Review Article | Published:

Gut microbial metabolites in obesity, NAFLD and T2DM

Nature Reviews Endocrinology (2019) | Download Citation

Abstract

Evidence is accumulating that the gut microbiome is involved in the aetiology of obesity and obesity-related complications such as nonalcoholic fatty liver disease (NAFLD), insulin resistance and type 2 diabetes mellitus (T2DM). The gut microbiota is able to ferment indigestible carbohydrates (for example, dietary fibre), thereby yielding important metabolites such as short-chain fatty acids and succinate. Numerous animal studies and a handful of human studies suggest a beneficial role of these metabolites in the prevention and treatment of obesity and its comorbidities. Interestingly, the more distal colonic microbiota primarily ferments peptides and proteins, as availability of fermentable fibre, the major energy source for the microbiota, is limited here. This proteolytic fermentation yields mainly harmful products such as ammonia, phenols and branched-chain fatty acids, which might be detrimental for host gut and metabolic health. Therefore, a switch from proteolytic to saccharolytic fermentation could be of major interest for the prevention and/or treatment of metabolic diseases. This Review focuses on the role of products derived from microbial carbohydrate and protein fermentation in relation to obesity and obesity-associated insulin resistance, T2DM and NAFLD, and discusses the mechanisms involved.

Key points

  • Gut microbial metabolites such as short-chain fatty acids (SCFAs) and succinate, which are derived from the fermentation of dietary fibre, have important metabolic functions.

  • SCFAs and succinate might prevent obesity by increasing energy expenditure, increasing anorexic hormone production and improving appetite regulation.

  • SCFAs have a crucial role in gut homeostasis, adipose tissue and liver substrate metabolism and function, through which they can prevent the progression of type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD).

  • The site of microbial SCFA production in the colon might be an important determinant for the aforementioned beneficial effects.

  • The microbial metabolites derived from protein fermentation, which are mainly produced in the distal colon, are most often considered detrimental for gut integrity and metabolic health.

  • Providing mixtures of dietary fibres to increase distal colonic microbial carbohydrate fermentation and thereby inhibit protein fermentation might be a putative target to ameliorate obesity, T2DM and NAFLD.

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References

  1. 1.

    World Health Organization. Obesity and overweight. WHO http://www.who.int/mediacentre/factsheets/fs311/en/ (2018).

  2. 2.

    Younossi, Z. M. et al. Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64, 73–84 (2016).

  3. 3.

    Zheng, Y., Ley, S. & Hu, F. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat. Rev. Endocrinol. 14, 88–98 (2017).

  4. 4.

    Seuring, T., Archangelidi, O. & Suhrcke, M. The economic costs of type 2 diabetes: a global systematic review. Pharmacoeconomics 33, 811–831 (2015).

  5. 5.

    Tremmel, M., Gerdtham, U.-G., Nilsson, P. M. & Saha, S. Economic burden of obesity: a systematic literature review. Int. J. Environ. Res. Public Health 14, E435 (2017).

  6. 6.

    Corpeleijn, E., Saris, W. & Blaak, E. Metabolic flexibility in the development of insulin resistance and type 2 diabetes: effects of lifestyle. Obes. Rev. 10, 178–193 (2009).

  7. 7.

    Shulman, G. I. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N. Engl. J. Med. 371, 1131–1141 (2014).

  8. 8.

    Reilly, S. M. & Saltiel, A. R. Adapting to obesity with adipose tissue inflammation. Nat. Rev. Endocrinol. 13, 633–343 (2017).

  9. 9.

    Stinkens, R., Goossens, G. H., Jocken, J. W. & Blaak, E. E. Targeting fatty acid metabolism to improve glucose metabolism. Obes. Rev. 16, 715–757 (2015).

  10. 10.

    Bäckhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004).

  11. 11.

    Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).

  12. 12.

    Le Chatelier, E. et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541–546 (2013).

  13. 13.

    Dao, M. C. et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut 65, 426–436 (2016).

  14. 14.

    Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).

  15. 15.

    Cani, P. D. et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57, 1470–1478 (2008).

  16. 16.

    Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).

  17. 17.

    Zhao, L. et al. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science 359, 1151–1156 (2018).

  18. 18.

    Kovatcheva-Datchary, P. et al. Dietary fiber-induced improvement in glucose metabolism is associated with increased abundance of Prevotella. Cell Metab. 22, 971–982 (2015).

