A dysregulated bile acid-gut microbiota axis contributes to obesity susceptibility
Meilin Wei, Fengjie Huang, Ling Zhao, Yunjing Zhang, Wei Yang, Shouli Wang, Mengci Li, Xiaolong Han, Kun Ge, Chun Qu, Cynthia Rajani, Guoxiang Xie, Xiaojiao Zheng, Aihua Zhao, Zhaoxiang Bian, Wei Jia, Meilin Wei, Fengjie Huang, Ling Zhao, Yunjing Zhang, Wei Yang, Shouli Wang, Mengci Li, Xiaolong Han, Kun Ge, Chun Qu, Cynthia Rajani, Guoxiang Xie, Xiaojiao Zheng, Aihua Zhao, Zhaoxiang Bian, Wei Jia
Abstract
Background: The composition of the bile acid (BA) pool is closely associated with obesity and is modified by gut microbiota. Perturbations of gut microbiota shape the BA composition, which, in turn, may alter important BA signaling and affect host metabolism.
Methods: We investigated BA composition of high BMI subjects from a human cohort study and a high fat diet (HFD) obesity prone (HF-OP) / HFD obesity resistant (HF-OR) mice model. Gut microbiota was analysed by metagenomics sequencing. GLP-1 secretion and gene regulation studies involved ELISA, qPCR, Western blot, Immunohistochemistry, and Immunofluorescence staining.
Findings: We found that the proportion of non-12-OH BAs was significantly decreased in the unhealthy high BMI subjects. The HF-OR mice had an enhanced level of non-12-OH BAs. Non-12-OH BAs including ursodeoxycholate (UDCA), chenodeoxycholate (CDCA), and lithocholate (LCA) were decreased in the HF-OP mice and associated with altered gut microbiota. Clostridium scindens was decreased in HF-OP mice and had a positive correlation with UDCA and LCA. Gavage of Clostridium scindens in mice increased the levels of hepatic non-12-OH BAs, accompanied by elevated serum 7α-hydroxy-4-cholesten-3-one (C4) levels. In HF-OP mice, altered BA composition was associated with significantly downregulated expression of GLP-1 in ileum and PGC1α, UCP1 in brown adipose tissue. In addition, we identified that UDCA attenuated the high fat diet-induced obesity via enhancing levels of non-12-OH BAs.
Interpretation: Our study highlights that dysregulated BA signaling mediated by gut microbiota contributes to obesity susceptibility, suggesting modulation of BAs could be a promising strategy for obesity therapy.
Keywords: Bile acids; Energy expenditure; GLP-1; Gut microbiota; Obesity; UCP1.
Conflict of interest statement
Declaration of Competing Interest The authors declare that they have no conflicts of interests.
Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.
Figures
References
- Castillo J.J., Orlando R.A., Garver W.S. Gene-nutrient interactions and susceptibility to human obesity. Genes Nutr. 2017;12(1):29.
- Stefan N., Häring H.-.U., Hu F.B., Schulze M.B. Metabolically healthy obesity: epidemiology, mechanisms, and clinical implications. Lancet Diabetes & Endocrinol. 2013;1(2):152–162.
- Levin B.E., Dunn-Meynell A.A., Balkan B., Keesey R. Selective breeding for diet-induced obesity and resistance in Sprague-Dawley rats. Am J Physiol. 1997;273(2):R725–RR30.
- Gu Y., Liu C., Zheng N., Jia W., Zhang W., Li H. Metabolic and gut microbial characterization of obesity-prone mice under a high-fat diet. J Proteome Res. 2019;18(4):1703–1714.
- Huang X.-.F., Zavitsanou K., Huang X. Dopamine transporter and D2 receptor binding densities in mice prone or resistant to chronic high fat diet-induced obesity. Behav Brain Res. 2006;175(2):415–419.
- Surwit R.S., Wang S., Petro A.E. Diet-induced changes in uncoupling proteins in obesity-prone and obesity-resistant strains of mice. Proc Natl Acad Sci U S A. 1998;95(7):4061–4065.
- Chang S., Graham B., Yakubu F., Lin D., Peters J., Hill J. Metabolic differences between obesity-prone and obesity-resistant rats. Am J Physiol Regul Integrat Compar Physiol. 1990;259(6):R1103–R1R10.
- Li H., Xie Z., Lin J. Transcriptomic and metabonomic profiling of obesity-prone and obesity-resistant rats under high fat diet. J Proteome Res. 2008;7(11):4775–4783.
- Geiger B.M., Behr G.G., Frank L.E. Evidence for defective mesolimbic dopamine exocytosis in obesity-prone rats. The FASEB J. 2008;22(8):2740–2746.
- Chiang J.Y. Bile acids: regulation of synthesis. J Lipid Res. 2009;50(10):1955–1966.
- 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. 2016;24(1):41–50.
- Ma H., Patti M.E. Bile acids, obesity, and the metabolic syndrome. Best Pract Res Clin Gastroenterol. 2014;28(4):573–583.
