Exercise Training Modulates Gut Microbiota Profile and Improves Endotoxemia

Kumail K Motiani, M Carmen Collado, Jari-Joonas Eskelinen, Kirsi A Virtanen, Eliisa Löyttyniemi, Seppo Salminen, Pirjo Nuutila, Kari K Kalliokoski, Jarna C Hannukainen, Kumail K Motiani, M Carmen Collado, Jari-Joonas Eskelinen, Kirsi A Virtanen, Eliisa Löyttyniemi, Seppo Salminen, Pirjo Nuutila, Kari K Kalliokoski, Jarna C Hannukainen

Abstract

Introduction: Intestinal metabolism and microbiota profiles are impaired in obesity and insulin resistance. Moreover, dysbiotic gut microbiota has been suggested to promote systemic low-grade inflammation and insulin resistance through the release of endotoxins particularly lipopolysaccharides. We have previously shown that exercise training improves intestinal metabolism in healthy men. To understand whether changes in intestinal metabolism interact with gut microbiota and its release of inflammatory markers, we studied the effects of sprint interval (SIT) and moderate-intensity continuous training (MICT) on intestinal metabolism and microbiota in subjects with insulin resistance.

Methods: Twenty-six, sedentary subjects (prediabetic, n = 9; type 2 diabetes, n = 17; age, 49 [SD, 4] yr; body mass index, 30.5 [SD, 3]) were randomized into SIT or MICT. Intestinal insulin-stimulated glucose uptake (GU) and fatty acid uptake (FAU) from circulation were measured using positron emission tomography. Gut microbiota composition was analyzed by 16S rRNA gene sequencing and serum inflammatory markers with multiplex assays and enzyme-linked immunoassay kit.

Results: V˙O2peak improved only after SIT (P = 0.01). Both training modes reduced systematic and intestinal inflammatory markers (tumor necrosis factor-α, lipopolysaccharide binding protein) (time P < 0.05). Training modified microbiota profile by increasing Bacteroidetes phylum (time P = 0.03) and decreasing Firmicutes/Bacteroidetes ratio (time P = 0.04). Moreover, there was a decrease in Clostridium genus (time P = 0.04) and Blautia (time P = 0.051). Only MICT decreased jejunal FAU (P = 0.02). Training had no significant effect on intestinal GU. Colonic GU associated positively with Bacteroidetes and inversely with Firmicutes phylum, ratio Firmicutes/Bacteroidetes and Blautia genus.

Conclusions: Intestinal substrate uptake associates with gut microbiota composition and whole-body insulin sensitivity. Exercise training improves gut microbiota profiles and reduces endotoxemia.

Trial registration: ClinicalTrials.gov NCT01344928.

Figures

FIGURE 1
FIGURE 1
A, Consort flow diagram showing the total number of subjects recruited and analyzed. B, Study design: Subjects were studied on three separate days before and after the exercise intervention. OGTT, oral glucose tolerance test.
FIGURE 2
FIGURE 2
Impact of exercise intervention on specific inflammatory markers. A, TNF α, (B) CRP, and (C) LBP. All values are expressed as model-based means and bars are 95% CI. (§) Log transformation was performed to achieve normal distribution. *P value for time interaction (i.e., the groups (SIT + MICT) behaved similarly for the change in the parameter with a significant difference between them.
FIGURE 3
FIGURE 3
Impact of exercise intervention on the gut microbiota composition. A, Ratio (Firmicutes/Bacteroidetes), (B) Bacteroidetes, and the genus (C) Blautia and (D) Clostridium. All values are expressed as model-based means and bars are 95% CI. (§) Log transformation was performed to achieve normal distribution. *P value for time interaction (i.e., the groups (SIT + MICT) behaved similarly for the change in the parameter with a significant difference between them.
FIGURE 4
FIGURE 4
A, Insulin-stimulated GU and (B) fasting free FAU in different parts of intestine before and after 2 wk of either SIT or MICT. All values are expressed as model-based means and bars are 95% CI. (§) Log transformation was performed to achieve normal distribution. **P value for time–training interaction (i.e., the groups behaved differently for the change in the parameter with a significant difference between them).
FIGURE 5
FIGURE 5
Correlation between insulin-stimulated colonic GU and (A) Firmicutes (B) Ratio (Firmicutes/Bacteroidetes), (C) Blautia, and (D) Bacteroides phylum in pooled analysis of both SIT and MICT subjects at baseline. (◊) SIT and (●) MICT. (§) Log transformation was performed to achieve normal distribution.

