Vi sinh vật đường ruột và sự đóng góp chuyển hóa của chúng đối với bệnh tiểu đường type 2 và béo phì

Journal of Diabetes & Metabolic Disorders - Tập 20 - Trang 1855-1870 - 2021
A. L. Cunningham1,2, J. W. Stephens1,2, D. A. Harris1
1Department of Surgery, Swansea Bay University Health Board, Singleton Hospital, Swansea, UK
2School of Medicine, Swansea University Medical School, Swansea University, Institute of Life Science 2, Swansea, UK

Tóm tắt

Béo phì và bệnh tiểu đường type 2 (T2DM) là những rối loạn chuyển hóa mãn tính phổ biến, có liên quan đến những vấn đề sức khỏe lâu dài đáng kể ở mức độ dịch tễ toàn cầu. Các vi sinh vật đường ruột được công nhận là đóng vai trò trung tâm trong việc duy trì sự cân bằng của vật chủ; và thông qua sự tiến bộ trong công nghệ ở cả mô hình động vật và con người, ngày càng rõ ràng rằng vi sinh vật đường ruột có liên quan mạnh mẽ đến các vai trò sinh bệnh chính trong nguyên nhân và sự tiến triển của cả hai tình trạng này. Bài tổng quan này sẽ tập trung vào những hiểu biết hiện tại về sự tương tác của vi sinh vật với axit béo chuỗi ngắn, phản ứng viêm của vật chủ, các con đường tín hiệu, tính toàn vẹn của hàng rào ruột, sự tương tác giữa trục ruột não và tác động tiếp theo đối với sức khỏe chuyển hóa của vật chủ.

Từ khóa

#béo phì #bệnh tiểu đường type 2 #vi sinh vật đường ruột #axit béo chuỗi ngắn #phản ứng viêm #trục ruột não

Tài liệu tham khảo

Obesity and overweight. World Health Organisation; 2018–02–09. Available from: http://www.who.int/mediacentre/factsheets/fs311/en. Accessed 01 March 2021. Power ML, Schulkin J. The evolution of obesity. Baltimore, MD: The Johns Hopkins University Press; 2009 International Diabetes Federation. IDF Diabetes Atlas, Ninth Edition 2019 (IDF, 2019). https://www.diabetesatlas.org/en. Accessed 01 March 2021 World Health Organisation. Global Report on Diabetes (WHO, 2016). https://www.who.int/publications/i/item/9789241565257. Accessed 01 March 2021. United Nations General Assembly. Political declaration of the high-level meeting of the general assembly on the prevention and control of non-communicable diseases (UN, 2012). https://www.who.int/nmh/events/un_ncd_summit2011/political_declaration_en.pdf. Accessed 01 March 2021. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33 Suppl 1(Suppl 1):S62-S69. https://doi.org/10.2337/dc10-S062 Ma R, Chan J. Metabolic complications of obesity. In: Williams G, Fruhbeck G, eds. Obesity: Science to Practice. John Wiley & Sons Ltd, 2009: 235–270 Bommer C, Sagalova V, Heesemann E, et al. Global Economic Burden of Diabetes in Adults: Projections From 2015 to 2030. Diabetes Care. 2018;41(5):963–970. https://doi.org/10.2337/dc17-1962 Aydin Ö, Nieuwdorp M, Gerdes V. The gut microbiome as a target for the treatment of type 2 diabetes. Curr Diab Rep. 2018;18(8):55. https://doi.org/10.1007/s11892-018-1020-6 Lederberg J. Infectious history. Science. 2000;288(5464):287–293. https://doi.org/10.1126/science.288.5464.287 Bested AC, Logan AC, Selhub EM. Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: Part I - autointoxication revisited. Gut Pathog. 2013;5(1):5. https://doi.org/10.1186/1757-4749-5-5 Lederberg J, McCray A. "Ome SweetOmics--A genealogical treasury of words." The scientist. 2001;15.7: 8–8. Gill SR, Pop M, Deboy RT, et al. Metagenomic analysis of the human distal gut microbiome. Science. 2006;312(5778):1355–1359. https://doi.org/10.1126/science.1124234 Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59–65. https://doi.org/10.1038/nature08821 O'Hara AM, Shanahan F. The gut flora as a forgotten organ. EMBO Rep. 2006;7(7):688–693. https://doi.org/10.1038/sj.embor.7400731 D'Argenio V. Human microbiome acquisition and bioinformatic challenges in metagenomic studies. Int J Mol Sci. 2018;19(2):383. https://doi.org/10.3390/ijms19020383 Jovel J, Patterson J, Wang W, et al. Characterization of the gut microbiome using 16S or shotgun metagenomics. Front Microbiol. 2016;7:459. https://doi.org/10.3389/fmicb.2016.00459 Harsch IA, Konturek PC. The role of gut microbiota in obesity and type 2 and type 1 diabetes mellitus: new insights into "Old" Diseases. Med Sci (Basel). 2018;6(2):32. https://doi.org/10.3390/medsci6020032 Hooper LV, Midtvedt T, Gordon JI. How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu Rev Nutr. 2002;22:283–307. https://doi.org/10.1146/annurev.nutr.22.011602.092259 Nicholson JK, Holmes E, Wilson ID. Gut microorganisms, mammalian metabolism and personalized health care. Nat Rev Microbiol. 2005;3(5):431–438. https://doi.org/10.1038/nrmicro1152 Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature. 2007;449(7164):804–810. https://doi.org/10.1038/nature06244 Delzenne NM, Cani PD. Gut microbiota and the pathogenesis of insulin resistance. Curr Diab Rep. 2011;11(3):154–159. https://doi.org/10.1007/s11892-011-0191-1 Kootte RS, Vrieze A, Holleman F, et al. The therapeutic potential of manipulating gut microbiota in obesity and type 2 diabetes mellitus. Diabetes Obes Metab. 2012;14(2):112–120. https://doi.org/10.1111/j.1463-1326.2011.01483.x Blaut M. Ecology and physiology of the intestinal tract. Curr Top Microbiol Immunol. 2013;358:247–272. https://doi.org/10.1007/82_2011_192 Scheithauer TP, Dallinga-Thie GM, de Vos WM, Nieuwdorp M, van Raalte DH. Causality of small and large intestinal microbiota in weight regulation and insulin resistance. Mol Metab. 2016;5(9):759–770. https://doi.org/10.1016/j.molmet.2016.06.002 :Meijnikman AS, Gerdes VE, Nieuwdorp M, Herrema H. Evaluating causality of gut microbiota in obesity and diabetes in humans. Endocr Rev. 2018;39(2):133–153. https://doi.org/10.1210/er.2017-00192 Saad MJ, Santos A, Prada PO. Linking gut microbiota and inflammation to obesity and insulin resistance. Physiology (Bethesda). 2016;31(4):283–293. https://doi.org/10.1152/physiol.00041.2015 Falony G, Joossens M, Vieira-Silva S, et al. Population-level analysis of gut microbiome variation. Science. 2016;352(6285):560–564. https://doi.org/10.1126/science.aad3503 Murphy EF, Cotter PD, Healy S, et al. Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models. Gut. 2010;59(12):1635–1642. https://doi.org/10.1136/gut.2010.215665 Brown K, DeCoffe D, Molcan E, Gibson DL. Diet-induced dysbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients. 2012;4(8):1095–1119. https://doi.org/10.3390/nu4081095 Guarner F, Malagelada JR. Gut flora in health and disease. Lancet. 2003;361(9356):512–519. https://doi.org/10.1016/S0140-6736(03)12489-0 Clemente JC, Ursell LK, Parfrey LW, Knight R. The impact of the gut microbiota on human health: an integrative view. Cell. 2012;148(6):1258–1270. https://doi.org/10.1016/j.cell.2012.01.035 Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI. Human nutrition, the gut microbiome and the immune system. Nature. 2011;474(7351):327–336. https://doi.org/10.1038/nature10213 Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. N Engl J Med. 2016;375(24):2369–2379. https://doi.org/10.1056/NEJMra1600266 Wong JM, de Souza R, Kendall CW, Emam A, Jenkins DJ. Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol. 2006;40(3):235–243. https://doi.org/10.1097/00004836-200603000-00015 Bäckhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism in the human intestine. Science. 2005;307(5717):1915–1920. https://doi.org/10.1126/science.1104816 Koliwad SK, Kuo T, Shipp LE, et al. Angiopoietin-like 4 (ANGPTL4, fasting-induced adipose factor) is a direct glucocorticoid receptor target and participates in glucocorticoid-regulated triglyceride metabolism. J Biol Chem. 2009;284(38):25593–25601. https://doi.org/10.1074/jbc.M109.025452 Sohail MU, Althani A, Anwar H, Rizzi R, Marei HE. Role of the gastrointestinal tract microbiome in the pathophysiology of diabetes mellitus. J Diabetes Res. 2017;2017:9631435. https://doi.org/10.1155/2017/9631435 Singer-Englar T, Barlow G, Mathur R. Obesity, diabetes, and the gut microbiome: an updated review. Expert Rev Gastroenterol Hepatol. 2019;13(1):3–15. https://doi.org/10.1080/17474124.2019.1543023 Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol. 2016;16(6):341–352. https://doi.org/10.1038/nri.2016.42 Baothman OA, Zamzami MA, Taher I, Abubaker J, Abu-Farha M. The role of gut microbiota in the development of obesity and diabetes. Lipids Health Dis. 2016;15:108. https://doi.org/10.1186/s12944-016-0278-4 Komaroff AL. The microbiome and risk for obesity and diabetes. JAMA. 2017;317(4):355–356. https://doi.org/10.1001/jama.2016.20099 Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol. 2015;11(10):577–591. https://doi.org/10.1038/nrendo.2015.128 Roy CC, Kien CL, Bouthillier L, Levy E. Short-chain fatty acids: ready for prime time?. Nutr Clin Pract. 2006;21(4):351–366. https://doi.org/10.1177/0115426506021004351 Khan MT, Nieuwdorp M, Bäckhed F. Microbial modulation of insulin sensitivity. Cell Metab. 2014;20(5):753–760. https://doi.org/10.1016/j.cmet.2014.07.006 Krajmalnik-Brown R, Ilhan ZE, Kang DW, DiBaise JK. Effects of gut microbes on nutrient absorption and energy regulation. Nutr Clin Pract. 2012;27(2):201–214. https://doi.org/10.1177/0884533611436116 Bauchop T, Mountfort DO. Cellulose fermentation by a rumen anaerobic fungus in both the absence and the presence of rumen methanogens. Appl Environ Microbiol. 1981;42(6):1103–1110. https://doi.org/10.1128/AEM.42.6.1103-1110.1981 Rosenbaum M, Knight R, Leibel RL. The gut microbiota in human energy homeostasis and obesity. Trends Endocrinol Metab. 2015;26(9):493–501. https://doi.org/10.1016/j.tem.2015.07.002 Bergman EN. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol Rev. 1990;70(2):567–590. https://doi.org/10.1152/physrev.1990.70.2.567 Shanahan F. The host-microbe interface within the gut. Best Pract Res Clin Gastroenterol. 2002;16(6):915–931. https://doi.org/10.1053/bega.2002.0342 Macfarlane GT, Macfarlane S. Bacteria, colonic fermentation, and gastrointestinal health. J AOAC Int. 2012;95(1):50–60. https://doi.org/10.5740/jaoacint.sge_macfarlane Willemsen LE, Koetsier MA, van Deventer SJ, van Tol EA. Short chain fatty acids stimulate epithelial mucin 2 expression through differential effects on prostaglandin E(1) and E(2) production by intestinal myofibroblasts. Gut. 2003;52(10):1442–1447. https://doi.org/10.1136/gut.52.10.1442 Feuerer M, Herrero L, Cipolletta D, et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med. 2009;15(8):930–939. https://doi.org/10.1038/nm.2002 Kim M, Qie Y, Park J, Kim CH. Gut microbial metabolites fuel host antibody responses. Cell Host Microbe. 2016;20(2):202–214. https://doi.org/10.1016/j.chom.2016.07.001 Ohira H, Tsutsui W, Fujioka Y. Are short chain fatty acids in gut microbiota defensive players for inflammation and atherosclerosis?. J Atheroscler Thromb. 2017;24(7):660–672. https://doi.org/10.5551/jat.RV17006 Belzer C, de Vos WM. Microbes inside--from diversity to function: the case of Akkermansia. ISME J. 2012;6(8):1449–1458. https://doi.org/10.1038/ismej.2012.6 Le Poul E, Loison C, Struyf S, et al. Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem. 2003;278(28):25481–25489. https://doi.org/10.1074/jbc.M301403200 Husted AS, Trauelsen M, Rudenko O, Hjorth SA, Schwartz TW. GPCR-Mediated Signaling of Metabolites. Cell Metab. 2017;25(4):777–796. https://doi.org/10.1016/j.cmet.2017.03.008 Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer RJ. Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther. 2008;27(2):104–119. https://doi.org/10.1111/j.1365-2036.2007.03562.x Mandøe MJ, Hansen KB, Hartmann B, Rehfeld JF, Holst JJ, Hansen HS. The 2-monoacylglycerol moiety of dietary fat appears to be responsible for the fat-induced release of GLP-1 in humans. Am J Clin Nutr. 2015;102(3):548–555. https://doi.org/10.3945/ajcn.115.106799 Ahmed K, Tunaru S, Offermanns S. GPR109A, GPR109B and GPR81, a family of hydroxy-carboxylic acid receptors. Trends Pharmacol Sci. 2009;30(11):557–562. https://doi.org/10.1016/j.tips.2009.09.001 Brown AJ, Goldsworthy SM, Barnes AA, et al. The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem. 2003;278(13):11312–11319. https://doi.org/10.1074/jbc.M211609200 Karaki S, Tazoe H, Hayashi H, et al. Expression of the short-chain fatty acid receptor, GPR43, in the human colon. J Mol Histol. 2008;39(2):135–142. https://doi.org/10.1007/s10735-007-9145-y Xiong Y, Miyamoto N, Shibata K, et al. Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proc Natl Acad Sci U S A. 2004;101(4):1045–1050. https://doi.org/10.1073/pnas.2637002100 Samuel BS, Shaito A, Motoike T, et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc Natl Acad Sci U S A. 2008;105(43):16767–16772. https://doi.org/10.1073/pnas.0808567105 Tazoe H, Otomo Y, Kaji I, Tanaka R, Karaki SI, Kuwahara A. Roles of short-chain fatty acids receptors, GPR41 and GPR43 on colonic functions. J Physiol Pharmacol. 2008;59 Suppl 2:251–262. 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. Diabetes. 2012;61(2):364–371. https://doi.org/10.2337/db11-1019 Amato A, Cinci L, Rotondo A, et al. Peripheral motor action of glucagon-like peptide-1 through enteric neuronal receptors. Neurogastroenterol Motil. 2010;22(6):664-e203. https://doi.org/10.1111/j.1365-2982.2010.01476.x Ge H, Li X, Weiszmann J, et al. Activation of G protein-coupled receptor 43 in adipocytes leads to inhibition of lipolysis and suppression of plasma free fatty acids. Endocrinology. 2008;149(9):4519–4526. https://doi.org/10.1210/en.2008-0059 Zhao Y, Chen F, Wu W, et al. GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3. Mucosal Immunol. 2018;11(3):752–762. https://doi.org/10.1038/mi.2017.118 Kim MH, Kang SG, Park JH, Yanagisawa M, Kim CH. Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology. 2013;145(2). https://doi.org/10.1053/j.gastro.2013.04.056 Kimura I, Ozawa K, Inoue D, et al. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun. 2013;4:1829. https://doi.org/10.1038/ncomms2852 Cresci GA, Thangaraju M, Mellinger JD, Liu K, Ganapathy V. Colonic gene expression in conventional and germ-free mice with a focus on the butyrate receptor GPR109A and the butyrate transporter SLC5A8. J Gastrointest Surg. 2010;14(3):449–461. https://doi.org/10.1007/s11605-009-1045-x Singh N, Gurav A, Sivaprakasam S, et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity. 2014;40(1):128–139. https://doi.org/10.1016/j.immuni.2013.12.007 Samuel BS, Gordon JI. A humanized gnotobiotic mouse model of host-archaeal-bacterial mutualism. Proc Natl Acad Sci U S A. 2006;103(26):10011–10016. https://doi.org/10.1073/pnas.0602187103 Cook SI, Sellin JH. Review article: short chain fatty acids in health and disease. Aliment Pharmacol Ther. 1998;12(6):499–507. https://doi.org/10.1046/j.1365-2036.1998.00337.x Frost G, Sleeth ML, Sahuri-Arisoylu M, et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat Commun. 