- Haeusler R.A., Astiarraga B., Camastra S., Accili D., Ferrannini E. Human insulin resistance is associated with increased plasma levels of 12alpha-hydroxylated bile acids. Diabetes. 2013;62(12):4184–4191.
- Brufau G., Stellaard F., Prado K. Improved glycemic control with colesevelam treatment in patients with type 2 diabetes is not directly associated with changes in bile acid metabolism. Hepatology. 2010;52(4):1455–1464.
- Fiorucci S., Mencarelli A., Palladino G., Cipriani S. Bile-acid-activated receptors: targeting TGR5 and farnesoid-X-receptor in lipid and glucose disorders. Trends Pharmacol Sci. 2009;30(11):570–580.
- Thomas C., Gioiello A., Noriega L. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 2009;10(3):167–177.
- Watanabe M., Houten S.M., Mataki C. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439(7075):484.
- Perino A., Pols T.W.H., Nomura M., Stein S., Pellicciari R., Schoonjans K. TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation. J Clin Invest. 2014;124(12):5424–5436.
- Matsubara T., Li F., Gonzalez F.J. FXR signaling in the enterohepatic system. Mol Cell Endocrinol. 2013;368(1–2):17–29.
- Cipriani S., Mencarelli A., Palladino G., Fiorucci S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res. 2010;51(4):771–784.
- Bäckhed F., Ding H., Wang T. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci. 2004;101(44):15718–15723.
- Sayin S.I., Wahlström A., Felin J. 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.
- Jiang C., Xie C., Li F. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest. 2015;125(1):386–402.
- Jiang C., Xie C., Lv Y. Intestine-selective farnesoid x receptor inhibition improves obesity-related metabolic dysfunction. Nat Commun. 2015;6(1):1–18.
- Ni Y., Zhao L., Yu H. Circulating unsaturated fatty acids delineate the metabolic status of obese individuals. EBioMedicine. 2015;2(10):1513–1522.
- Mukhopadhyay S., Maitra U. Chemistry and biology of bile acids. Curr Sci. 2004;87(12):1666–1683.
- Xie G., Zhong W., Li H. Alteration of bile acid metabolism in the rat induced by chronic ethanol consumption. FASEB J. 2013;27(9):3583–3593.
- Zhao L., Yang W., Chen Y. A Clostridia-Rich microbiota enhances bile acid excretion in diarrhea-predominant irritable bowel syndrome. J Clin Invest. 2019;130(1)
- Zhu W., Lomsadze A., Borodovsky M. Ab initio gene identification in metagenomic sequences. Nucleic Acids Res. 2010;38(12):e132.
- Livak K.J., Schmittgen T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods. 2001;25(4):402–408.
- Ridlon J.M., Harris S.C., Bhowmik S., Kang D-J, Hylemon P.B. Consequences of bile salt biotransformations by intestinal bacteria. Gut Microbes. 2016;7(1):22–39.
- Everard A., Belzer C., Geurts L. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013;110(22):9066–9071.
- Mytilineou C., Kramer B.C., Yabut J.A. Glutathione depletion and oxidative stress. Parkinsonism Relat Disord. 2002;8(6):385–387.
- Porez G, Prawitt J, Gross B, Staels BJJolr. Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease. J Lipid Res. 2012:jlr. R024794.
- Thomas C., Pellicciari R., Pruzanski M., Auwerx J., Schoonjans K. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov. 2008;7(8):678.
- Bertaggia E., Jensen K.K., Castro-Perez J. Cyp8b1 ablation prevents Western diet-induced weight gain and hepatic steatosis because of impaired fat absorption. Am J Physiol Endocrinol Metabolism. 2017;313(2):E121–EE33.
- Kaur A., Patankar J.V., de Haan W. Loss of CYP8B1 improves glucose homeostasis by increasing GLP-1. Diabetes. 2015;64(4):1168–1179.
- Li P., Ruan X., Yang L. A liver-enriched long non-coding RNA, lncLSTR, regulates systemic lipid metabolism in mice. Cell Metab. 2015;21(3):455–467.
- McGavigan A.K., Garibay D., Henseler Z.M. TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice. Gut. 2017;66(2):226–234.
- Wang D.Q.-.H., Tazuma S., Cohen D.E., Carey M.C. Feeding natural hydrophilic bile acids inhibits intestinal cholesterol absorption: studies in the gallstone-susceptible mouse. Am J Physiol Gastrointestinal Liver Physiol. 2003;285(3):G494–G502.
- Joyce S.A., MacSharry J., Casey P.G. Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut. Proc Natl Acad Sci. 2014;111(20):7421–7426.
- Matsuoka K., Suzuki M., Honda C., Endo K., Moroi Y. Micellization of conjugated chenodeoxy-and ursodeoxycholates and solubilization of cholesterol into their micelles: comparison with other four conjugated bile salts species. Chem Phys Lipids. 2006;139(1):1–10.
- Nordskog B.K., Phan C.T., Nutting D.F., Tso P. An examination of the factors affecting intestinal lymphatic transport of dietary lipids. Adv. Drug Deliv. Rev. 2001;50(1–2):21–44.