References

    1. Cronin O, O’Sullivan O, Barton W, Cotter PD, Molloy MG, Shanahan F. Gut microbiota: implications for sports and exercise medicine. Br J Sports Med. 2017;51(9):700–1.
    1. Manco M, Putignani L, Bottazzo GF. Gut microbiota, lipopolysaccharides, and innate immunity in the pathogenesis of obesity and cardiovascular risk. Endocr Rev. 2010;31(6):817–44.
    1. Estaki M, Pither J, Baumeister P, et al. Cardiorespiratory fitness as a predictor of intestinal microbial diversity and distinct metagenomic functions. Microbiome. 2016;4(1):42.
    1. Clarke SF, Murphy EF, O’Sullivan O, et al. Exercise and associated dietary extremes impact on gut microbial diversity. Gut. 2014;63(12):1913–20.
    1. Mika A, Fleshner M. Early-life exercise may promote lasting brain and metabolic health through gut bacterial metabolites. Immunol Cell Biol. 2016;94(2):151–7.
    1. O’Mahony SM, Clarke G, Dinan TG, Cryan JF. Early-life adversity and brain development: is the microbiome a missing piece of the puzzle? Neuroscience. 2017;342:37–54.
    1. Cook MD, Allen JM, Pence BD, et al. Exercise and gut immune function: evidence of alterations in colon immune cell homeostasis and microbiome characteristics with exercise training. Immunol Cell Biol. 2016;94(2):158–63.
    1. O’Sullivan O, Cronin O, Clarke SF, et al. Exercise and the microbiota. Gut Microbes. 2015;6(2):131–6.
    1. Ringel Y. The gut microbiome in irritable bowel syndrome and other functional bowel disorders. Gastroenterol Clin North Am. 2017;46(1):91–101.
    1. Khalili H, Ananthakrishnan AN, Konijeti GG, et al. Physical activity and risk of inflammatory bowel disease: prospective study from the nurses’ health study cohorts. BMJ. 2013;347:f6633.
    1. Motiani KK, Savolainen AM, Eskelinen JJ, et al. Two weeks of moderate-intensity continuous training, but not high-intensity interval training, increases insulin-stimulated intestinal glucose uptake. J Appl Physiol (1985). 2017;122(5):1188–97.
    1. American Diabestes Association Classification and diagnosis of diabetes. Diabetes Care. 2015;38(Suppl):S8–16.
    1. Heiskanen MA, Sjoros TJ, Heinonen IHA, et al. Sprint interval training decreases left-ventricular glucose uptake compared to moderate-intensity continuous training in subjects with type 2 diabetes or prediabetes. Sci Rep. 2017;7(1):10531.
    1. Kiviniemi AM, Tulppo MP, Eskelinen JJ, et al. Cardiac autonomic function and high-intensity interval training in middle-age men. Med Sci Sports Exerc. 2014;46(10):1960–7.
    1. Patlak CS, Blasberg RG. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab. 1985;5(4):584–90.
    1. Rodriguez-Diaz J, Garcia-Mantrana I, Vila-Vicent S, et al. Relevance of secretor status genotype and microbiota composition in susceptibility to rotavirus and norovirus infections in humans. Sci Rep. 2017;7:45559.
    1. Collado MC, Isolauri E, Laitinen K, Salminen S. Effect of mother’s weight on infant’s microbiota acquisition, composition, and activity during early infancy: a prospective follow-up study initiated in early pregnancy. Am J Clin Nutr. 2010;92(5):1023–30.
    1. Caporaso JG, Kuczynski J, Stombaugh J, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010;7(5):335–6.
    1. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979;237(3):E214–23.
    1. Sjoros TJ, Heiskanen MA, Motiani KK, et al. Increased insulin-stimulated glucose uptake in both leg and arm muscles after sprint interval and moderate-intensity training in subjects with type 2 diabetes or prediabetes. Scand J Med Sci Sports. 2018;28(1):77–87.
    1. Mariat D, Firmesse O, Levenez F, et al. The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol. 2009;9:123.
    1. Tuovinen E, Keto J, Nikkila J, Matto J, Lahteenmaki K. Cytokine response of human mononuclear cells induced by intestinal clostridium species. Anaerobe. 2013;19:70–6.
    1. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444(7122):1022–3.
    1. Cani PD, Bibiloni R, Knauf C, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008;57(6):1470–81.
    1. Cohen J. The detection and interpretation of endotoxaemia. Intensive Care Med. 2000;26(1 Suppl):S51–6.