2014;5:3611. https://doi.org/10.1038/ncomms4611 Perry RJ, Peng L, Barry NA, et al. Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome. Nature. 2016;534(7606):213–217. https://doi.org/10.1038/nature18309 Topping DL, Clifton PM. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiol Rev. 2001;81(3):1031–1064. https://doi.org/10.1152/physrev.2001.81.3.1031 De Vadder F, Kovatcheva-Datchary P, Goncalves D, et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell. 2014;156(1–2):84–96. https://doi.org/10.1016/j.cell.2013.12.016 Lazarova DL, Chiaro C, Wong T, et al. CBP activity mediates effects of the histone deacetylase inhibitor butyrate on WNT activity and apoptosis in colon cancer cells. J Cancer. 2013;4(6):481–490. https://doi.org/10.7150/jca.6583 Kelly CJ, Zheng L, Campbell EL, et al. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe. 2015;17(5):662–671. https://doi.org/10.1016/j.chom.2015.03.005 Maslowski KM, Vieira AT, Ng A, et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009;461(7268):1282–1286. https://doi.org/10.1038/nature08530 Martin FP, Wang Y, Sprenger N, et al. Probiotic modulation of symbiotic gut microbial-host metabolic interactions in a humanized microbiome mouse model. Mol Syst Biol. 2008;4:157. https://doi.org/10.1038/msb4100190 Donohoe DR, Garge N, Zhang X, et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 2011;13(5):517–526. https://doi.org/10.1016/j.cmet.2011.02.018 Davie JR. Inhibition of histone deacetylase activity by butyrate. J Nutr. 2003;133(7 Suppl):2485S-2493S. https://doi.org/10.1093/jn/133.7.2485S Chang PV, Hao L, Offermanns S, Medzhitov R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci U S A. 2014;111(6):2247–2252. https://doi.org/10.1073/pnas.1322269111 Venter CS, Vorster HH, Cummings JH. Effects of dietary propionate on carbohydrate and lipid metabolism in healthy volunteers. Am J Gastroenterol. 1990;85(5):549–553. Baird GD, Lomax MA, Symonds HW, Shaw SR. Net hepatic and splanchnic metabolism of lactate, pyruvate and propionate in dairy cows in vivo in relation to lactation and nutrient supply. Biochem J. 1980;186(1):47–57. https://doi.org/10.1042/bj1860047 Al-Lahham SH, Peppelenbosch MP, Roelofsen H, Vonk RJ, Venema K. Biological effects of propionic acid in humans; metabolism, potential applications and underlying mechanisms. Biochim Biophys Acta. 2010;1801(11):1175–1183. https://doi.org/10.1016/j.bbalip.2010.07.007 Foley JE. Rationale and application of fatty acid oxidation inhibitors in treatment of diabetes mellitus. Diabetes Care. 1992;15(6):773–784. https://doi.org/10.2337/diacare.15.6.773 Alhabeeb H, Chambers ES, Frost G, Morrison DJ, Preston T. Inulin propionate ester increases satiety and decreases appetite but does not affect gastric emptying in healthy humans. Proceedings of the Nutrition Society. 2014;73(OCE1). Mortensen PB, Clausen MR. Short-chain fatty acids in the human colon: relation to gastrointestinal health and disease. Scand J Gastroenterol Suppl. 1996;216:132–148. https://doi.org/10.3109/00365529609094568 Dai ZL, Wu G, Zhu WY. Amino acid metabolism in intestinal bacteria: links between gut ecology and host health. Front Biosci (Landmark Ed). 2011;16:1768–1786. https://doi.org/10.2741/3820 Macfarlane GT, Allison C, Gibson SA, Cummings JH. Contribution of the microflora to proteolysis in the human large intestine. J Appl Bacteriol. 1988;64(1):37–46. https://doi.org/10.1111/j.1365-2672.1988.tb02427.x De Vadder F, Kovatcheva-Datchary P, Zitoun C, Duchampt A, Bäckhed F, Mithieux G. Microbiota-Produced Succinate Improves Glucose Homeostasis via Intestinal Gluconeogenesis. Cell Metab. 2016;24(1):151–157. https://doi.org/10.1016/j.cmet.2016.06.013 Pedersen HK, Gudmundsdottir V, Nielsen HB, et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature. 2016;535(7612):376–381. https://doi.org/10.1038/nature18646 Wang TJ, Larson MG, Vasan RS, et al. Metabolite profiles and the risk of developing diabetes. Nat Med. 2011;17(4):448–453. https://doi.org/10.1038/nm.2307 de Mello VD, Paananen J, Lindström J, et al. Indolepropionic acid and novel lipid metabolites are associated with a lower risk of type 2 diabetes in the Finnish Diabetes Prevention Study. Sci Rep. 2017;7:46337. https://doi.org/10.1038/srep46337 Chimerel C, Emery E, Summers DK, Keyser U, Gribble FM, Reimann F. Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells. Cell Rep. 2014;9(4):1202–1208. https://doi.org/10.1016/j.celrep.2014.10.032 Gribble FM, Reimann F. Function and mechanisms of enteroendocrine cells and gut hormones in metabolism. Nat Rev Endocrinol. 2019;15(4):226–237. https://doi.org/10.1038/s41574-019-0168-8 Koh A, Molinaro A, Ståhlman M, et al. Microbially produced imidazole propionate impairs insulin signaling through mTORC1. Cell. 2018;175(4):947–961.e17. https://doi.org/10.1016/j.cell.2018.09.055 Thomas C, Gioiello A, Noriega L, et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 2009;10(3):167–177. https://doi.org/10.1016/j.cmet.2009.08.001 Nicholson JK, Holmes E, Kinross J, et al. Host-gut microbiota metabolic interactions. Science. 2012;336(6086):1262–1267. https://doi.org/10.1126/science.1223813 Swann JR, Want EJ, Geier FM, et al. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc Natl Acad Sci U S A. 2011;108 Suppl 1(Suppl 1):4523–4530. https://doi.org/10.1073/pnas.1006734107 Shapiro H, Kolodziejczyk AA, Halstuch D, Elinav E. Bile acids in glucose metabolism in health and disease. J Exp Med. 2018;215(2):383–396. https://doi.org/10.1084/jem.20171965 Kir S, Beddow SA, Samuel VT, et al. FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science. 2011;331(6024):1621–1624. https://doi.org/10.1126/science.1198363 Cicione C, Degirolamo C, Moschetta A. Emerging role of fibroblast growth factors 15/19 and 21 as metabolic integrators in the liver. Hepatology. 2012;56(6):2404–2411. https://doi.org/10.1002/hep.25929 Potthoff MJ, Kliewer SA, Mangelsdorf DJ. Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes Dev. 2012;26(4):312–324. https://doi.org/10.1101/gad.184788.111 Lazar V, Ditu LM, Pircalabioru GG, et al. Gut microbiota, host organism, and diet trialogue in diabetes and obesity. Front Nutr. 2019;6:21. https://doi.org/10.3389/fnut.2019.00021 Sayin SI, Wahlström A, Felin J, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 2013;17(2):225–235. https://doi.org/10.1016/j.cmet.2013.01.003 Watanabe M, Houten SM, Mataki C, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439(7075):484–489. https://doi.org/10.1038/nature04330 Hartmann P, Chen P, Wang HJ, et al. Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice. Hepatology. 2013;58(1):108–119. https://doi.org/10.1002/hep.26321 Everard A, Cani PD. Diabetes, obesity and gut microbiota. Best Pract Res Clin Gastroenterol. 2013;27(1):73–83. https://doi.org/10.1016/j.bpg.2013.03.007 Tomasova L, Konopelski P, Ufnal M. Gut Bacteria and Hydrogen sulfide: the new old players in circulatory system homeostasis. Molecules. 2016;21(11):1558. https://doi.org/10.3390/molecules21111558 Derrien M, Van Baarlen P, Hooiveld G, Norin E, Müller M, de Vos WM. Modulation of mucosal immune response, tolerance, and proliferation in mice colonized by the mucin-degrader akkermansia muciniphila. Front Microbiol. 2011;2:166. https://doi.org/10.3389/fmicb.2011.00166 Everard A, Belzer C, Geurts L, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013;110(22):9066–9071. https://doi.org/10.1073/pnas.1219451110 Wang HB, Wang PY, Wang X, Wan YL, Liu YC. Butyrate enhances intestinal epithelial barrier function via up-regulation of tight junction protein Claudin-1 transcription. Dig Dis Sci. 2012;57(12):3126–3135. https://doi.org/10.1007/s10620-012-2259-4 Burger-van Paassen N, Vincent A, Puiman PJ, et al. The regulation of intestinal mucin MUC2 expression by short-chain fatty acids: implications for epithelial protection. Biochem J. 2009;420(2):211–219. https://doi.org/10.1042/BJ20082222 Muccioli GG, Naslain D, Bäckhed F, et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol. 2010;6:392. https://doi.org/10.1038/msb.2010.46 Cani PD, Osto M, Geurts L, Everard A. Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity. Gut Microbes. 2012;3(4):279–288. https://doi.org/10.4161/gmic.19625 Cani PD, Possemiers S, Van de Wiele T, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut. 2009;58(8):1091–1103. https://doi.org/10.1136/gut.2008.165886 Brun P, Castagliuolo I, Di Leo V, et al. Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol. 2007;292(2):G518-G525. https://doi.org/10.1152/ajpgi.00024.2006 Hansen J, Gulati A, Sartor RB. The role of mucosal immunity and host genetics in defining intestinal commensal bacteria. Curr Opin Gastroenterol. 2010;26(6):564–571. https://doi.org/10.1097/MOG.0b013e32833f1195 Kashyap PC, Marcobal A, Ursell LK, et al. Complex interactions among diet, gastrointestinal transit, and gut microbiota in humanized mice. Gastroenterology. 2013;144(5):967–977. https://doi.org/10.1053/j.gastro.2013.01.047 Fukumoto S, Tatewaki M, Yamada T, et al. Short-chain fatty acids stimulate colonic transit via intraluminal 5-HT release in rats. Am J Physiol Regul Integr Comp Physiol. 2003;284(5):R1269-R1276. https://doi.org/10.1152/ajpregu.00442.2002 Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol. 2004;25(1):4–7. https://doi.org/10.1016/j.it.2003.10.013 Reyes M, Quintanilla C, Burrows R, Blanco E, Cifuentes M, Gahagan S. Obesity is associated with acute inflammation in a sample of adolescents. Pediatr Diabetes. 2015;16(2):109–116. https://doi.org/10.1111/pedi.12129 Delzenne NM, Cani PD, Everard A, Neyrinck AM, Bindels LB. Gut microorganisms as promising targets for the management of type 2 diabetes. Diabetologia. 2015;58(10):2206–2217. https://doi.org/10.1007/s00125-015-3712-7 Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259(5091):87–91. https://doi.org/10.1126/science.7678183 Ley RE. Obesity and the human microbiome. Curr Opin Gastroenterol. 2010;26(1):5–11. https://doi.org/10.1097/MOG.0b013e328333d751 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):1470–1481. https://doi.org/10.2337/db07-1403 Cani PD, Neyrinck AM, Fava F, et al. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia. 2007;50(11):2374–2383. https://doi.org/10.1007/s00125-007-0791-0 Lindberg AA, Weintraub A, Zähringer U, Rietschel ET. Structure-activity relationships in lipopolysaccharides of Bacteroides fragilis. Rev Infect Dis. 1990;12 Suppl 2:S133-S141. https://doi.org/10.1093/clinids/12.supplement_2.s133 Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56(7):1761–1772. https://doi.org/10.2337/db06-1491 Zhao L. The gut microbiota and obesity: from correlation to causality. Nat Rev Microbiol. 2013;11(9):639–647. https://doi.org/10.1038/nrmicro3089 Chen X, Devaraj S. Gut microbiome in obesity, metabolic syndrome, and diabetes. Curr Diab Rep. 2018;18(12):129. https://doi.org/10.1007/s11892-018-1104-3 Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004;118(2):229–241. https://doi.org/10.1016/j.cell.2004.07.002 Rui L, Yuan M, Frantz D, Shoelson S, White MF. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J Biol Chem. 2002;277(44):42394–42398. https://doi.org/10.1074/jbc.C200444200 Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, et al. Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes. 2007;56(8):1986–1998. https://doi.org/10.2337/db06-1595 Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006;116(11):3015–3025. https://doi.org/10.1172/JCI28898 Li X, Watanabe K, Kimura I. Gut microbiota dysbiosis drives and implies novel therapeutic strategies for diabetes mellitus and related metabolic diseases. Front Immunol. 2017;8:1882. https://doi.org/10.3389/fimmu.2017.01882 de Lartigue G, Barbier de la Serre C, Espero E, Lee J, Raybould HE. Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons. Am J Physiol Endocrinol Metab. 2011;301(1):E187-E195. https://doi.org/10.1152/ajpendo.00056.2011 Raybould HE. Gut microbiota, epithelial function and derangements in obesity. J Physiol. 2012;590(3):441–446. https://doi.org/10.1113/jphysiol.2011.222133 O'Mahony D, Murphy S, Boileau T, et al. Bifidobacterium animalis AHC7 protects against pathogen-induced NF-κB activation in vivo. BMC Immunol. 2010;11:63. https://doi.org/10.1186/1471-2172-11-63 Amar J, Chabo C, Waget A, et al. Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment. EMBO Mol Med. 2011;3(9):559–572. https://doi.org/10.1002/emmm.201100159 Jernberg C, Löfmark S, Edlund C, Jansson JK. Long-term ecological impacts of antibiotic administration on the human intestinal microbiota. ISME J. 2007;1(1):56–66. https://doi.org/10.1038/ismej.2007.3 Modi SR, Collins JJ, Relman DA. Antibiotics and the gut microbiota. J Clin Invest. 2014;124(10):4212–4218. https://doi.org/10.1172/JCI72333 Rasmussen SH, Shrestha S, Bjerregaard LG, et al. Antibiotic exposure in early life and childhood overweight and obesity: A systematic review and meta-analysis. Diabetes Obes Metab. 2018;20(6):1508–1514. https://doi.org/10.1111/dom.13230 Mikkelsen KH, Knop FK, Frost M, Hallas J, Pottegård A. Use of antibiotics and risk of type 2 diabetes: a population-based case-control study. J Clin Endocrinol Metab. 2015;100(10):3633–3640. https://doi.org/10.1210/jc.2015-2696 Vrieze A, Out C, Fuentes S, et al. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. J Hepatol. 2014;60(4):824–831. https://doi.org/10.1016/j.jhep.2013.11.034 de Clercq NC, Frissen MN, Groen AK, Nieuwdorp M. Gut microbiota and the gut-brain axis: new insights in the pathophysiology of metabolic syndrome. Psychosom Med. 2017;79(8):874–879. https://doi.org/10.1097/PSY.0000000000000495 Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13(10):701–712. https://doi.org/10.1038/nrn3346 Torres-Fuentes C, Schellekens H, Dinan TG, Cryan JF. The microbiota-gut-brain axis in obesity. Lancet Gastroenterol Hepatol. 2017;2(10):747–756. https://doi.org/10.1016/S2468-1253(17)30147-4 Heiss CN, Olofsson LE. Gut microbiota-dependent modulation of energy metabolism. J Innate Immun. 2018;10(3):163–171. https://doi.org/10.1159/000481519 De Silva A, Bloom SR. Gut hormones and appetite control: a focus on PYY and GLP-1 as therapeutic targets in obesity. Gut Liver. 2012;6(1):10–20. https://doi.org/10.5009/gnl.2012.6.1.10 Savage AP, Adrian TE, Carolan G, Chatterjee VK, Bloom SR. Effects of peptide YY (PYY) on mouth to caecum intestinal transit time and on the rate of gastric emptying in healthy volunteers. Gut. 1987;28(2):166–170. https://doi.org/10.1136/gut.28.2.166 Murphy KG, Bloom SR. Gut hormones and the regulation of energy homeostasis. Nature. 2006;444(7121):854–859. https://doi.org/10.1038/nature05484 Näslund E, Bogefors J, Skogar S, et al. GLP-1 slows solid gastric emptying and inhibits insulin, glucagon, and PYY release in humans. Am J Physiol. 1999;277(3):R910-R916. https://doi.org/10.1152/ajpregu.1999.277.3.R910