- Pavlović N., Goločorbin-Kon S., Ðanić M. Bile acids and their derivatives as potential modifiers of drug release and pharmacokinetic profiles. Front Pharmacol. 2018;9:1283.
- Kaddurah-Daouk R., Baillie R.A., Zhu H. Enteric microbiome metabolites correlate with response to simvastatin treatment. PLoS ONE. 2011;6(10)
- Worthmann A., John C., Ruhlemann M.C. Cold-induced conversion of cholesterol to bile acids in mice shapes the gut microbiome and promotes adaptive thermogenesis. Nat Med. 2017;23(7):839–849.
- Inagaki T., Choi M., Moschetta A. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2005;2(4):217–225.
- Yang Z.-.X., Shen W., Sun H. Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease. Hepatol Int. 2010;4(4):741–748.
- Watanabe M., Houten S.M., Wang L. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest. 2004;113(10):1408–1418.
- Ma K., Saha P.K., Chan L., Moore D.D. Farnesoid x receptor is essential for normal glucose homeostasis. J Clin Invest. 2006;116(4):1102–1109.
- Song P., Rockwell C.E., Cui J.Y., Klaassen C.D. Individual bile acids have differential effects on bile acid signaling in mice. Toxicol Appl Pharmacol. 2015;283(1):57–64.
- Mueller M., Thorell A., Claudel T. Ursodeoxycholic acid exerts farnesoid x receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity. J Hepatol. 2015;62(6):1398–1404.
- Ridlon J.M., Kang D-J, Hylemon P.B. Bile salt biotransformations by human intestinal bacteria. J Lipid Res. 2006;47(2):241–259.
- Broeders E.P., Nascimento E.B., Havekes B. The bile acid chenodeoxycholic acid increases human brown adipose tissue activity. Cell Metab. 2015;22(3):418–426.
- Sato H., Macchiarulo A., Thomas C. Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure− activity relationships, and molecular modeling studies. J Med Chem. 2008;51(6):1831–1841.
- Pols T.W., Noriega L.G., Nomura M., Auwerx J., Schoonjans K. The bile acid membrane receptor TGR5: a valuable metabolic target. Dig Dis. 2011;29(1):37–44.
- Ding X., Saxena N.K., Lin S., Gupta N.A., Anania F.A. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatol. 2006;43(1):173–181.
- Ratziu V., De Ledinghen V., Oberti F. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol. 2011;54(5):1011–1019.
- Murakami M., Une N., Nishizawa M., Suzuki S., Ito H., Horiuchi T. Incretin secretion stimulated by ursodeoxycholic acid in healthy subjects. Springerplus. 2013;2(1):20.
- Trabelsi M.S., Daoudi M., Prawitt J. Farnesoid x receptor inhibits glucagon-like peptide-1 production by enteroendocrine l cells. Nat Commun. 2015;6:7629.
- Sun L., Xie C., Wang G. Gut microbiota and intestinal fxr mediate the clinical benefits of metformin. Nat Med. 2018;24(12):1919.
- Wang K., Liao M., Zhou N. Parabacteroides distasonis alleviates obesity and metabolic dysfunctions via production of succinate and secondary bile acids. Cell Rep. 2019;26(1):222–235. e5.
- Buffie C.G., Bucci V., Stein R.R. Precision microbiome reconstitution restores bile acid mediated resistance to clostridium difficile. Nature. 2015;517(7533):205.
- Wang S., Martins R., Sullivan M.C. Diet-induced remission in chronic enteropathy is associated with altered microbial community structure and synthesis of secondary bile acids. Microbiome. 2019;7(1):126.
- Ussar S., Griffin N.W., Bezy O. Interactions between gut microbiota, host genetics and diet modulate the predisposition to obesity and metabolic syndrome. Cell Metab. 2015;22(3):516–530.
- Kim I., Ahn S.-.H., Inagaki T. Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res. 2007;48(12):2664–2672.
- Qin J., Li Y., Cai Z. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490(7418):55–60.
- Petersen C., Bell R., Klag K.A. T cell–mediated regulation of the microbiota protects against obesity. Science. 2019;365(6451):eaat9351.
- Feldmann H.M., Golozoubova V., Cannon B., Nedergaard J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab. 2009;9(2):203–209.
- Zietak M., Kozak L.P. Bile acids induce uncoupling protein 1-dependent thermogenesis and stimulate energy expenditure at thermoneutrality in mice. Am J Physiol Endocrinol Metab. 2016;310(5):E346–E354.
- Beiroa D., Imbernon M., Gallego R. GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes. 2014;63(10):3346–3358.
- Velazquez-Villegas L.A., Perino A., Lemos V. TGR5 signalling promotes mitochondrial fission and beige remodelling of white adipose tissue. Nat Commun. 2018;9(1):1–13.
- Donepudi A.C., Boehme S., Li F., Chiang J.Y. G-protein-coupled bile acid receptor plays a key role in bile acid metabolism and fasting-induced hepatic steatosis in mice. Hepatology. 2017;65(3):813–827.
Source: PubMed