  19. 19.

    De Vadder, F. et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 156, 84–96 (2014).

  20. 20.

    Menni, C. et al. Gut microbiome diversity and high-fibre intake are related to lower long-term weight gain. Int. J. Obes. (Lond.) 41, 1099 (2017).

  21. 21.

    Cani, P. D., Joly, E., Horsmans, Y. & Delzenne, N. M. Oligofructose promotes satiety in healthy human: a pilot study. Eur. J. Clin. Nutr. 60, 567–572 (2006).

  22. 22.

    Canfora, E. E., Jocken, J. W. & Blaak, E. E. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat. Rev. Endocrinol. 11, 577–591 (2015).

  23. 23.

    Koh, A., De Vadder, F., Kovatcheva-Datchary, P. & Bäckhed, F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 165, 1332–1345 (2016).

  24. 24.

    den Besten, G. et al. Short-chain fatty acids protect against high-fat diet-induced obesity via a PPARγ-dependent switch from lipogenesis to fat oxidation. Diabetes 64, 2398–2408 (2015).

  25. 25.

    Frost, G. et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat. Commun. 5, 3611 (2014).

  26. 26.

    Lu, Y. et al. Short chain fatty acids prevent high-fat-diet-induced obesity in mice by regulating G protein-coupled receptors and gut microbiota. Sci. Rep. 6, 37589 (2016).

  27. 27.

    De Vadder, F. et al. Microbiota-produced succinate improves glucose homeostasis via intestinal gluconeogenesis. Cell Metab. 24, 151–157 (2016).

  28. 28.

    Mollica, M. P. et al. Butyrate regulates liver mitochondrial function, efficiency, and dynamics in insulin-resistant obese mice. Diabetes 66, 1405–1418 (2017).

  29. 29.

    Li, Z. et al. Butyrate reduces appetite and activates brown adipose tissue via the gut-brain neural circuit. Gut 67, 1269–1279 (2017).

  30. 30.

    Canfora, E. E. et al. Colonic infusions of short-chain fatty acid mixtures promote energy metabolism in overweight/obese men: a randomized crossover trial. Sci. Rep. 7, 2360 (2017).

  31. 31.

    Robertson, M. D., Bickerton, A. S., Dennis, A. L., Vidal, H. & Frayn, K. N. Insulin-sensitizing effects of dietary resistant starch and effects on skeletal muscle and adipose tissue metabolism. Am. J. Clin. Nutr. 82, 559–567 (2005).

  32. 32.

    Chambers, E. S. et al. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut 64, 1744–1754 (2015).

  33. 33.

    Chambers, E. S. et al. Acute oral sodium propionate supplementation raises resting energy expenditure and lipid oxidation in fasted humans. Diabetes Obes. Metab. 20, 1034–1039 (2018).

  34. 34.

    van der Beek, C. M. et al. Distal, not proximal, colonic acetate infusions promote fat oxidation and improve metabolic markers in overweight/obese men. Clin. Sci. 130, 2073–2082 (2016).

  35. 35.

    Bouter, K. et al. Differential metabolic effects of oral butyrate treatment in lean versus metabolic syndrome subjects. Clin. Transl Gastroenterol. 9, 155 (2018).

  36. 36.

    Windey, K., De Preter, V. & Verbeke, K. Relevance of protein fermentation to gut health. Mol. Nutr. Food Res. 56, 184–196 (2012).

  37. 37.

    Russell, W. R. et al. High-protein, reduced-carbohydrate weight-loss diets promote metabolite profiles likely to be detrimental to colonic health. Am. J. Clin. Nutr. 93, 1062–1072 (2011).

  38. 38.

    Wahlström, A., Sayin, S. I., Marschall, H.-U. & Bäckhed, F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 24, 41–50 (2016).

  39. 39.

    Sonnenburg, J. L. & Bäckhed, F. Diet–microbiota interactions as moderators of human metabolism. Nature 535, 56–64 (2016).

  40. 40.

    Cani, P. D., 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 3, 279–288 (2012).

  41. 41.

    Gilbert, J. A. et al. Current understanding of the human microbiome. Nat. Med. 24, 392–400 (2018).

  42. 42.

    Maier, L. et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 555, 623–628 (2018).

  43. 43.

