@article{e1c494c18c244c1787d70ea1e7bd86ad,
title = "A dysregulated bile acid-gut microbiota axis contributes to obesity susceptibility",
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",
author = "Meilin Wei and Fengjie Huang and Ling Zhao and Yunjing Zhang and Wei Yang and Shouli Wang and Mengci Li and Xiaolong Han and Kun Ge and Chun Qu and Cynthia Rajani and Guoxiang Xie and Xiaojiao Zheng and Aihua Zhao and Zhaoxiang Bian and Wei Jia",
note = "Funding Information: This work was supported by National Key R and D Program of China ( 2017YFC0906800 ), National Natural Science Foundation of China ( 81772530 , 81974073 ), the National Institutes of Health/National Cancer Institute Grant 1U01CA188387-01A1, and the China Scholarship Council (No. 201706230089 ). The funders had no role in the study design, data collection, data analysis, interpretation, and writing of the report. Funding Information: We thank all participants who provided written informed consent and donated specimens for this study. We thank Prof. Zhaoxiang Bian and Dr. Ling Zhao (Hong Kong Baptist University) for providing C.scindens manipulation mice specimens and valuable support. This work was supported by National Key R and D Program of China (2017YFC0906800), National Natural Science Foundation of China (81772530, 81974073), the National Institutes of Health/National Cancer Institute Grant 1U01CA188387-01A1, and the China Scholarship Council (No. 201706230089). The funders had no role in the study design, data collection, data analysis, interpretation, and writing of the report. Wei Jia was principal investigator of this study. Zhaoxiang Bian provided valuable support for C. scindens gavage animal experiment. Wei Jia, Aaihua Zhao, Xiaojiao Zheng, and Guoxiang Xie designed the study. Meilin Wei conducted key experiments of the study and perform the data analysis and drafted the manuscript. Fengjie Huang, Yunjing Zhang, Wei Yang, and Ling Zhao conducted the animal experiments. Kun Ge, Chun Qu, Mengci Li, Shouli Wang, and Xiaolong Han helped to perform the experiments and collected the data. Wei Jia and Cynthia Rajani revised the manuscript. The metagenomic sequences were provided and available at NCBI Sequence Read Archive (SRA) repository with accession code PRJNA616396. Datasets and R-code related to this study can be found at https://github.com/mweixq/OPOR.",
year = "2020",
month = may,
doi = "10.1016/j.ebiom.2020.102766",
language = "English",
volume = "55",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",
}
