eutrophic individuals [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ]. Huang et al. [
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ] observed that the intervention with aerobic exercise along with strength training for six weeks reduced the abundance of the Firmicutes phylum bacteria in children and adolescents, a result that reflected in the decrease in the Firmicutes:Bacteroidetes ratio. In obese adult women [
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ], however, there was no change in the Firmicutes:Bacteroidetes ratio after exercise intervention, but there was an increase in the Bifidobacteriaceae family and the Akkermansia genus, and a reduction in the presence of the Proteobacteria phylum. Quiroga et al. [
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ] found a significant reduction in the Proteobacteria phylum in obese children and adolescents after an intervention with aerobic exercise combined with strength training.

      3.4.2 Studies in subjects with T2DM

      No change in the bacterial diversity was observed after intervention with physical activity in the included studies [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ,
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ]. However, aerobic training for two weeks at different intensities increased the abundance of Bacteroidetes phylum bacteria, decreased the Firmicutes:Bacteroidetes ratio, and increased the Faecalibacterium genus, in the group that performed the moderate-intensity continuous training (MICT) [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ]. Pasini et al. [
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ], in turn, evaluated 11 species of bacteria and found no significant change in older adults with T2DM undergoing aerobic exercise combined with strength and flexibility training. In both studies [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ,
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ], exercise was able to reduce markers related to metabolic endotoxemia: decrease in serum lipopolysaccharide binding protein (LBP) concentrations [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ], and in fecal concentrations of zonulin (Zon, haptoglobin-2 precursor) [
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ], a protein that modulates the permeability of tight junctions in the gut epithelial cells [
      • Fasano A.
      Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications.
      ] (Table 2).

      4. Discussion

      This systematic review analyzed the current scientific evidence on the effect of physical exercise on GM in relation to the bacterial diversity and abundance, and associated metabolites, in subjects with obesity or T2DM. Concerning six included studies in individuals with obesity, the physical exercise positively modulated at least one parameter of bacterial diversity [
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ,
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ,
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ], or abundance of beneficial bacteria species [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ,
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ], except one [
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ], which no significant changes in the composition of gut microbiota was observed. The main findings of the studies in subjects with T2DM are the increase in the abundance of some bacteria genera and species [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ], and the reduction of biomarkers related to metabolic endotoxemia [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ,
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ]. Currently, this systematic review differs from other five published on physical exercise and GM [
      • Dorelli B.
      • Gallè F.
      • De Vito C.
      • Duranti G.
      • Iachini M.
      • Zaccarin M.
      • et al.
      Can physical activity influence human gut microbiota composition independently of diet? a systematic review.
      ,
      • Aya V.
      • Flórez A.
      • Perez L.
      • Ramírez J.D.
      Association between physical activity and changes in intestinal microbiota composition: a systematic review.
      ,
      • Shahar R.T.
      • Koren O.
      • Matarasso S.
      • Shochat T.
      • Magzal F.
      • Agmon M.
      Attributes of physical activity and gut microbiome in adults: a systematic review.
      ,
      • Mitchell C.M.
      • Davy B.M.
      • Hulver M.W.
      • Neilson A.P.
      • Bennett B.J.
      • Davy K.P.
      Does exercise alter gut microbial composition? a systematic review.
      ,
      • Ortiz-Alvarez L.
      • Xu H.
      • Martinez-Tellez B.
      Influence of exercise on the human gut microbiota of healthy adults: a systematic review.
      ], as it is the first on individuals with obesity or T2DM undergoing intervention with physical exercise in clinical trials.
      Regarding the scientific quality of the included studies, seven studies were classified as of reasonable methodological quality [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ,
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ,
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ,
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ,
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ,
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ], and only one as of good quality [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ]. In addition, there was great heterogeneity among the samples, which were composed by individuals of different age groups and of both sexes. The intervention with physical exercise was performed mostly by aerobic training, under supervision [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ,
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ,
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ,
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ], or with a combination of aerobic training and strength training [
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ,
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ,
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ]. Concerning the diet, three studies did not assess the food consumption [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ,
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ,
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ], and others did intervention with diet during the trial [
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ,
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ,
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ], facts that might have influenced the analysis of the effect of the exercise on GM modulation.
      According to the body weight changes, six studies reported a reduction in fat mass after the intervention with physical exercise [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ,
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ,
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ,
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ,
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ], but none of them investigated the influence of weight changes on GM changes. Nevertheless, Allen et al. [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ] analyzed the association between differences in BMI and GM changes and observed that the body mass influenced bacterial diversity and abundance. This finding suggests an eventual association between changes in body composition and improvement in the GM composition. So, in order to clarify this association, it would be very important for future studies to assess whether or not changes in GM depend on changes in body composition resulting from physical exercise, as weight loss may be a GM modulator factor [
      • Mailing L.J.
      • Allen J.M.
      • Buford T.W.
      • Fields C.J.
      • Woods J.A.
      Exercise and the gut microbiome: a review of the evidence, potential mechanisms, and implications for human health.
      ].
      The plausible mechanisms related to the positive effects of the physical exercise on the GM have not been completely elucidated, but one hypothesis is that the physical exercise could enhances the SCFA production [
      • Aya V.
      • Flórez A.
      • Perez L.
      • Ramírez J.D.
      Association between physical activity and changes in intestinal microbiota composition: a systematic review.
      ]. SCFA play a regulatory role in transepithelial fluid transport, attenuate inflammation and the oxidative state, reinforce the gut defense barrier, modulate visceral sensitivity and gut motility, and contribute to the regulation of energy metabolism [
      • Den Besten G.
      • Van Eunen K.
      • Groen A.K.
      • Venema K.
      • Reijngoud D.J.
      • Bakker B.M.
      The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism.
      ]. In one study in individuals with obesity and eutrophics [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ], the concentrations of propionate, acetate, and butyrate increased only in the subjects with eutrophic BMI, thus suggesting an influence of body mass on GM modulation. This finding indicates that, despite the evidence associating physical exercise with improved production of these metabolites [
      • Aya V.
      • Flórez A.
      • Perez L.
      • Ramírez J.D.
      Association between physical activity and changes in intestinal microbiota composition: a systematic review.
      ,
      • Barton W.
      • Penney N.C.
      • Cronin O.
      • Garcia-Perez I.
      • Molloy M.G.
      • Holmes E.
      • et al.
      The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level.
      ], further studies are needed to investigate this association in individuals with obesity. In another study [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ], it was observed an increase in the abundance of Veillonella genus, which metabolizes lactate to SCFA [
      • Ng S.K.
      • Hamilton I.R.
      Carbon dioxide fixation by Veillonella parvula M 4 and its relation to propionic acid formation.
      ]. In aerobic exercise, especially at high intensity, there is an excessive production of lactate [
      • Messonnier L.A.
      • Emhoff C.A.W.
      • Fattor J.A.
      • Horning M.A.
      • Carlson T.J.
      • Brooks G.A.
      Lactate kinetics at the lactate threshold in trained and untrained men.
      ], which favor the proliferation and metabolism of Veillonella genus, and consequently, the synthesis of metabolites like propionate. This hypothesis was initially proposed by Scheiman et al. [
      • Scheiman J.
      • Luber J.M.
      • Chavkin T.A.
      • MacDonald T.
      • Tung A.
      • Pham L.-D.
      • et al.
      Meta-omics analysis of elite athletes identifies a performance-enhancing microbe that functions via lactate metabolism.
      ], who observed that runner athletes showed greater relative abundance of the Veillonella genus associated to the increase in propionate concentrations.
      Interventions with physical exercise that stimulate the excessive production of lactate may increase satiety [
      • Islam H.
      • Townsend L.K.
      • McKie G.L.
      • Medeiros P.J.
      • Gurd B.J.
      • Hazell T.J.
      Potential involvement of lactate and interleukin-6 in the appetite-regulatory hormonal response to an acute exercise bout.
      ], since the propionate produced from the metabolism of lactate by bacteria of the Veillonella genus may stimulate the production of anorectic hormones, such as the gastrointestinal hormone glucagon-like peptide 1 (GLP1) [
      • Ranganath L.R.
      • Beety J.M.
      • Morgan L.M.
      • Wright J.W.
      • Howland R.
      • Marks V.
      Attenuated GLP-1 secretion in obesity: cause or consequence?.
      ]. In addition, the increase in lactate produced by physical exercise may contribute to a decrease in appetite through the reduction of orexigenic hormones, such as ghrelin, and this effect depends on its intensity, since aerobic exercises performed at higher intensity promote a greater feeling of satiety [
      • Hazell T.J.
      • Islam H.
      • Townsend L.K.
      • Schmale M.S.
      • Copeland J.L.
      Effects of exercise intensity on plasma concentrations of appetite-regulating hormones: potential mechanisms.
      ]. This association may be explained by the fact that the greater the exercise intensity, the greater the lactate release, and the increase in lactate seems to be correlated with the decrease of ghrelin and appetite [
      • Islam H.
      • Townsend L.K.
      • McKie G.L.
      • Medeiros P.J.
      • Gurd B.J.
      • Hazell T.J.
      Potential involvement of lactate and interleukin-6 in the appetite-regulatory hormonal response to an acute exercise bout.
      ]. It is noteworthy that, although none of the studies included in this review have assessed lactate concentrations, most interventions were performed with aerobic exercise at moderate or high intensity [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ,
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ,
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ,
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ], which may have affected the lactate-propionate interaction.
      The studies showed an increase in the abundance of Bifidobacteriaceae family, and Bacteroides [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ] and Akkermansia [
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ] genera, which encompass important bacteria related to host health and the pathophysiogenesis of obesity and T2DM [
      • Chang Y.C.
      • Ching Y.H.
      • Chiu C.C.
      • Liu J.Y.
      • Hung S.W.
      • Huang W.C.
      • et al.
      TLR2 and interleukin-10 are involved in Bacteroides fragilis-mediated prevention of DSS-induced colitis in gnotobiotic mice.
      ,
      • Zhang L.
      • Qin Q.
      • Liu M.
      • Zhang X.
      • He F.
      • Wang G.
      Akkermansia muciniphila can reduce the damage of gluco/lipotoxicity, oxidative stress and inflammation, and normalize intestine microbiota in streptozotocin-induced diabetic rats.
      ,
      • Xu Y.
      • Wang N.
      • Tan H.Y.
      • Li S.
      • Zhang C.
      • Feng Y.
      Function of akkermansia muciniphila in obesity: interactions with lipid metabolism, immune response and gut systems.
      ,
      • Turroni F.
      • Van Sinderen D.
      • Ventura M.
      Bifidobacteria: from ecology to genomics.
      ]. Indeed, lower abundance of these bacterial genera seems to be related to obesity, especially with the lower presence of species such as Bacteroides fragilis and Akkermansia Muciniphila [
      • Fernandes J.
      • Su W.
      • Rahat-Rozenbloom S.
      • Wolever T.M.S.
      • Comelli E.M.
      Adiposity, gut microbiota and faecal short chain fatty acids are linked in adult humans.
      ], and to T2DM [
      • Gurung M.
      • Li Z.
      • You H.
      • Rodrigues R.
      • Jump D.B.
      • Morgun A.
      • et al.
      Role of gut microbiota in type 2 diabetes pathophysiology.
      ]. Bacteroides fragilis is an important SCFA producer, and the decrease in the production of these metabolites may affect the balance between fatty acid synthesis and oxidation and body lipolysis, with a consequent increase in body fat accumulation [
      • Den Besten G.
      • Van Eunen K.
      • Groen A.K.
      • Venema K.
      • Reijngoud D.J.
      • Bakker B.M.
      The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism.
      ,
      • Fernandes J.
      • Su W.
      • Rahat-Rozenbloom S.
      • Wolever T.M.S.
      • Comelli E.M.
      Adiposity, gut microbiota and faecal short chain fatty acids are linked in adult humans.
      ]. Moreover, the presence of the Bacteroides fragilis species is related to a decrease in the inflammation status and in the expression of interleukin 6 (IL-6), and increasing in IL-10 [
      • Chang Y.C.
      • Ching Y.H.
      • Chiu C.C.
      • Liu J.Y.
      • Hung S.W.
      • Huang W.C.
      • et al.
      TLR2 and interleukin-10 are involved in Bacteroides fragilis-mediated prevention of DSS-induced colitis in gnotobiotic mice.
      ]. Likewise, different species and strains of the Bifidobacterium genus may modulate immune responses and contribute to the inhibition of the proliferation of harmful hindgut bacteria, as well as participate in the synthesis of B-complex vitamins, and in the bioconversion of dietary compounds, such as oligosaccharides and galactooligosaccharides, into bioactive molecules [
      • Turroni F.
      • Van Sinderen D.
      • Ventura M.
      Bifidobacteria: from ecology to genomics.
      ]. Akkermansia muciniphila, in turn, has been associated to the prevention and treatment of obesity, among other metabolic diseases [
      • Zhang L.
      • Qin Q.
      • Liu M.
      • Zhang X.
      • He F.
      • Wang G.
      Akkermansia muciniphila can reduce the damage of gluco/lipotoxicity, oxidative stress and inflammation, and normalize intestine microbiota in streptozotocin-induced diabetic rats.
      ,
      • Xu Y.
      • Wang N.
      • Tan H.Y.
      • Li S.
      • Zhang C.
      • Feng Y.
      Function of akkermansia muciniphila in obesity: interactions with lipid metabolism, immune response and gut systems.
      ]. A. muciniphila may reduce the expression of inflammatory cytokines, such as IL-2, interferon gamma (IFN-γ), and IL-12; regulate the permeability of gut barrier through tight junction proteins, such as claudin 3 (Cldn3); and attenuate the process of lipid overload associated with the low-density lipoprotein cholesterol (LDL-c) receptor pathway, reducing apolipoprotein B-48 (apoB48) and apolipoprotein B-100 (apoB100) proteins [
      • Xu Y.
      • Wang N.
      • Tan H.Y.
      • Li S.
      • Zhang C.
      • Feng Y.
      Function of akkermansia muciniphila in obesity: interactions with lipid metabolism, immune response and gut systems.
      ]. Dietary fibers and polyphenols consumption are related to the increase in A. muciniphila abundance [
      • Alves-Santos A.M.
      • Sugizaki C.S.A.
      • Lima G.C.
      • Naves M.M.V.
      Prebiotic effect of dietary polyphenols: a systematic review.
      ]. Physical exercise also seems to influence the proliferation of this species, as physically active individuals have a greater abundance of A. muciniphila compared to sedentary people [
      • Bressa C.
      • Bailen-Andrino M.
      • Perez-Santiago J.
      • Gonzalez-Soltero R.
      • Perez M.
      • Gregoria Montalvo-Lominchar M.
      • et al.
      Differences in gut microbiota profile between women with active lifestyle and sedentary women.
      ].
      On the other hand, the cardiorespiratory fitness may be related to a healthy GM, as there is a positive association between cardiorespiratory capacity and GM diversity, so the higher the VO2max values, the greater the GM diversity [
      • Estaki M.
      • Pither J.
      • Baumeister P.
      • Little J.P.
      • Gill S.K.
      • Ghosh S.
      • et al.
      Cardiorespiratory fitness as a predictor of intestinal microbial diversity and distinct metagenomic functions.
      ]. In the study carried out by Allen et al. [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ], there was a positive correlation between the increase in VO2max and the abundance of bacteria, such as Veillonella spp., Paraprevotela, Lachnospira spp., and Barnesiella spp. The others studies included in this review did not evaluate such association, but five of them observed improvements in cardiorespiratory fitness, such as VO2peak [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ,
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ,
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ] and VO2max [
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ,
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ] which may be related to positive changes in GM composition [
      • Estaki M.
      • Pither J.
      • Baumeister P.
      • Little J.P.
      • Gill S.K.
      • Ghosh S.
      • et al.
      Cardiorespiratory fitness as a predictor of intestinal microbial diversity and distinct metagenomic functions.
      ].
      The decrease in intestinal transit time is another stimulus provided by physical exercise to the large intestine, which may contribute to metabolic health and to the improvement of GM composition [
      • Oettlé G.J.
      Effect of moderate exercise on bowel habit.
      ,
      • Dainese R.
      • Serra J.
      • Azpiroz F.
      • Malagelada J.R.
      Effects of physical activity on intestinal gas transit and evacuation in healthy subjects.
      ]. Increased intestinal transit reduces the time of exposure of the gut epithelium to probable pathogens [
      • Müller M.
      • Canfora E.E.
      • Blaak E.E.
      Gastrointestinal transit time, glucose homeostasis and metabolic health: modulation by dietary fibers.
      ]. No study included in this review evaluated changes in intestinal transit time, but Huang et al. [
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ] observed an increase in the abundance of bacteria of the Butyricimonas genus, which is associated with increased bowel motility [
      • Vandeputte D.
      • Falony G.
      • Vieira-Silva S.
      • Tito R.Y.
      • Joossens M.
      • Raes J.
      Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates.
      ].
      The reduction in the abundance of the bacteria from the Proteobacteria phylum, observed by Munukka et al. [
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ] and Quiroga et al. [
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ], may contribute to the improvement of the bacterial balance in GM, via reduction in dysbiosis and low-intensity systemic inflammation. The Proteobacteria phylum is composed of potentially pathogenic gram-negative bacteria (Escherichia, Salmonella, Vibrio and Helicobacter), which contain a large amount of lipopolysaccharides (LPS) in their membrane composition, an important substance with proinflammatory features [
      • Rizzatti G.
      • Lopetuso L.R.
      • Gibiino G.
      • Binda C.
      • Gasbarrini A.
      Proteobacteria: a common factor in human diseases.
      ]. Furthermore, dysbiosis in metabolic diseases and some types of cancer is associated with a greater presence of bacteria from the Proteobacteria phylum [
      • Shin N.R.
      • Whon T.W.
      • Bae J.W.
      Proteobacteria: microbial signature of dysbiosis in gut microbiota.
      ]. In the studies carried out with individuals with T2DM [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ,
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ], it was observed an improvement in biomarkers related to the integrity of the gut barrier, which also contribute to the reduction of inflammation. Motiani et al. [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ] observed a reduction in LBP, a lipid transfer protein that binds to bacterial LPS, facilitating its interaction with important immune system recognition receptors, such as cluster of differentiation 14 (CD14) and toll-like receptor 4 (TLR4) [
      • Kirschning C.J.
      • Au-Young J.
      • Lamping N.
      • Reuter D.
      • Pfeil D.
      • Seilhamer J.J.
      • et al.
      Similar organization of the lipopolysaccharide-binding protein (LBP) and phospholipid transfer protein (PLTP) genes suggests a common gene family of lipid-binding proteins.
      ]. Pasini et al. [
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ], in turn, found a decrease in fecal concentrations of zonulin, and lower concentration of zonulin is related to decreased permeability of the gut barrier [
      • Fasano A.
      Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications.
      ].
      There was a considerable variation in the training methods applied in the studies, in terms of volume, intensity and duration of the intervention. Kern et al. [
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ] counseled the participants for the practice of physical activity, from moderate to high intensity, monitored by a heart rate monitor (leisure physical activity, cycling to the work) with a volume around 150 min per week. Rettedal et al. [
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ] applied a supervised high-intensity interval training on an ergometric bicycle, with a volume of about 50 min per week. Huang et al. [
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ], on the other hand, performed an intervention with several aerobic leisure activities (cycling, walking, running, dancing and playing ball), associated with the supervised practice of strength training with a total training volume of 1800 min per week. Thus, the differences in the volume and modalities of the applied training must be taken into account, as aerobic exercise, strength training or concurrent training (strength training associated with aerobic training) are different modalities, which can produce diverse physiological responses [
      • MacInnis M.J.
      • Gibala M.J.
      Physiological adaptations to interval training and the role of exercise intensity.
      ,
      • Chodzko-Zajko W.J.
      • Proctor D.N.
      • Minson C.T.
      • Nigg C.R.
      American College of Sports Medicine position stand. Exercise and physical activity for older adults.
      ,
      American College of Sports Medicine position stand
      Progression models in resistance training for healthy adults.
      ].
      The time of intervention with physical exercise is another divergent factor in the studies included in the present review. The intervention times varied from 3 [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ,
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ], 6 [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ], 12 [
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ] to 24 weeks [
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ,
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ,
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ], and such range of time may have a considerable influence on the microbiota modulation. The acute exercise generates stimulus that are related to the increased permeability of the gut barrier [
      • Mailing L.J.
      • Allen J.M.
      • Buford T.W.
      • Fields C.J.
      • Woods J.A.
      Exercise and the gut microbiome: a review of the evidence, potential mechanisms, and implications for human health.
      ,
      • Hagio M.
      • Matsumoto M.
      • Yajima T.
      • Hara H.
      • Ishizuka S.
      Voluntary wheel running exercise and dietary lactose concomitantly reduce proportion of secondary bile acids in rat feces.
      ,
      • Meissner M.
      • Lombardo E.
      • Havinga R.
      • Tietge U.J.F.
      • Kuipers F.
      • Groen A.K.
      Voluntary wheel running increases bile acid as well as cholesterol excretion and decreases atherosclerosis in hypercholesterolemic mice.
      ,
      • Rowell L.B.
      • Brengelmann G.L.
      • Blackmon J.R.
      • Twiss R.D.
      • Kusumi F.
      Splanchnic blood flow and metabolism in heat-stressed man.
      ,
      • Packer N.
      • Hoffman-Goetz L.
      Exercise training reduces inflammatory mediators in the intestinal tract of healthy older adult mice.
      ,
      • Hoffman-Goetz L.
      • Pervaiz N.
      • Guan J.
      Voluntary exercise training in mice increases the expression of antioxidant enzymes and decreases the expression of TNF-α in intestinal lymphocytes.
      ]. However, the chronic adaptations that exercise provides to the gastrointestinal tract may improve the gut barrier and other parameters related to GM health [
      • Campbell S.C.
      • Wisniewski P.J.
      • Noji M.
      • McGuinness L.R.
      • Haeggblom M.M.
      • Lightfoot S.A.
      • et al.
      The effect of diet and exercise on intestinal integrity and microbial diversity in mice.
      ,
      • Lira F.S.
      • Rosa J.C.
      • Pimentel G.D.
      • Souza H.A.
      • Caperuto E.C.
      • Carnevali L.C.
      • et al.
      Endotoxin levels correlate positively with a sedentary lifestyle and negatively with highly trained subjects.
      ]. Indeed, no significant changes in the GM composition after the intervention with physical exercise were observed in a short-term study (3 weeks) [
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ], but other studies with an intervention time of 6 weeks or longer found an improvement in the GM composition [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ,
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ,
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ,
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ].
      Studies with individuals with different age groups (children and adolescents, adults, and elderly) were included in this review, which can be considered an important confounding factor, as the composition and stability of GM varies throughout the different stages of life [
      • Nagpal R.
      • Mainali R.
      • Ahmadi S.
      • Wang S.
      • Singh R.
      • Kavanagh K.
      • et al.
      Gut microbiome and aging: physiological and mechanistic insights.
      ]. Thus, the GM composition of each participant may provide different responses on the modulation of GM by factors like physical exercise or diet.
      Methodological approaches related to the diet would have to be taken into account in the included studies. Three studies carried out dietary intervention along with physical exercise intervention [
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ,
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ,
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ], and three studies did not assess food consumption [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ,
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ,
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ]. These approaches may have influenced the interpretation of the impact of physical exercise on GM composition, as diet is one of the main modulating agents of the gut bacterial communities [
      • Fan Y.
      • Pedersen O.
      Gut microbiota in human metabolic health and disease.
      ]. Therefore, the most reliable results are those of the studies that did not interfere with the diet, and that assessed the food consumption and observed no diet changes during the intervention. Three studies in individuals with obesity met these criteria [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ,
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ]. These studies reported modulation of GM diversity and abundance of bacteria that are potentially beneficial to health (Fig. 2). Furthermore, only two studies were randomized and controlled [
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ,
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ], and the others were considered quasi-experimental [
      • Motiani K.K.
      • Collado M.C.
      • Eskelinen J.J.
      • Virtanen K.A.
      • Löyttyniemi E.
      • Salminen S.
      • et al.
      Exercise training modulates gut microbiota profile and improves endotoxemia.
      ,
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Huang J.
      • Liao J.
      • Fang Y.
      • Deng H.
      • Yin H.
      • Shen B.
      • et al.
      Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
      ,
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ,
      • Rettedal E.A.
      • Cree J.M.E.
      • Adams S.E.
      • MacRae C.
      • Skidmore P.M.L.
      • Cameron-Smith D.
      • et al.
      Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
      ,
      • Pasini E.
      • Corsetti G.
      • Assanelli D.
      • Testa C.
      • Romano C.
      • Dioguardi F.S.
      • et al.
      Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
      ].
      Figure 2
      Figure 2Summary of the main results reported on the modulation of the gut microbiota and its positive effects on the metabolism of individuals with obesity, after intervention with physical exercise.
      As previously discussed, there was a great variation among studies regarding the intensity and type of physical exercise, but the studies with the most reliable results [
      • Allen J.M.
      • Mailing L.J.
      • Niemiro G.M.
      • Moore R.
      • Cook M.D.
      • White B.A.
      • et al.
      Exercise alters gut microbiota composition and function in lean and obese humans.
      ,
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ,
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ] performed interventions with aerobic exercises at moderate or high intensity during 6 weeks to 6 months. Thus, aerobic exercises with such characteristics likely have positive effects on GM modulation, but studies comparing different training protocols should be carried out to clarify the influence of type and intensity of training on GM.
      We emphasize that the option of including in this review studies with methodological limitations was necessary, as the topic investigated is at the frontier of knowledge, and thus, there is a scarcity of studies on that in literature. Considering the limitations of the included studies, more studies with better methodological design are warranted. Therefore, we highlight some recommendations for future research (Fig. 3): accurate and enough description of the methodology of the study, including the eligibility criteria of the participants, how the sample size was estimated and by which test, and the methods used to collect and store fecal samples; inclusion of a control group out of the intervention group; and allocation of the participants per groups by randomized, validated and reliable methods, according to the guideline for randomized clinical trials (Consolidated Standards of Reporting Trials - CONSORT) [
      • Moher D.
      • Hopewell S.
      • Schulz K.F.
      • Montori V.
      • Gøtzsche P.C.
      • Devereaux P.J.
      • et al.
      CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials.
      ]. In addition, physical exercise must be controlled and aspects related to training should be specified, such as: type of training (aerobic, strength, and concurrent training); training method (interval, continuous, hypertrophy, strength, power); supervision (supervised or free-form physical exercise or physical activity); training variables (volume, intensity, recovery interval, movement speed, load); training volume (daily, weekly or total volume); and pre-intervention fitness level (sedentary or trained individuals). Controlling and detailing such aspects will contribute to minimize the confounding factors and help researchers to carry out future clinical trials on this field. Furthermore, different types of training may produce different physiological responses [
      • MacInnis M.J.
      • Gibala M.J.
      Physiological adaptations to interval training and the role of exercise intensity.
      ,
      • Chodzko-Zajko W.J.
      • Proctor D.N.
      • Minson C.T.
      • Nigg C.R.
      American College of Sports Medicine position stand. Exercise and physical activity for older adults.
      ,
      American College of Sports Medicine position stand
      Progression models in resistance training for healthy adults.
      ]. Thus, the performance of a single type of training would be better to clarify the interaction between physical exercise and GM and the specific effect of each modality.
      Figure 3
      Figure 3Recommendations for further studies based on the guidelines of the Consolidated Standards of Reporting Trials (CONSORT). DXA: Dual-energy X-ray Absorptiometry; Vo2max: maximal oxygen consumption; GM: gut microbiota; SCFA: short-chain fatty acids; LPS: lipopolissacarídeos; LBP: lipopolysaccharide binding protein. Source: adapted from Moher et al. [
      • Moher D.
      • Hopewell S.
      • Schulz K.F.
      • Montori V.
      • Gøtzsche P.C.
      • Devereaux P.J.
      • et al.
      CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials.
      ].
      The positive GM modulation and the maintenance of the intestinal homeostasis by physical exercise have the potential to promote and improve the health in patients with obesity or T2DM by different mechanisms. The increase in diversity and abundance of gut beneficial bacterial increases the SCFA production, which induces the production of hormones, such as GLP-1, thus improving satiety and reducing LPS translocation [
      • Ranganath L.R.
      • Beety J.M.
      • Morgan L.M.
      • Wright J.W.
      • Howland R.
      • Marks V.
      Attenuated GLP-1 secretion in obesity: cause or consequence?.
      ,
      • Hazell T.J.
      • Islam H.
      • Townsend L.K.
      • Schmale M.S.
      • Copeland J.L.
      Effects of exercise intensity on plasma concentrations of appetite-regulating hormones: potential mechanisms.
      ]. Through calcium mobilization and membrane hyperpolarization, a protein is activated (NLRP3) resulting in the production of IL-18 [
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ], which promotes epithelial repair and protection against inflammatory bowel disease [
      • Kern T.
      • Blond M.B.
      • Hansen T.H.
      • Rosenkilde M.
      • Quist J.S.
      • Gram A.S.
      • et al.
      Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
      ,
      • Munukka E.
      • Ahtiainen J.P.
      • Puigbó P.
      • Jalkanen S.
      • Pahkala K.
      • Keskitalo A.
      • et al.
      Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
      ]. By reducing the metabolic endotoxemia markers, physical exercise may improve the inflammatory status and immunity in subjects with obesity or T2DM [
      • Singer-Englar T.
      • Barlow G.
      • Mathur R.
      Obesity, diabetes, and the gut microbiome: an updated review.
      ,
      • Fan Y.
      • Pedersen O.
      Gut microbiota in human metabolic health and disease.
      ].

      5. Conclusion

      Physical exercise may be a promising strategy for positive modulation of gut microbiota in individuals with obesity, by improving the diversity and abundance of hindgut beneficial bacteria. In subjects with T2DM, fragile evidence suggests that physical exercise may reduce metabolic endotoxemia markers. Aerobic exercises carried out for at least 6 weeks with moderate or high intensity likely has a beneficial effect on the gut microbiota of individuals with obesity. The main mechanisms suggested supporting the beneficial association between physical exercise and gut microbiota are the increase in the abundance of bacteria that metabolize lactate to SCFA, and the positive effects on gut barrier integrity. Nevertheless, well-designed clinical trials are needed in this field, notably those randomized and controlled, and with assessment of food consumption without dietary intervention. Furthermore, we highlight the importance of investigating whether changes in GM are dependent on body mass changes resulting from physical exercise. Further studies with better methodological approaches will contribute to the development of more efficient strategies for the prevention and control of obesity and T2DM.

      Authors' contributions

      JSCS, CSS and MMVN designed the study; JSCS and CSS performed the literature review, analyzed the articles, and wrote the first version and edited the manuscript; MMVN coordinated and assisted the data collection and the analysis and the discussion of the results, and critically revised the manuscript. All authors read and agreed with the published version of the manuscript.

      Funding

      This research did not receive any funding.

      Declaration of competing interest

      The authors declare no conflict of interest.

      Acknowledgments

      The authors would like to thank the Graduate Program in Nutrition and Health (PPGNUT) and the Laboratory of Experimental Nutrition (LANUTE) of the School of Nutrition, Federal University of Goiás, Brazil, for their administrative and technical support. C. S. Seguro would like to thank the scholarship received from the Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG, GO, Brazil).

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

      References

        • WHO - World Health Organization
        Health topics - obesity [Internet].
        2016 ([cited 2021 Jun 15]. Available from:)
        • Aschner P.
        • Karuranga S.
        • James S.
        • Simmons D.
        • Basit A.
        • Shaw J.
        The International Diabetes Federation's guide for diabetes epidemiological studies.
        Diabetes Res Clin Pract. 2021; 172: 108630https://doi.org/10.1016/j.diabres.2020.108630
        • Saeedi P.
        • Petersohn I.
        • Salpea P.
        • Malanda B.
        • Karuranga S.
        • Unwin N.
        • et al.
        Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition.
        Diabetes Res Clin Pract. 2019; 157: 107843https://doi.org/10.1016/j.diabres.2019.107843
        • Singer-Englar T.
        • Barlow G.
        • Mathur R.
        Obesity, diabetes, and the gut microbiome: an updated review.
        Expet Rev Gastroenterol Hepatol. 2019; 13: 3-15https://doi.org/10.1080/17474124.2019.1543023
        • Fan Y.
        • Pedersen O.
        Gut microbiota in human metabolic health and disease.
        Nat Rev Microbiol. 2021; 19: 55-71https://doi.org/10.1038/s41579-020-0433-9
        • Gurung M.
        • Li Z.
        • You H.
        • Rodrigues R.
        • Jump D.B.
        • Morgun A.
        • et al.
        Role of gut microbiota in type 2 diabetes pathophysiology.
        EBioMedicine. 2020; 51: 102590https://doi.org/10.1016/j.ebiom.2019.11.051
        • Gomes A.C.
        • Hoffmann C.
        • Mota J.F.
        The human gut microbiota: metabolism and perspective in obesity.
        Gut Microb. 2018; 9: 308-325https://doi.org/10.1080/19490976.2018.1465157
        • Castaner O.
        • Goday A.
        • Park Y.M.
        • Lee S.H.
        • Magkos F.
        • Shiow S.
        • et al.
        The gut microbiome profile in obesity: a systematic review.
        Internet J Endocrinol. 2018; 2018: 4095789https://doi.org/10.1155/2018/4095789
        • Houghton D.
        • Hardy T.
        • Stewart C.
        • Errington L.
        • Day C.P.
        • Trenell M.I.
        • et al.
        Systematic review assessing the effectiveness of dietary intervention on gut microbiota in adults with type 2 diabetes.
        Diabetologia. 2018; 61: 1700-1711https://doi.org/10.1007/s00125-018-4632-0
        • Dorelli B.
        • Gallè F.
        • De Vito C.
        • Duranti G.
        • Iachini M.
        • Zaccarin M.
        • et al.
        Can physical activity influence human gut microbiota composition independently of diet? a systematic review.
        Nutrients. 2021; 13: 1-14https://doi.org/10.3390/nu13061890
        • Mailing L.J.
        • Allen J.M.
        • Buford T.W.
        • Fields C.J.
        • Woods J.A.
        Exercise and the gut microbiome: a review of the evidence, potential mechanisms, and implications for human health.
        Exerc Sport Sci Rev. 2019; 47: 75-85https://doi.org/10.1249/JES.0000000000000183
        • Aya V.
        • Flórez A.
        • Perez L.
        • Ramírez J.D.
        Association between physical activity and changes in intestinal microbiota composition: a systematic review.
        PLoS One. 2021; 16e0247039https://doi.org/10.1371/journal.pone.0247039
        • Clark A.
        • Mach N.
        Exercise-induced stress behavior, gut-microbiota-brain axis and diet: a systematic review for athletes.
        J Int Soc Sports Nutr. 2016; 13: 1-21https://doi.org/10.1186/s12970-016-0155-6
        • Oettlé G.J.
        Effect of moderate exercise on bowel habit.
        Gut. 1991; 32: 941-944https://doi.org/10.1136/gut.32.8.941
        • Dainese R.
        • Serra J.
        • Azpiroz F.
        • Malagelada J.R.
        Effects of physical activity on intestinal gas transit and evacuation in healthy subjects.
        Am J Med. 2004; 116: 536-539https://doi.org/10.1016/j.amjmed.2003.12.018
        • Hagio M.
        • Matsumoto M.
        • Yajima T.
        • Hara H.
        • Ishizuka S.
        Voluntary wheel running exercise and dietary lactose concomitantly reduce proportion of secondary bile acids in rat feces.
        J Appl Physiol. 2010; 109: 663-668https://doi.org/10.1152/japplphysiol.00777.2009
        • Meissner M.
        • Lombardo E.
        • Havinga R.
        • Tietge U.J.F.
        • Kuipers F.
        • Groen A.K.
        Voluntary wheel running increases bile acid as well as cholesterol excretion and decreases atherosclerosis in hypercholesterolemic mice.
        Atherosclerosis. 2011; 218: 323-329https://doi.org/10.1016/j. atherosclerosis.2011.06.040
        • Rowell L.B.
        • Brengelmann G.L.
        • Blackmon J.R.
        • Twiss R.D.
        • Kusumi F.
        Splanchnic blood flow and metabolism in heat-stressed man.
        J Appl Physiol. 1968; 24: 475-484https://doi.org/10.1152/jappl.1968.24.4.475
        • Packer N.
        • Hoffman-Goetz L.
        Exercise training reduces inflammatory mediators in the intestinal tract of healthy older adult mice.
        Can J Aging. 2012; 31: 161-171https://doi.org/10.1017/S0714980812000104
        • Hoffman-Goetz L.
        • Pervaiz N.
        • Guan J.
        Voluntary exercise training in mice increases the expression of antioxidant enzymes and decreases the expression of TNF-α in intestinal lymphocytes.
        Brain Behav Immun. 2009; 23: 498-506https://doi.org/10.1016/j.bbi.2009.01.015
        • Campbell S.C.
        • Wisniewski P.J.
        • Noji M.
        • McGuinness L.R.
        • Haeggblom M.M.
        • Lightfoot S.A.
        • et al.
        The effect of diet and exercise on intestinal integrity and microbial diversity in mice.
        PLoS One. 2016; 11e0150502https://doi.org/10.1371/journal.pone.0150502
        • Lira F.S.
        • Rosa J.C.
        • Pimentel G.D.
        • Souza H.A.
        • Caperuto E.C.
        • Carnevali L.C.
        • et al.
        Endotoxin levels correlate positively with a sedentary lifestyle and negatively with highly trained subjects.
        Lipids Health Dis. 2010; 9: 1-5https://doi.org/10.1186/1476-511X-9-82
        • Sohail M.U.
        • Yassine H.M.
        • Sohail A.
        • Al Thani A.A.
        Impact of physical exercise on gut microbiome, inflammation, and the pathobiology of metabolic disorders.
        Rev Diabet Stud. 2019; 15: 35-48https://doi.org/10.1900/RDS.2019.15.35
        • Bressa C.
        • Bailen-Andrino M.
        • Perez-Santiago J.
        • Gonzalez-Soltero R.
        • Perez M.
        • Gregoria Montalvo-Lominchar M.
        • et al.
        Differences in gut microbiota profile between women with active lifestyle and sedentary women.
        PLoS One. 2017; 12e0171352https://doi.org/10.1371/journal.pone.0171352
        • Clarke S.F.
        • Murphy E.F.
        • O’Sullivan O.
        • Lucey A.J.
        • Humphreys M.
        • Hogan A.
        • et al.
        Exercise and associated dietary extremes impact on gut microbial diversity.
        Gut. 2014; 63: 1913-1920https://doi.org/10.1136/gutjnl-2013-306541
        • Shahar R.T.
        • Koren O.
        • Matarasso S.
        • Shochat T.
        • Magzal F.
        • Agmon M.
        Attributes of physical activity and gut microbiome in adults: a systematic review.
        Int J Sports Med. 2020; 41: 801-814https://doi.org/10.1055/a-1157-9257
        • Mitchell C.M.
        • Davy B.M.
        • Hulver M.W.
        • Neilson A.P.
        • Bennett B.J.
        • Davy K.P.
        Does exercise alter gut microbial composition? a systematic review.
        Med Sci Sports Exerc. 2019; 51: 160-167https://doi.org/10.1249/MSS.0000000000001760
        • Ortiz-Alvarez L.
        • Xu H.
        • Martinez-Tellez B.
        Influence of exercise on the human gut microbiota of healthy adults: a systematic review.
        Clin Transl Gastroenterol. 2020; 11e00126https://doi.org/10.14309/ctg.0000000000000126
        • Booth A.
        • Clarke M.
        • Dooley G.
        • Ghersi D.
        • Moher D.
        • Petticrew M.
        • et al.
        The nuts and bolts of PROSPERO: an international prospective register of systematic reviews.
        Syst Rev. 2012; 1: 2https://doi.org/10.1186/2046-4053-1-2
        • Page M.J.
        • McKenzie J.E.
        • Bossuyt P.M.
        • Boutron I.
        • Hoffmann T.C.
        • Mulrow C.D.
        • et al.
        The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
        BMJ. 2021; 372: n72https://doi.org/10.1136/bmj.n71
        • Morton N.A.
        The PEDro scale is a valid measure of the methodological quality of clinical trials: a demographic study.
        Aust J Physiother. 2009; 55: 129-133https://doi.org/10.1016/s0004-9514(09)70043-1
        • Motiani K.K.
        • Collado M.C.
        • Eskelinen J.J.
        • Virtanen K.A.
        • Löyttyniemi E.
        • Salminen S.
        • et al.
        Exercise training modulates gut microbiota profile and improves endotoxemia.
        Med Sci Sports Exerc. 2020; 52: 94-104https://doi.org/10.1249/MSS.0000000000002112
        • Allen J.M.
        • Mailing L.J.
        • Niemiro G.M.
        • Moore R.
        • Cook M.D.
        • White B.A.
        • et al.
        Exercise alters gut microbiota composition and function in lean and obese humans.
        Med Sci Sports Exerc. 2018; 50: 747-757https://doi.org/10.1249/MSS.0000000000001495
        • Huang J.
        • Liao J.
        • Fang Y.
        • Deng H.
        • Yin H.
        • Shen B.
        • et al.
        Six-week exercise training with dietary restriction improves central hemodynamics associated with altered gut microbiota in adolescents with obesity.
        Front Endocrinol. 2020; 11: 569085https://doi.org/10.3389/fendo.2020.569085
        • Kern T.
        • Blond M.B.
        • Hansen T.H.
        • Rosenkilde M.
        • Quist J.S.
        • Gram A.S.
        • et al.
        Structured exercise alters the gut microbiota in humans with overweight and obesity: a randomized controlled trial.
        Int J Obes. 2020; 44: 125-135https://doi.org/10.1038/s41366-019-0440
        • Munukka E.
        • Ahtiainen J.P.
        • Puigbó P.
        • Jalkanen S.
        • Pahkala K.
        • Keskitalo A.
        • et al.
        Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women.
        Front Microbiol. 2018; 9: 2323https://doi.org/10.3389/fmicb.2018.02323
        • Quiroga R.
        • Nistal E.
        • Estébanez B.
        • Porras D.
        • Juárez-Fernández M.
        • Martínez-Flórez S.
        • et al.
        Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
        Exp Mol Med. 2020; 52: 1048-1061https://doi.org/10.1038/s12276-020-0459-0
        • Rettedal E.A.
        • Cree J.M.E.
        • Adams S.E.
        • MacRae C.
        • Skidmore P.M.L.
        • Cameron-Smith D.
        • et al.
        Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.
        Exp Physiol. 2020; 105: 1268-1279https://doi.org/10.1113/EP088744
        • Pasini E.
        • Corsetti G.
        • Assanelli D.
        • Testa C.
        • Romano C.
        • Dioguardi F.S.
        • et al.
        Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.
        Minerva Med. 2019; 110: 3-11https://doi.org/10.23736/S0026-4806.18.05589-1
        • Fasano A.
        Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications.
        Clin Gastroenterol Hepatol. 2012; 10: 1096-1100https://doi.org/10.1016/j. cgh.2012.08.012
        • Den Besten G.
        • Van Eunen K.
        • Groen A.K.
        • Venema K.
        • Reijngoud D.J.
        • Bakker B.M.
        The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism.
        J Lipid Res. 2013; 54: 2325-2340https://doi.org/10.1194/jlr.R036012
        • Barton W.
        • Penney N.C.
        • Cronin O.
        • Garcia-Perez I.
        • Molloy M.G.
        • Holmes E.
        • et al.
        The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level.
        Gut. 2018; 67: 625-633https://doi.org/10.1136/gutjnl-2016-313627
        • Ng S.K.
        • Hamilton I.R.
        Carbon dioxide fixation by Veillonella parvula M 4 and its relation to propionic acid formation.
        Can J Microbiol. 1973; 19: 715-723https://doi.org/10.1139/m73-116
        • Messonnier L.A.
        • Emhoff C.A.W.
        • Fattor J.A.
        • Horning M.A.
        • Carlson T.J.
        • Brooks G.A.
        Lactate kinetics at the lactate threshold in trained and untrained men.
        J Appl Physiol. 2013; 114: 1593-1602https://doi.org/10.1152/japplphysiol.00043.2013
        • Scheiman J.
        • Luber J.M.
        • Chavkin T.A.
        • MacDonald T.
        • Tung A.
        • Pham L.-D.
        • et al.
        Meta-omics analysis of elite athletes identifies a performance-enhancing microbe that functions via lactate metabolism.
        Nat Med. 2019; 25: 1104-1109https://doi.org/10.1038/s41591-019-0485-4
        • Islam H.
        • Townsend L.K.
        • McKie G.L.
        • Medeiros P.J.
        • Gurd B.J.
        • Hazell T.J.
        Potential involvement of lactate and interleukin-6 in the appetite-regulatory hormonal response to an acute exercise bout.
        J Appl Physiol. 2017; 123: 614-623https://doi.org/10.1152/japplphysiol.00218.2017
        • Ranganath L.R.
        • Beety J.M.
        • Morgan L.M.
        • Wright J.W.
        • Howland R.
        • Marks V.
        Attenuated GLP-1 secretion in obesity: cause or consequence?.
        Gut. 1996; 38: 916-919https://doi.org/10.1136/gut.38.6.916
        • Hazell T.J.
        • Islam H.
        • Townsend L.K.
        • Schmale M.S.
        • Copeland J.L.
        Effects of exercise intensity on plasma concentrations of appetite-regulating hormones: potential mechanisms.
        Appetite. 2015; 98: 80-88https://doi.org/10.1016/j.appet.2015.12.016
        • Chang Y.C.
        • Ching Y.H.
        • Chiu C.C.
        • Liu J.Y.
        • Hung S.W.
        • Huang W.C.
        • et al.
        TLR2 and interleukin-10 are involved in Bacteroides fragilis-mediated prevention of DSS-induced colitis in gnotobiotic mice.
        PLoS One. 2017; 12e0180025https://doi.org/10.1371/journal.pone.0180025
        • Zhang L.
        • Qin Q.
        • Liu M.
        • Zhang X.
        • He F.
        • Wang G.
        Akkermansia muciniphila can reduce the damage of gluco/lipotoxicity, oxidative stress and inflammation, and normalize intestine microbiota in streptozotocin-induced diabetic rats.
        Pathog Dis. 2018; 76: fty028https://doi.org/10.1093/femspd/fty028
        • Xu Y.
        • Wang N.
        • Tan H.Y.
        • Li S.
        • Zhang C.
        • Feng Y.
        Function of akkermansia muciniphila in obesity: interactions with lipid metabolism, immune response and gut systems.
        Front Microbiol. 2020; 11: 219https://doi.org/10.3389/fmicb.2020.00219
        • Turroni F.
        • Van Sinderen D.
        • Ventura M.
        Bifidobacteria: from ecology to genomics.
        Front Biosci. 2009; 14: 4673-4684https://doi.org/10.2741/3559
        • Fernandes J.
        • Su W.
        • Rahat-Rozenbloom S.
        • Wolever T.M.S.
        • Comelli E.M.
        Adiposity, gut microbiota and faecal short chain fatty acids are linked in adult humans.
        Nutr Diabetes. 2014; 4: e121https://doi.org/10.1038/nutd.2014.23
        • Alves-Santos A.M.
        • Sugizaki C.S.A.
        • Lima G.C.
        • Naves M.M.V.
        Prebiotic effect of dietary polyphenols: a systematic review.
        J Funct Foods. 2020; 74: 104169https://doi.org/10.1016/j.jff.2020.104169
        • Estaki M.
        • Pither J.
        • Baumeister P.
        • Little J.P.
        • Gill S.K.
        • Ghosh S.
        • et al.
        Cardiorespiratory fitness as a predictor of intestinal microbial diversity and distinct metagenomic functions.
        Microbiome. 2016; 4: 1-13https://doi.org/10.1186/s40168-016-0189-7
        • Müller M.
        • Canfora E.E.
        • Blaak E.E.
        Gastrointestinal transit time, glucose homeostasis and metabolic health: modulation by dietary fibers.
        Nutrients. 2018; 10: 275https://doi.org/10.3390/nu10030275
        • Vandeputte D.
        • Falony G.
        • Vieira-Silva S.
        • Tito R.Y.
        • Joossens M.
        • Raes J.
        Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates.
        Gut. 2016; 65: 57-62https://doi.org/10.1136/gutjnl-2015-309618
        • Rizzatti G.
        • Lopetuso L.R.
        • Gibiino G.
        • Binda C.
        • Gasbarrini A.
        Proteobacteria: a common factor in human diseases.
        BioMed Res Int. 2017; 2017: 9351507https://doi.org/10.1155/2017/9351507
        • Shin N.R.
        • Whon T.W.
        • Bae J.W.
        Proteobacteria: microbial signature of dysbiosis in gut microbiota.
        Trends Biotechnol. 2015; 33: 496-503https://doi.org/10.1016/j.tibtech.2015.06.011
        • Kirschning C.J.
        • Au-Young J.
        • Lamping N.
        • Reuter D.
        • Pfeil D.
        • Seilhamer J.J.
        • et al.
        Similar organization of the lipopolysaccharide-binding protein (LBP) and phospholipid transfer protein (PLTP) genes suggests a common gene family of lipid-binding proteins.
        Genomics. 1997; 46: 416-425https://doi.org/10.1006/geno.1997.5030
        • MacInnis M.J.
        • Gibala M.J.
        Physiological adaptations to interval training and the role of exercise intensity.
        J Physiol. 2017; 595: 2915-2930https://doi.org/10.1113/JP273196
        • Chodzko-Zajko W.J.
        • Proctor D.N.
        • Minson C.T.
        • Nigg C.R.
        American College of Sports Medicine position stand. Exercise and physical activity for older adults.
        Med Sci Sports Exerc. 2009; 41: 1510-1530https://doi.org/10.1249/MSS.0b013e3181a0c95c
        • American College of Sports Medicine position stand
        Progression models in resistance training for healthy adults.
        Med Sci Sports Exerc. 2009; 41: 687-708https://doi.org/10.1249/MSS.0b013e3181915670
        • Nagpal R.
        • Mainali R.
        • Ahmadi S.
        • Wang S.
        • Singh R.
        • Kavanagh K.
        • et al.
        Gut microbiome and aging: physiological and mechanistic insights.
        Nutr Healthy Aging. 2018; 4: 267-285https://doi.org/10.3233/NHA-170030
        • Moher D.
        • Hopewell S.
        • Schulz K.F.
        • Montori V.
        • Gøtzsche P.C.
        • Devereaux P.J.
        • et al.
        CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials.
        BMJ. 2010; 11: 1-8https://doi.org/10.1136/bmj.c869