    Schmidt, T. S., Raes, J. & Bork, P. The human gut microbiome: from association to modulation. Cell 172, 1198–1215 (2018).

  44. 44.

    Liu, R. et al. Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention. Nat. Med. 23, 859–868 (2017).

  45. 45.

    Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).

  46. 46.

    Wong, J. M., de Souza, R., Kendall, C. W., Emam, A. & Jenkins, D. J. Colonic health: fermentation and short chain fatty acids. J. Clin. Gastroenterol. 40, 235–243 (2006).

  47. 47.

    Cummings, J., Pomare, E., Branch, W., Naylor, C. & Macfarlane, G. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 28, 1221–1227 (1987).

  48. 48.

    Dodd, D. et al. A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Nature 551, 648–652 (2017).

  49. 49.

    Beaumont, M. et al. The gut microbiota metabolite indole alleviates liver inflammation in mice. FASEB J. 32, 6681–6693 (2018).

  50. 50.

    Okamoto, M. et al. Endogenous hydrogen sulfide protects pancreatic beta-cells from a high-fat diet-induced glucotoxicity and prevents the development of type 2 diabetes. Biochem. Biophys. Res. Commun. 442, 227–233 (2013).

  51. 51.

    Pedersen, H. K. et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 535, 376–381 (2016).

  52. 52.

    Venema, K. Microbial metabolites produced by the colonic microbiota as drivers for immunomodulation in the host. FASEB J. 27 (Suppl. 1), 643.12–643.13 (2013).

  53. 53.

    Pylkas, A. M., Juneja, L. R. & Slavin, J. L. Comparison of different fibers for in vitro production of short chain fatty acids by intestinal microflora. J. Med. Food 8, 113–116 (2005).

  54. 54.

    El Oufir, L. et al. Relationships between transit time in man and in vitro fermentation of dietary fiber by fecal bacteria. Eur. J. Clin. Nutr. 54, 603–609 (2000).

  55. 55.

    Serena, C. et al. Elevated circulating levels of succinate in human obesity are linked to specific gut microbiota. ISME J. 12, 1642–1657 (2018).

  56. 56.

    Bloemen, J. G. et al. Short chain fatty acids exchange: is the cirrhotic, dysfunctional liver still able to clear them? Clin. Nutr. 29, 365–369 (2010).

  57. 57.

    Bloemen, J. G. et al. Short chain fatty acids exchange across the gut and liver in humans measured at surgery. Clin. Nutr. 28, 657–661 (2009).

  58. 58.

    Boets, E. et al. Systemic availability and metabolism of colonic-derived short-chain fatty acids in healthy subjects: a stable isotope study. J. Physiol. 595, 541–555 (2017).

  59. 59.

    Neis, E. P. et al. Distal versus proximal intestinal short-chain fatty acid release in man. Gut https://doi.org/10.1136/gutjnl-2018-316161 (2018).

  60. 60.

    Swanson, K. S. et al. Fructooligosaccharides and Lactobacillus acidophilus modify bowel function and protein catabolites excreted by healthy humans. J. Nutr. 132, 3042–3050 (2002).

  61. 61.

    Pieper, R. et al. Fermentable fiber ameliorates fermentable protein-induced changes in microbial ecology, but not the mucosal response, in the colon of piglets. J. Nutr. 142, 661–667 (2012).

  62. 62.

    Geypens, B. A. et al. Influence of dietary protein supplements on the formation of bacterial metabolites in the colon. Gut 41, 70–76 (1997).

  63. 63.

    Macfarlane, G., Gibson, G. & Cummings, J. Comparison of fermentation reactions in different regions of the human colon. J. Appl. Bacteriol. 72, 57–64 (1992).

  64. 64.

    Tolhurst, G. et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61, 364–371 (2012).

  65. 65.

    Psichas, A. et al. The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int. J. Obes. (Lond.) 39, 424–429 (2015).

  66. 66.

    Reimer, R. A. et al. A human cellular model for studying the regulation of glucagon-like peptide-1 secretion. Endocrinology 142, 4522–4528 (2001).

  67. 67.

    Larraufie, P. et al. SCFAs strongly stimulate PYY production in human enteroendocrine cells. Sci. Rep. 8, 74 (2018).

  68. 68.

    Zhou, J. et al. Dietary resistant starch upregulates total GLP-1 and PYY in a sustained day-long manner through fermentation in rodents. Am. J. Physiol. Endocrinol. Metab. 295, E1160–E1166 (2008).

