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Cold-induced conversion of cholesterol to bile acids in mice shapes the gut microbiome and promotes adaptive thermogenesis

Abstract

Adaptive thermogenesis is an energy-demanding process that is mediated by cold-activated beige and brown adipocytes, and it entails increased uptake of carbohydrates, as well as lipoprotein-derived triglycerides and cholesterol, into these thermogenic cells. Here we report that cold exposure in mice triggers a metabolic program that orchestrates lipoprotein processing in brown adipose tissue (BAT) and hepatic conversion of cholesterol to bile acids via the alternative synthesis pathway. This process is dependent on hepatic induction of cytochrome P450, family 7, subfamily b, polypeptide 1 (CYP7B1) and results in increased plasma levels, as well as fecal excretion, of bile acids that is accompanied by distinct changes in gut microbiota and increased heat production. Genetic and pharmacological interventions that targeted the synthesis and biliary excretion of bile acids prevented the rise in fecal bile acid excretion, changed the bacterial composition of the gut and modulated thermogenic responses. These results identify bile acids as important metabolic effectors under conditions of sustained BAT activation and highlight the relevance of cholesterol metabolism by the host for diet-induced changes of the gut microbiota and energy metabolism.

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Figure 1: BAT activation alters the gut microbiome, lipoprotein levels and cholesterol uptake.
Figure 2: BAT activation induces the alternative bile acid synthesis pathway independently of FXR.
Figure 3: Cold exposure promotes fecal excretion of CYP7B1-derived bile acids.
Figure 4: Hepatic uptake of cholesterol-rich lipoproteins determines fecal bile acid excretion in cold-exposed mice.
Figure 5: Cold-induced bile acid excretion determines the composition of the gut microbiome.
Figure 6: CYP7B1-derived bile acids promote adaptive thermogenesis.

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Acknowledgements

We thank S. Ehret, B. Henkel, A. Kuhl and E.-M. Azizi for excellent technical assistance, P. Dawson (Emory University School of Medicine) for the ASBT-specific polyclonal antibody, and J. Nedergaard and B. Cannon (Wenner-Gren Institute, Stockholm University) for the UCP1-spcific polyclonal antibody. This work was supported by grants funded by the Deutsche Forschungsgemeinschaft (SFB841, “Liver inflammation: infection, immune regulation und consequences” (J.H. and M.D.); KFO306, “Primary sclerosing cholangitis (J.H. and to A.F.)), a Heisenberg Professorship (HE3645/7-1 (J.H.) and DA1063/3-2 (M.D.)), an EFSD award supported by Merck Sharp Dohme (MSD) (J.H.), the EU FP7 project RESOLVE FP7-HEALTH-2012-305707 (J.H.), a University Medical Center Hamburg–Eppendorf MD/PhD fellowship (C.S.) and the US National Institutes of Health grant HL087564 (P.W.S.).

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A.W., C.J., L.S. and J.H. designed the study, were involved in all aspects of the experiments and wrote the manuscript; M.C.R., F.-A.H. and A.F. were responsible for the microbiome analysis; M.B., N.S., M.H., I.E., C.S. and C.M. were involved in the metabolic studies; M.F., M.D., A.F., C.K. und P.W.S. were involved in study design; and all authors read and commented on the manuscript.

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Correspondence to Joerg Heeren.

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Competing interests

C.K. is a co-founder and shareholder of Phenex Pharmaceuticals AG.

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Worthmann, A., John, C., Rühlemann, M. et al. Cold-induced conversion of cholesterol to bile acids in mice shapes the gut microbiome and promotes adaptive thermogenesis. Nat Med 23, 839–849 (2017). https://doi.org/10.1038/nm.4357

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