Journal
GUT
Volume 66, Issue 3, Pages 429-437Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2015-310283
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Funding
- Human Frontier of Science Program [RGY64/2008]
- Swedish Research Council
- NovoNordisk Foundation
- Torsten Soderberg's Foundation
- Ragnar Soderberg's Foundation
- Swedish Diabetes Foundation
- Swedish Heart Lung Foundation
- IngaBritt och Arne Lundbergs Foundation
- Knut and Alice Wallenberg Foundation
- Swedish Foundation for Strategic Research
- EU [FP7-KBBE-222639]
- Ake Wiberg Foundation
- Magnus Bergvall Foundation
- Lars Hierta's Foundation
- Nanna Svartz Foundation
- Fredrik and Ingrid Thurings Foundation
- Sahlgrenska University Hospital
- ERC [615362-METABASE]
- NNF Center for Basic Metabolic Research [Bäckhed Group] Funding Source: researchfish
- Novo Nordisk Fonden [NNF13OC0008163] Funding Source: researchfish
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Objective The gut microbiota has been implicated as an environmental factor that modulates obesity, and recent evidence suggests that microbiota-mediated changes in bile acid profiles and signalling through the bile acid nuclear receptor farnesoid X receptor (FXR) contribute to impaired host metabolism. Here we investigated if the gut microbiota modulates obesity and associated phenotypes through FXR. Design We fed germ-free (GF) and conventionally raised (CONV-R) wild-type and Fxr(-/-) mice a high-fat diet (HFD) for 10 weeks. We monitored weight gain and glucose metabolism and analysed the gut microbiota and bile acid composition, beta-cell mass, accumulation of macrophages in adipose tissue, liver steatosis, and expression of target genes in adipose tissue and liver. We also transferred the microbiota of wild-type and Fxr(-) deficient mice to GF wild-type mice. Results The gut microbiota promoted weight gain and hepatic steatosis in an FXR-dependent manner, and the bile acid profiles and composition of faecal microbiota differed between Fxr(-/-) and wild-type mice. The obese phenotype in colonised wild-type mice was associated with increased beta-cell mass, increased adipose inflammation, increased steatosis and expression of genes involved in lipid uptake. By transferring the caecal microbiota from HFD-fed Fxr(-/-) and wild-type mice into GF mice, we showed that the obesity phenotype was transferable. Conclusions Our results indicate that the gut microbiota promotes diet-induced obesity and associated phenotypes through FXR, and that FXR may contribute to increased adiposity by altering the microbiota composition.
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