  69. 69.

    Forbes, S. et al. Selective FFA2 agonism appears to act via intestinal PYY to reduce transit and food intake but does not improve glucose tolerance in mouse models. Diabetes 64, 3763–3771 (2015).

  70. 70.

    Xiong, Y. et al. Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proc. Natl Acad. Sci. USA 101, 1045–1050 (2004).

  71. 71.

    Soliman, M. et al. Inverse regulation of leptin mRNA expression by short-and long-chain fatty acids in cultured bovine adipocytes. Domest. Anim. Endocrinol. 33, 400–409 (2007).

  72. 72.

    Al-Lahham, S. H. et al. Regulation of adipokine production in human adipose tissue by propionic acid. Eur. J. Clin. Invest. 40, 401–407 (2010).

  73. 73.

    Freeland, K. R. & Wolever, T. Acute effects of intravenous and rectal acetate on glucagon-like peptide-1, peptide YY, ghrelin, adiponectin and tumour necrosis factor-alpha. Br. J. Nutr. 103, 460–466 (2010).

  74. 74.

    Goswami, C., Iwasaki, Y. & Yada, T. Short-chain fatty acids suppress food intake by activating vagal afferent neurons. J. Nutr. Biochem. 57, 130–135 (2018).

  75. 75.

    Plamboeck, A. et al. The effect of exogenous GLP-1 on food intake is lost in male truncally vagotomized subjects with pyloroplasty. Am. J. Physiol. Gastrointest. Liver Physiol. 304, G1117–G1127 (2013).

  76. 76.

    Byrne, C. S. et al. Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods. Am. J. Clin. Nutr. 104, 5–14 (2016).

  77. 77.

    Gulanski, B. I. et al. Increased brain transport and metabolism of acetate in hypoglycemia unawareness. J. Clin. Endocrinol. Metab. 98, 3811–3820 (2013).

  78. 78.

    Gao, Z. et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 58, 1509–1517 (2009).

  79. 79.

    Sahuri-Arisoylu, M. et al. Reprogramming of hepatic fat accumulation and’browning’of adipose tissue by the short-chain fatty acid acetate. Int. J. Obes. (Lond.) 40, 955–963 (2016).

  80. 80.

    Kondo, T., Kishi, M., Fushimi, T. & Kaga, T. Acetic acid upregulates the expression of genes for fatty acid oxidation enzymes in liver to suppress body fat accumulation. J. Agr. Food Chem. 57, 5982–5986 (2009).

  81. 81.

    Schwiertz, A. et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity 18, 190–195 (2010).

  82. 82.

    Teixeira, T. F. et al. Higher level of faecal SCFA in women correlates with metabolic syndrome risk factors. Br. J. Nutr. 109, 914–919 (2013).

  83. 83.

    Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).

  84. 84.

    den Besten, G. et al. The short-chain fatty acid uptake fluxes by mice on a guar gum supplemented diet associate with amelioration of major biomarkers of the metabolic syndrome. PLOS ONE 9, e107392 (2014).

  85. 85.

    Pauline, K.-B. & Rimm, E. B. Whole grain consumption and weight gain: a review of the epidemiological evidence, potential mechanisms and opportunities for future research. Proc. Nutr. Soc. 62, 25–29 (2003).

  86. 86.

    Thompson, S. V., Hannon, B. A., An, R. & Holscher, H. D. Effects of isolated soluble fiber supplementation on body weight, glycemia, and insulinemia in adults with overweight and obesity: a systematic review and meta-analysis of randomized controlled trials. Am. J. Clin. Nutr. 106, 1514–1528 (2017).

  87. 87.

    Wanders, A. J. et al. Effects of dietary fibre on subjective appetite, energy intake and body weight: a systematic review of randomized controlled trials. Obes. Rev. 12, 724–739 (2011).

  88. 88.

    Parnell, J. A. & Reimer, R. A. Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults. Am. J. Clin. Nutr. 89, 1751–1759 (2009).

  89. 89.

    Cani, P. D. et al. Gut microbiota fermentation of prebiotics increases satietogenic and incretin gut peptide production with consequences for appetite sensation and glucose response after a meal. Am. J. Clin. Nutr. 90, 1236–1243 (2009).

  90. 90.

