Exercise, Gut Microbial Metabolite: Short Chain Fatty Acid and Regulation of Skeletal Muscle Metabolism
XU Lei1), NI Zhen2), ZHANG Ying1)*
1)Sport Science College of Beijing Sport University, Beijing 100084, China; 2)China Academy of Sport and Health Sciences of Beijing Sport University, Beijing 100084, China
Abstract：Gut microbiota, which is influenced by genetics, environment, diet, age and exercise, is a highly dynamic and individualized complex ecosystem and has a wide range of response effects with many tissues and organs through its metabolites. Short chain fatty acids (SCFA) are mainly produced by bacteria in cecum and colon by fermentation with dietary fiber as substrate, which is absorbed into the superior and inferior mesenteric vein, and then converges into the portal vein to the liver. Part of SCFA is used as the substrate of gluconeogenesis and lipid biosynthesis by liver, and the remaining SCFA enters the peripheral circulation through hepatic vein in the form of free fatty acids. It is found that exercise can improve the abundance of gut microbiota producing SCFA and the expression of genes involved in the regulation of SCFA production, and then increase the content of SCFA in the lumen. Glucagon like peptide-1 (GLP-1) is synthesized and secreted by colon endocrine cells stimulated by SCFA. GLP-1 can promote islet B cells to synthesize and secrete insulin, which regulates skeletal muscle glucose uptake and glycogen synthesis. In addition, SCFA enhances the insulin sensitivity of skeletal muscle by increasing histone acetylation level on chromatin in proximity of the insulin receptor substrate 1 (Irs1) transcriptional start site. At the same time, SCFA can promote fatty acid uptake, lipid catabolism and mitochondrial biogenesis of skeletal muscle by activating AMP-activated protein kinase (AMPK), and then inhibit lipid anabolism. This paper reviewed the latest research progress in three aspects: summary of the gut microbial metabolites (SCFA), the effect of exercise on the gut microbiota producing SCFA, and the possible mechanism of exercise mediated SCFA on skeletal muscle metabolism. It may provide theoretical basis for the research on the new mechanism in the exercise adaptation of skeletal muscle.
徐磊, 倪震, 张缨. 运动、肠道菌群代谢物——短链脂肪酸与骨骼肌代谢调控[J]. 中国生物化学与分子生物学报, 2022, 38(1): 1-7.
XU Lei, NI Zhen, ZHANG Ying. Exercise, Gut Microbial Metabolite: Short Chain Fatty Acid and Regulation of Skeletal Muscle Metabolism. Chinese Journal of Biochemistry and Molecular Biol, 2022, 38(1): 1-7.
[1] Ursell LK, Metcalf JL, Parfrey LW, et al. Defining the human microbiome[J]. Nutr Rev, 2012, 70 (Suppl 1):S38-44 [2] Lahiri S, Kim H, GarciaPerez I, et al. The gut microbiota influences skeletal muscle mass and function in mice[J]. Sci Transl Med, 2019, 11(502):eaan5662 [3] Nay K, Jollet M, Goustard B, et al. Gut bacteria are critical for optimal muscle function: a potential link with glucose homeostasis[J]. Am J Physiol Endocrinol Metab, 2019, 317(1):E158-E171 [4] Chen YM, Wei L, Chiu YS, et al. Lactobacillus plantarum TWK10 supplementation improves exercise performance and increases muscle mass in mice[J]. Nutrients, 2016, 8(4):205 [5] Buigues C, FernandezGarrido J, Pruimboom L, et al. Effect of a prebiotic formulation on frailty syndrome: a randomized, double-blind clinical trial[J]. Int J Mol Sci, 2016, 17(6):932 [6] Frampton J, Murphy KG, Frost G, et al. Short-chain fatty acids as potential regulators of skeletal muscle metabolism and function[J]. Nat Metab, 2020, 2(9):840-848 [7] Monda V, Villano I, Messina A, et al. Exercise modifies the gut microbiota with positive health effects[J]. Oxid Med Cell Longev, 2017, 2017:3831972 [8] Koh A, De Vadder F, Kovatcheva-Datchary P, et al. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites[J]. Cell, 2016, 165(6):1332-1345 [9] Stumpff F. A look at the smelly side of physiology: transport of short chain fatty acids[J]. Pflugers Arch, 2018, 470(4):571-598 [10] Sivaprakasam S, Bhutia YD, Yang S, et al. Short-chain fatty acid transporters: role in colonic homeostasis[J]. Compr Physiol, 2017, 8(1):299-314 [11] Sun M, Wu W, Liu Z, et al. Microbiota metabolite short chain fatty acids, GPCR, and inflammatory bowel diseases[J]. J Gastroenterol, 2017, 52(1):1-8 [12] den Besten G, van Eunen K, Groen AK, et al. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism[J]. J Lipid Res, 2013, 54(9):2325-2340 [13] Kasubuchi M, Hasegawa S, Hiramatsu T, et al. Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation[J]. Nutrients, 2015, 7(4):2839-2849 [14] Maruta H, Yamashita H. Acetic acid stimulates G-protein-coupled receptor GPR43 and induces intracellular calcium influx in L6 myotube cells[J]. PLoS One, 2020, 15(9):e0239428 [15] Han JH, Kim IS, Jung SH, et al. The effects of propionate and valerate on insulin responsiveness for glucose uptake in 3T3-L1 adipocytes and C2C12 myotubes via G protein-coupled receptor 41[J]. PLoS One, 2014, 9(4):e95268 [16] Zhou Y, Mihindukulasuriya KA, Gao H, et al. Exploration of bacterial community classes in major human habitats[J]. Genome Biol, 2014, 15(5):R66 [17] Keohane DM, Woods T, O′Connor P, et al. Four men in a boat: Ultra-endurance exercise alters the gut microbiome[J]. J Sci Med Sport, 2019, 22(9):1059-1064 [18] Scheiman J, Luber JM, Chavkin TA, et al. Meta-omics analysis of elite athletes identifies a performance-enhancing microbe that functions via lactate metabolism[J]. Nat Med, 2019, 25(7):1104-1109 [19] Munukka E, Ahtiainen JP, Puigbo P, et al. Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women[J]. Front Microbiol, 2018, 9:2323 [20] Motiani KK, Collado MC, Eskelinen JJ, et al. Exercise training modulates gut microbiota profile and improves endotoxemia[J]. Med Sci Sports Exerc, 2020, 52(1):94-104 [21] Liu Y, Wang Y, Ni Y, et al. Gut microbiome fermentation determines the efficacy of exercise for diabetes prevention[J]. Cell Metab, 2020, 31(1):77-91.e5 [22] Allen JM, Mailing LJ, Niemiro GM, et al. Exercise alters gut microbiota composition and function in lean and obese humans[J]. Med Sci Sports Exerc, 2018, 50(4):747-757 [23] Fushimi T, Tayama K, Fukaya M, et al. Acetic acid feeding enhances glycogen repletion in liver and skeletal muscle of rats[J]. J Nutr, 2001, 131(7):1973-1977 [24] Fushimi T, Sato Y. Effect of acetic acid feeding on the circadian changes in glycogen and metabolites of glucose and lipid in liver and skeletal muscle of rats[J]. Br J Nutr, 2005, 94(5):714-719 [25] Sakakibara S, Yamauchi T, Oshima Y, et al. Acetic acid activates hepatic AMPK and reduces hyperglycemia in diabetic KK-A(y) mice[J]. Biochem Biophys Res Commun, 2006, 344(2):597-604 [26] Kaji I, Karaki Si, Kuwahara A. Short-chain fatty acid receptor and its contribution to glucagon-like peptide-1 release[J]. Digestion, 2014, 89(1):31-36 [27] Freeland KR, Wolever TMS. Acute effects of intravenous and rectal acetate on glucagon-like peptide-1, peptide YY, ghrelin, adiponectin and tumour necrosis factor-alpha[J]. Br J Nutr, 2010, 103(3):460-466 [28] Tolhurst G, Heffron H, Lam YS, et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2[J]. Diabetes, 2012, 61(2):364-371 [29] Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1[J]. Cell Metab, 2018, 27(4):740-756 [30] Smith EP, An Z, Wagner C, et al. The role of beta cell glucagon-like peptide-1 signaling in glucose regulation and response to diabetes drugs[J]. Cell Metab, 2014, 19(6):1050-1057 [31] Shen Y, Wei W, Zhou DX. Histone acetylation enzymes coordinate metabolism and gene expression[J]. Trends Plant Sci, 2015, 20(10):614-621 [32] Chriett S, Zerzaihi O, Vidal H, et al. The histone deacetylase inhibitor sodium butyrate improves insulin signalling in palmitate-induced insulin resistance in L6 rat muscle cells through epigenetically-mediated up-regulation of Irs1[J]. Mol Cell Endocrinol, 2017, 439:224-232 [33] Yamashita H, Maruta H, Jozuka M, et al. Effects of acetate on lipid metabolism in muscles and adipose tissues of type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats[J]. Biosci Biotechnol Biochem, 2009, 73(3):570-576 [34] Gao Z, Yin J, Zhang J, et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice[J]. Diabetes, 2009, 58(7):1509-1517 [35] Maruta H, Yoshimura Y, Araki A, et al. Activation of AMP-activated protein kinase and stimulation of energy metabolism by acetic Acid in L6 myotube cells[J]. PLoS One, 2016, 11(6):e0158055 [36] Hong J, Jia Y, Pan S, et al. Butyrate alleviates high fat diet-induced obesity through activation of adiponectin-mediated pathway and stimulation of mitochondrial function in the skeletal muscle of mice[J]. Oncotarget, 2016, 7(35):56071-56082 [37] Pan JH, Kim JH, Kim HM, et al. Acetic acid enhances endurance capacity of exercise-trained mice by increasing skeletal muscle oxidative properties[J]. Biosci Biotechnol Biochem, 2015, 79(9):1535-1541 [38] Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis[J]. Nat Rev Mol Cell Biol, 2012, 13(4):251-262 [39] Liu L, Fu C, Li F. Acetate affects the process of lipid metabolism in rabbit liver, skeletal muscle and adipose tissue[J]. Animals (Basel), 2019, 9(10):799 [40] Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis[J]. Nat Rev Mol Cell Biol, 2018, 19(2):121-135 [41] Walsh ME, Bhattacharya A, Sataranatarajan K, et al. The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging[J]. Aging Cell, 2015, 14(6):957-970 [42] Jornayvaz FR, Shulman GI. Regulation of mitochondrial biogenesis[J]. Essays Biochem, 2010, 47:69-84 [43] 钱帅伟, 孙易, 漆正堂,等.运动对线粒体稳态调控机制的研究述评——基于运动介导TFEB调节线粒体质量控制的关键机制探讨[J]. 体育科学(Qian Shuai-Wei, Sun Yi, Qi Zheng-Tang, et al. A review on the regulation of mitochondrial homeostasis controlled by exercise—the key mechanism of exercise-mediated transcription factor EB in regulation of mitochondrial quality control[J]. Chin Sport Sci),2020,40(2):70-82
