Table 1.

Effects of exercise training on the gut microbiota and the gut barrier function in animals/patients with type 2 diabetes mellitus. Overview of included studies.

Author(s), Year, Country	Animal Model Used or Subjects’ Characteristics	Microbiota/ Microbiome Analysis Method	(Exercise) Intervention	Duration	Main Results
ANIMAL STUDIES
Yang et al., 2020 [27], China	60 C57BI/6 J mice (HFD-induced diabetes)	16S rRNA sequencing SCFA-analysis: gas chromatography	Three groups: -Non-diabetic controls (no training) -Diabetic animals (no training) -Trained diabetic animals Swimming exercise (60 min/day; 5 times/wk)	8 weeks	Exercise training reduced IR and resulted in a more balanced abundance of Firmicutes and Bacteroidetes (abundance of Bacteroidetes was decreased in diabetes and increased through training) Physical activity increased intestinal and plasma SCFA concentrations GLPG0974 abolished exercise-mediated improvement of IR and acetate-mediated reduction of skeletal muscle IR Muscle cell investigation showed that exercise and acetate-mediated improvement of skeletal muscle IR depends on GPR43 (and its interaction with SCFAs)
Lambert et al., 2015 [25], Canada	Diabetic C57BL/KsJ-leprdb/leprdb mice and non-diabetic db/+ littermates	RT-qPCR	Three groups: -Non-diabetic animals (no training) -Diabetic animals (no training) -Trained non-diabetic animals -Trained diabetic animals Moderate- to high-intensity treadmill running, 5 times/wk); physical capacity and genotype of mice determined exercise intensity: db/+ mice: 60 min/session at a speed of 4.79 m/min (287 m/session), db/db mice: 66 min/session at a speed of 2.87 m/min (189 m/session)	6 weeks	Main effect of exercise, with increased abundance of the Firmicutes species Clostridium cluster C-I and lower abundance of Bacteroides/Prevotella spp. and Methanobrevibacter spp. Interaction effect of diabetes × exercise on total bacteria abundance Abundance of Bifidobacterium spp. increased in exercised normal mice but decreased in exercised diabetic mice (exercise × diabetes interaction)
HUMAN STUDIES
Liu et al., 2020 [33], China	Overweight/Obese prediabetic men; n = 39 (20–60 years) C57BL/6J mice	Whole metagenome shotgun analysis and fecal metabolomics	Control group: -No exercise Intervention group: -HI(I)T 70 min combined endurance and resistance interval training; 3 times/wk Training sessions divided in: -10 min warm-up -Three 10 min stations of high-intensity (interval) training (treadmill running, ergometer cycling, resistance, and calisthenics exercises), with 3–4 min recovery between stations. -10–15 min cool-down and stretching exercises. -Treadmill running: 3–4 exercise bouts of 2 min running at 85–95% VO2max separated by 30–45 s intervals of active recovery at 50% VO2max. -Ergometer cycling: 4–5 45–60 s cycling intervals at 90–95% PPO with 60–75 s active recovery at 30% PPO between intervals. -Resistance/calisthenics exercises: 2–3 sets of high-intensity exercises (squats, kettlebell swings, planks, burpees) with 30 s rest between each set	12 weeks	Microbiota composition was differently affected in exercise responders and non-responders from pre- to post-training Exercise responders: decrease in abundance of Bacteroides xylanisolvens, increase in abundance of the Streptococcus mitis group and Lachnospiraceae bacterium, reduction in abundance of Alistipes shahii, decrease in replication rate of Prevotella copri Exercise non-responders: decrease in abundance of Ruminococcus gnavus, increase in abundance of Alistipes shahii Exercise training-related gut microbiota changes were associated with improvements in insulin sensitivity The microbiome of responders had increased functional capacity for SCFA synthesis and BCAA breakdown An established learning algorithm was developed to predict individual responses to exercise training based on baseline microbiome Fecal microbiota transplantation from responders in antibiotics-treated mice led to benefits in insulin sensitivity
Motiani et al., 2020 [29], Finland	Overweight/Obese, prediabetic/T2DM men and women; n = 26 (49 ± 4 years)	16S rRNA amplicon analysis (V3 and V4 regions)	Two groups -SIT: 30 s exercise bouts (4–6) of all out cycling efforts (4 min recovery); 3 times/wk -MICT: 40–60 min cycling at 60% VO2 peak; 3 times/wk	2 weeks	Increased abundance of Bacteroidetes in both groups post-training as well as decreased F/B ratio. Decreased abundance of Clostridium and by trend (p = 0.051) of Blautia genus in both groups post-training Lower abundance of Blautia genus was associated with better whole-body insulin sensitivity Effects after SIT: higher abundance of Lachnospira genus post- training Effects after MICT: higher abundance of Veillonella genus and by trend (p = 0.055) of Faecalibacterium genus (F. prausnitzii) post-training Colonic GU from circulation was positively associated with abundance of Bacteroidetes and inversely with that of Firmicutes phylum, F/B ratio, and abundance of Blautia genus
Pasini et al., 2019 [31], Italy	T2DM patients; n = 30 (70 ± 2 years)	Stool analysis: Selective agar culture medium	Exercise training: 90 min per session, 3 times/wk + energy-restricted diet Training sessions divided in: -Endurance training 15–35 min cycling, first 3 months: training heart rate 5 bpm below HRGET, last 3 months training heart rate between HRGET and HRVCP -Resistance training: 40–50 min of various exercises (calisthenics, exercises with equipment) involving major muscle groups, 3 sets of 8–15 repetitions, progressively increased -Flexibility training: Static stretching exercises	6 months	Exercise training reduced mycetes overgrowth Decreased abundance of Candida albicans and reduced zonulin concentration following chronic exercise Improvements in insulin sensitivity and chronic low-grade inflammation (CRP) post-training

BCAA = branched-chain amino acids. bpm = beats per minute. CRP = C-reactive protein. d = day. ELISA = enzyme-linked immunosorbent assay. F/B ratio = Firmicutes/Bacteroidetes ratio. FTI = fat tissue index. GPR 43 = G protein-coupled receptor 43. GU = glucose uptake. HFD = high-fat diet. HI(I)T = high-intensity (interval) training. HOMA-IR index = homeostatic model assessment of insulin resistance index. HR_GET = heart rate gas exchange threshold. HR_max = maximal heart rate. HR_VCP = heart rate ventilatory compensation point. IR = insulin resistance. MICT = moderate-intensity continuous training. min = minutes. RT-qPCR = real-time quantitative polymerase chain reaction. rRNA = ribosomal RNA. SCFA = short-chain fatty acid. SIT = sprint interval training. T2DM = type 2 diabetes mellitus. VO_2max = maximal oxygen uptake. VO_2peak = peak oxygen uptake. wk = week.