    Daud, N. M. et al. The impact of oligofructose on stimulation of gut hormones, appetite regulation and adiposity. Obesity 22, 1430–1438 (2014).

  91. 91.

    Ridaura, V. K. et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214 (2013).

  92. 92.

    Newgard, C. B. et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 9, 311–326 (2009).

  93. 93.

    Kondo, T., Kishi, M., Fushimi, T., Ugajin, S. & Kaga, T. Vinegar intake reduces body weight, body fat mass, and serum triglyceride levels in obese Japanese subjects. Biosci. Biotechnol. Biochem. 73, 1837–1843 (2009).

  94. 94.

    Meex, R. C. & Watt, M. J. Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat. Rev. Endocrinol. 13, 509–520 (2017).

  95. 95.

    Kelly, C. J. et al. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe 17, 662–671 (2015).

  96. 96.

    Wang, H.-B., Wang, P.-Y., Wang, X., Wan, Y.-L. & Liu, Y.-C. Butyrate enhances intestinal epithelial barrier function via up-regulation of tight junction protein Claudin-1 transcription. Dig. Dis. Sci. 57, 3126–3135 (2012).

  97. 97.

    Pussinen, P. J., Havulinna, A. S., Lehto, M., Sundvall, J. & Salomaa, V. Endotoxemia is associated with an increased risk of incident diabetes. Diabetes Care 34, 392–397 (2011).

  98. 98.

    Jayashree, B. et al. Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes. Mol. Cell. Biochem. 388, 203–210 (2014).

  99. 99.

    Hoyles, L. et al. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat. Med. 24, 1070–1080 (2018).

  100. 100.

    Maslowski, K. M. et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282–1286 (2009).

  101. 101.

    Macia, L. et al. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat. Commun. 6, 6734 (2015).

  102. 102.

    Tremaroli, V. & Bäckhed, F. Functional interactions between the gut microbiota and host metabolism. Nature 489, 242–249 (2012).

  103. 103.

    Yamashita, H. et al. Improvement of obesity and glucose tolerance by acetate in type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Biosci. Biotechnol. Biochem. 71, 1236–1243 (2007).

  104. 104.

    Sakakibara, S., Yamauchi, T., Oshima, Y., Tsukamoto, Y. & Kadowaki, T. Acetic acid activates hepatic AMPK and reduces hyperglycemia in diabetic KK-A (y) mice. Biochem. Biophys. Res. Commun. 344, 597–604 (2006).

  105. 105.

    Zhu, L. et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 57, 601–609 (2013).

  106. 106.

    Nair, S., Cope, K., Terence, R. H. & Diehl, A. M. Obesity and female gender increase breath ethanol concentration: potential implications for the pathogenesis of nonalcoholic steatohepatitis. Am. J. Gastroenterol. 96, 1200–1204 (2001).

  107. 107.

    Zhu, L., Baker, R. D., Zhu, R. & Baker, S. S. Gut microbiota produce alcohol and contribute to NAFLD. Gut 65, 1232 (2016).

  108. 108.

    Xu, J. et al. Synergistic steatohepatitis by moderate obesity and alcohol in mice despite increased adiponectin and p-AMPK. J. Hepatol. 55, 673–682 (2011).

  109. 109.

    Baker, S. S., Baker, R. D., Liu, W., Nowak, N. J. & Zhu, L. Role of alcohol metabolism in non-alcoholic steatohepatitis. PLOS ONE 5, e9570 (2010).

  110. 110.

    Rao, R., Seth, A. & Sheth, P. Recent advances in alcoholic liver disease I. Role of intestinal permeability and endotoxemia in alcoholic liver disease. Am. J. Physiol. Gastrointest. Liver Physiol. 286, G881–G884 (2004).

  111. 111.

    Shen, Z. et al. Role of SIRT1 in regulation of LPS-or two ethanol metabolites-induced TNF-α production in cultured macrophage cell lines. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G1047–G1053 (2009).

  112. 112.

    Blanco, A. M., Perez-Arago, A., Fernandez-Lizarbe, S. & Guerri, C. Ethanol mimics ligand-mediated activation and endocytosis of IL-1RI/TLR4 receptors via lipid rafts caveolae in astroglial cells. J. Neurochem. 106, 625–639 (2008).

  113. 113.

    Round, J. L. & Mazmanian, S. K. The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 9, 313–323 (2009).

  114. 114.

    Yao, C., Muir, J. & Gibson, P. Insights into colonic protein fermentation, its modulation and potential health implications. Aliment. Pharmacol. Ther. 43, 181–196 (2016).

  115. 115.

    Andriamihaja, M. et al. Colon luminal content and epithelial cell morphology are markedly modified in rats fed with a high-protein diet. Am. J. Physiol. Gastrointest. Liver Physiol. 299, G1030–G1037 (2010).

  116. 116.

    Le Roy, T. et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 62, 1787–1794 (2013).

  117. 117.

    Bansal, T., Alaniz, R. C., Wood, T. K. & Jayaraman, A. The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates indicators of inflammation. Proc. Natl Acad. Sci. USA 107, 228–233 (2010).

  118. 118.

    Cervantes-Barragan, L. et al. Lactobacillus reuteri induces gut intraepithelial CD4+ CD8αα+ T cells. Science 357, 806–810 (2017).

  119. 119.

    Wang, B. et al. Altered fecal microbiota correlates with liver biochemistry in nonobese patients with non-alcoholic fatty liver disease. Sci. Rep. 6, 32002 (2016).

  120. 120.

    Mouzaki, M. et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 58, 120–127 (2013).

  121. 121.

    Silva, H. E. et al. Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance. Sci. Rep. 8, 1466 (2018).

  122. 122.

    Daubioul, C., Horsmans, Y., Lambert, P., Danse, E. & Delzenne, N. M. Effects of oligofructose on glucose and lipid metabolism in patients with nonalcoholic steatohepatitis: results of a pilot study. Eur. J. Clin. Nutr. 59, 723–726 (2005).

  123. 123.

    Malaguarnera, M. et al. Bifidobacterium longum with fructo-oligosaccharides in patients with non alcoholic steatohepatitis. Dig. Dis. Sci. 57, 545–553 (2012).

  124. 124.

    DeFronzo, R. et al. The effect of insulin on the disposal of intravenous glucose: results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 30, 1000–1007 (1981).

  125. 125.

    Aberdein, N., Schweizer, M. & Ball, D. Sodium acetate decreases phosphorylation of hormone sensitive lipase in isoproterenol-stimulated 3T3-L1 mature adipocytes. Adipocyte 3, 121–125 (2014).

  126. 126.

    Jocken, J. W. et al. Short-chain fatty acids differentially affect intracellular lipolysis in a human white adipocyte model. Front. Endocrinol. (Lausanne) 8, 372 (2017).

  127. 127.

    Girousse, A. et al. Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass. PLOS Biol. 11, e1001485 (2013).

  128. 128.

    Fernandes, J., Vogt, J. & Wolever, T. M. Intravenous acetate elicits a greater free fatty acid rebound in normal than hyperinsulinaemic humans. Eur. J. Clin. Nutr. 66, 1029–1034 (2012).

  129. 129.

    Ohira, H. et al. Butyrate attenuates inflammation and lipolysis generated by the interaction of adipocytes and macrophages. J. Atheroscler. Thromb. 20, 425–442 (2013).

  130. 130.

    Al-Lahham, S.a. et al. Propionic acid affects immune status and metabolism in adipose tissue from overweight subjects. Eur. J. Clin. Invest. 42, 357–364 (2012).

  131. 131.

    Yamashita, H. et al. Effects of acetate on lipid metabolism in muscles and adipose tissues of type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Biosci. Biotechnol. Biochem. 73, 570–576 (2009).

  132. 132.

    Priyadarshini, M. et al. An acetate-specific GPCR, FFAR2, regulates insulin secretion. Mol. Endocrinol. 29, 1055–1066 (2015).

  133. 133.

    McNelis, J. C. et al. GPR43 potentiates β-cell function in obesity. Diabetes 64, 3203–3217 (2015).

  134. 134.

    Veprik, A., Laufer, D., Weiss, S., Rubins, N. & Walker, M. D. GPR41 modulates insulin secretion and gene expression in pancreatic β-cells and modifies metabolic homeostasis in fed and fasting states. FASEB J. 30, 3860–3869 (2016).

  135. 135.

    Pingitore, A. et al. The diet-derived short chain fatty acid propionate improves beta-cell function in humans and stimulates insulin secretion from human islets in vitro. Diabetes Obes. Metab. 19, 257–265 (2017).

  136. 136.

    Tannahill, G. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013).

  137. 137.

    Holmes, A. J. et al. Diet-microbiome interactions in health are controlled by intestinal nitrogen source constraints. Cell Metab. 25, 140–151 (2017).

  138. 138.

    Wu, L. et al. Pancreatic islet overproduction of H 2 S and suppressed insulin release in Zucker diabetic rats. Lab. Invest. 89, 59–67 (2009).

  139. 139.

    Yang, G., Yang, W., Wu, L. & Wang, R. H2S, endoplasmic reticulum stress, and apoptosis of insulin-secreting beta cells. J. Biol. Chem. 282, 16567–16576 (2007).

  140. 140.

    Zhang, L. et al. Hydrogen sulfide impairs glucose utilization and increases gluconeogenesis in hepatocytes. Endocrinology 154, 114–126 (2013).

  141. 141.

    Jain, S. K. et al. Low levels of hydrogen sulfide in the blood of diabetes patients and streptozotocin-treated rats causes vascular inflammation? Antioxid. Redox Signal. 12, 1333–1338 (2010).

  142. 142.

    Koppe, L. et al. p-Cresyl sulfate promotes insulin resistance associated with CKD. J. Am. Soc. Nephrol. 24, 88–99 (2013).

  143. 143.

    Müller, M., Canfora, E. E. & Blaak, E. E. Gastrointestinal transit time, glucose homeostasis and metabolic health: modulation by dietary fibers. Nutrients 10, E275 (2018).

  144. 144.

    Dewulf, E. et al. Insight into the prebiotic concept: lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women. Gut 62, 1112–1121 (2013).

  145. 145.

    Vulevic, J., Juric, A., Tzortzis, G. & Gibson, G. R. A mixture of trans-galactooligosaccharides reduces markers of metabolic syndrome and modulates the fecal microbiota and immune function of overweight adults. J. Nutr. 143, 324–331 (2013).

  146. 146.

    Canfora, E. E. & Blaak, E. E. The role of polydextrose in body weight control and glucose regulation. Curr. Opin. Clin. Nutr. Metab. Care 18, 395–400 (2015).

  147. 147.

    Canfora, E. E. & van der Beek, C. M. Supplementation of diet with galacto-oligosaccharides increases bifidobacteria, but not insulin sensitivity, in obese prediabetic individuals. Gastroenterology 153, 87–97 (2017).

  148. 148.

    Liu, F. et al. Fructooligosaccharide (FOS) and galactooligosaccharide (GOS) increase bifidobacterium but reduce butyrate producing bacteria with adverse glycemic metabolism in healthy young population. Sci. Rep. 7, 11789 (2017).

  149. 149.

    Canfora, E. E. & Blaak, E. E. Acetate: a diet-derived key metabolite in energy metabolism: good or bad in context of obesity and glucose homeostasis? Curr. Opin. Clin. Nutr. Metab. Care 20, 477–483 (2017).

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PubMed and Google Scholar were searched for relevant topics, using the search terms “SCFA”, “acetate”, “butyrate”, “propionate”, “succinate”, “dietary fibre”, probiotics”, “BCFA”, “ethanol”, “indoles”,”amines”, “sulfate”, “choline”, “bile acids” and “proteolytic fermentation” in combination with “intestinal concentrations”, “blood concentrations”, “microbiota”, “fermentation”, “intestinal homeostasis”, “obesity”, “NASH”, NAFLD”, “weight”, “satiety”, “type 2 diabetes”, “insulin sensitivity”, “insulin resistance”, “glycaemic control”, “glucose-lowering mechanisms”, “energy metabolism”, “inflammation”, “treg”, “vagal activity”, “cardiovascular disease” and “metabolic control”, without publication time constraints. References cited in this article include English-language original research and in some specific case reviews by experts in the field.

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Nature Reviews Endocrinology thanks G. Frost and other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, Netherlands

    • Emanuel E. Canfora
    • , Ruth C. R. Meex
    • , Koen Venema
    •  & Ellen E. Blaak

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All authors provided a substantial contribution to the discussion of content; E.E.C. researched data for the article and wrote the article; and R.C.R.M., K.V. and E.E.B. reviewed and edited the manuscript before submission.

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The authors declare no competing interests.

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Correspondence to Ellen E. Blaak.

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https://doi.org/10.1038/s41574-019-0156-z