    1. Gonzalez-Quintela A, Alonso M, Campos J, Vizcaino L, Loidi L, Gude F. Determinants of serum concentrations of lipopolysaccharide-binding protein (LBP) in the adult population: the role of obesity. PLoS One. 2013;8(1):e54600.
    1. Albillos A, de la Hera A, González M, et al. Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement. Hepatology. 2003;37(1):208–17.
    1. Tobias PS, Ulevitch RJ. Lipopolysaccharide binding protein and CD14 in LPS dependent macrophage activation. Immunobiology. 1993;187(3–5):227–32.
    1. Triantafilou M, Triantafilou K. Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster. Trends Immunol. 2002;23(6):301–4.
    1. Sun L, Yu Z, Ye X, et al. A marker of endotoxemia is associated with obesity and related metabolic disorders in apparently healthy Chinese. Diabetes Care. 2010;33(9):1925–32.
    1. Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature. 2008;453(7195):620–5.
    1. Egshatyan L, Kashtanova D, Popenko A, et al. Gut microbiota and diet in patients with different glucose tolerance. Endocr Connect. 2016;5(1):1–9.
    1. Pache I, Rogler G, Felley C. TNF-alpha blockers in inflammatory bowel diseases: practical consensus recommendations and a user’s guide. Swiss Med Wkly. 2009;139(19–20):278–87.
    1. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444(7122):1027–31.
    1. Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A. 2005;102(31):11070–5.
    1. Turnbaugh PJ, Backhed F, Fulton L, Gordon JI. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe. 2008;3(4):213–23.
    1. Rajilic-Stojanovic M, de Vos WM. The first 1000 cultured species of the human gastrointestinal microbiota. FEMS Microbiol Rev. 2014;38(5):996–1047.
    1. Rajilić-Stojanović M, Biagi E, Heilig HG, et al. Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology. 2011;141(5):1792–801.
    1. Bressa C, Bailen-Andrino M, Perez-Santiago J, et al. Differences in gut microbiota profile between women with active lifestyle and sedentary women. PLoS One. 2017;12(2):e0171352.
    1. Lambert JE, Myslicki JP, Bomhof MR, Belke DD, Shearer J, Reimer RA. Exercise training modifies gut microbiota in normal and diabetic mice. Appl Physiol Nutr Metab. 2015;40(7):749–52.
    1. Evans CC, LePard KJ, Kwak JW, et al. Exercise prevents weight gain and alters the gut microbiota in a mouse model of high fat diet-induced obesity. PLoS One. 2014;9(3):e92193.
    1. Shukla SK, Cook D, Meyer J, et al. Changes in gut and plasma microbiome following exercise challenge in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). PLoS One. 2015;10(12):e0145453.
    1. Munukka E, Ahtiainen JP, Puigbó P, et al. Six-week endurance exercise alters gut Metagenome that is not reflected in systemic metabolism in over-weight women. Front Microbiol. 2018;9:2323.
    1. Zhao X, Zhang Z, Hu B, Huang W, Yuan C, Zou L. Response of gut microbiota to metabolite changes induced by endurance exercise. Front Microbiol. 2018;9:765.
    1. Allen JM, Mailing LJ, Niemiro GM, et al. Exercise alters gut microbiota composition and function in lean and obese humans. Med Sci Sports Exerc. 2018;50(4):747–57.
    1. Mitchell CM, Davy BM, Hulver MW, Neilson AP, Bennett BJ, Davy KP. Does exercise alter gut microbial composition? A systematic review. Med Sci Sports Exerc. 2019;51(1):160–7.
    1. Koffert J, Stahle M, Karlsson H, et al. Morbid obesity and type 2 diabetes alter intestinal fatty acid uptake and blood flow. Diabetes Obes Metab. 2018;20(6):1384–90.
    1. Lu Y, Hajifathalian K, Ezzati M, Woodward M, Rimm EB, Danaei G. Metabolic mediators of the effects of body-mass index, overweight, and obesity on coronary heart disease and stroke: a pooled analysis of 97 prospective cohorts with 1·8 million participants. Lancet. 2014;383(9921):970–83.
    1. Forslund K, Hildebrand F, Nielsen T, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015;528(7581):262–6.
    1. de la Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V, et al. Metformin is associated with higher relative abundance of mucin-degrading Akkermansia muciniphila and several short-chain fatty acid-producing microbiota in the gut. Diabetes Care. 2017;40(1):54–62.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere