Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist

Sama I. Sayin, Annika Wahlström, Jenny Felin, Sirkku Jäntti, Hanns-Ulrich Marschall, Krister Bamberg, Bo Angelin, Tuulia Hyötyläinen, Matej Orešič, Fredrik Bäckhed

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Abstract

Bile acids are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids. Bile acid synthesis is under negative feedback control through activation of the nuclear receptor farnesoid X receptor (FXR) in the ileum and liver. Here we profiled the bile acid composition throughout the enterohepatic system in germ-free (GF) and conventionally raised (CONV-R) mice. We confirmed a dramatic reduction in muricholic acid, but not cholic acid, levels in CONV-R mice. Rederivation of Fxr-deficient mice as GF demonstrated that the gut microbiota regulated expression of fibroblast growth factor 15 in the ileum and cholesterol 7α-hydroxylase (CYP7A1) in the liver by FXR-dependent mechanisms. Importantly, we identified tauro-conjugated beta- and alpha-muricholic acids as FXR antagonists. These studies suggest that the gut microbiota not only regulates secondary bile acid metabolism but also inhibits bile acid synthesis in the liver by alleviating FXR inhibition in the ileum.
Original languageEnglish
Pages (from-to)225-235
JournalCell Metabolism
Volume17
Issue number2
DOIs
Publication statusPublished - 2013
MoE publication typeA1 Journal article-refereed

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Bile Acids and Salts
Ileum
Liver
Cholesterol 7-alpha-Hydroxylase
Cholic Acid
Fibroblast Growth Factors
Cytoplasmic and Nuclear Receptors
Gastrointestinal Microbiome
tauromuricholic acid
Cholesterol
muricholic acid

Cite this

Sayin, S. I., Wahlström, A., Felin, J., Jäntti, S., Marschall, H-U., Bamberg, K., ... Bäckhed, F. (2013). Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metabolism, 17(2), 225-235. https://doi.org/10.1016/j.cmet.2013.01.003
Sayin, Sama I. ; Wahlström, Annika ; Felin, Jenny ; Jäntti, Sirkku ; Marschall, Hanns-Ulrich ; Bamberg, Krister ; Angelin, Bo ; Hyötyläinen, Tuulia ; Orešič, Matej ; Bäckhed, Fredrik. / Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. In: Cell Metabolism. 2013 ; Vol. 17, No. 2. pp. 225-235.
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abstract = "Bile acids are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids. Bile acid synthesis is under negative feedback control through activation of the nuclear receptor farnesoid X receptor (FXR) in the ileum and liver. Here we profiled the bile acid composition throughout the enterohepatic system in germ-free (GF) and conventionally raised (CONV-R) mice. We confirmed a dramatic reduction in muricholic acid, but not cholic acid, levels in CONV-R mice. Rederivation of Fxr-deficient mice as GF demonstrated that the gut microbiota regulated expression of fibroblast growth factor 15 in the ileum and cholesterol 7α-hydroxylase (CYP7A1) in the liver by FXR-dependent mechanisms. Importantly, we identified tauro-conjugated beta- and alpha-muricholic acids as FXR antagonists. These studies suggest that the gut microbiota not only regulates secondary bile acid metabolism but also inhibits bile acid synthesis in the liver by alleviating FXR inhibition in the ileum.",
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Sayin, SI, Wahlström, A, Felin, J, Jäntti, S, Marschall, H-U, Bamberg, K, Angelin, B, Hyötyläinen, T, Orešič, M & Bäckhed, F 2013, 'Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist', Cell Metabolism, vol. 17, no. 2, pp. 225-235. https://doi.org/10.1016/j.cmet.2013.01.003

Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. / Sayin, Sama I.; Wahlström, Annika; Felin, Jenny; Jäntti, Sirkku; Marschall, Hanns-Ulrich; Bamberg, Krister; Angelin, Bo; Hyötyläinen, Tuulia; Orešič, Matej; Bäckhed, Fredrik.

In: Cell Metabolism, Vol. 17, No. 2, 2013, p. 225-235.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist

AU - Sayin, Sama I.

AU - Wahlström, Annika

AU - Felin, Jenny

AU - Jäntti, Sirkku

AU - Marschall, Hanns-Ulrich

AU - Bamberg, Krister

AU - Angelin, Bo

AU - Hyötyläinen, Tuulia

AU - Orešič, Matej

AU - Bäckhed, Fredrik

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N2 - Bile acids are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids. Bile acid synthesis is under negative feedback control through activation of the nuclear receptor farnesoid X receptor (FXR) in the ileum and liver. Here we profiled the bile acid composition throughout the enterohepatic system in germ-free (GF) and conventionally raised (CONV-R) mice. We confirmed a dramatic reduction in muricholic acid, but not cholic acid, levels in CONV-R mice. Rederivation of Fxr-deficient mice as GF demonstrated that the gut microbiota regulated expression of fibroblast growth factor 15 in the ileum and cholesterol 7α-hydroxylase (CYP7A1) in the liver by FXR-dependent mechanisms. Importantly, we identified tauro-conjugated beta- and alpha-muricholic acids as FXR antagonists. These studies suggest that the gut microbiota not only regulates secondary bile acid metabolism but also inhibits bile acid synthesis in the liver by alleviating FXR inhibition in the ileum.

AB - Bile acids are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids. Bile acid synthesis is under negative feedback control through activation of the nuclear receptor farnesoid X receptor (FXR) in the ileum and liver. Here we profiled the bile acid composition throughout the enterohepatic system in germ-free (GF) and conventionally raised (CONV-R) mice. We confirmed a dramatic reduction in muricholic acid, but not cholic acid, levels in CONV-R mice. Rederivation of Fxr-deficient mice as GF demonstrated that the gut microbiota regulated expression of fibroblast growth factor 15 in the ileum and cholesterol 7α-hydroxylase (CYP7A1) in the liver by FXR-dependent mechanisms. Importantly, we identified tauro-conjugated beta- and alpha-muricholic acids as FXR antagonists. These studies suggest that the gut microbiota not only regulates secondary bile acid metabolism but also inhibits bile acid synthesis in the liver by alleviating FXR inhibition in the ileum.

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VL - 17

SP - 225

EP - 235

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

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