Cell Stem Cell Shanghai Institute of Materia Medica collaborated to discover the molecular mechanism of hepatic bile acid metabolism affecting intestinal barrier function

Intestinal epithelial barrier damage has received much attention in the study of cellular and molecular pathogenesis of inflammatory bowel disease (IBD)
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The structural and functional integrity of the intestinal epithelial barrier depends on stably renewed epithelial cells and properly functioning paracellular pathways
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Bile acid is the final product of cholesterol decomposition in the liver, and it mainly regulates energy metabolism and immune function of the body through farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5)
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Studies have shown that bile acids are important regulators of intestinal epithelial barrier function, but the underlying mechanism has not been elucidated
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The joint team of Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Longhua Hospital of Shanghai University of Traditional Chinese Medicine, and National Institutes of Health of the United States has made important discoveries in the study of the cross-organ regulatory mechanism of intestinal epithelial barrier repair.
intestinal epithelial injury in colitis by suppressing intestinal stem cell renewal" was published online on September 1, 2022 in Cell Stem Cell , a professional journal in the field of stem cells
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The researchers found that bile acid metabolism was disordered in active IBD patients and colitis mice, bile acid (CA) levels were significantly up-regulated, and the liver bile acid canonical synthesis pathway metabolic enzyme CYP8B1 was overactivated
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Exogenous supplementation of CA or overexpression of CYP8B1 can aggravate the IBD phenotype in mice and damage the intestinal barrier and its repair function, while interference with the expression of CYP8B1 can promote the remission of intestinal inflammation and restore the ability of intestinal epithelial regeneration
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Self-renewal of crypt intestinal stem cells (Lgr5 ⁺ ISCs) plays an important role in maintaining intestinal homeostasis and defending against microbial invasion
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To gain insight into the mechanism by which the CYP8B1-CA metabolic axis affects intestinal stem cell (ISC) renewal, the researchers isolated intestinal crypts and ISCs from mice with colitis and cultured them in vitro, and found that pathological concentrations of CA significantly attenuated the crypts in the crypts of mice with colitis.
budding and passaging capacity of organoids, and directly inhibited the proliferation of Lgr5 ⁺ ISCs (Fig.
1)
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Figure 1.
CA directly inhibits the proliferation of Lgr5+ ISCs
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　　In further RNA-Seq and metabolomic analyses, we found that CA inhibited fatty acid oxidation (FAO) and PPARα signaling in crypts of colitis mice
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They confirmed the CYP8B1-CA metabolic axis by inhibiting PPARα-mediated FAO, impairing the renewal ability of Lgr5 ⁺ ISCs and aggravating intestinal barrier damage in colitis mice with gut-specific knockout of Pparα .
Finally, the researchers applied the FXR agonist obeticholic acid (OCA) to indirectly inhibit the activity of CYP8B1 in mice with colitis, which can promote the proliferation and passage of Lgr5 ⁺ ISCs, verifying the role of the hepatic FXR-CYP8B1-CA metabolic axis in IBD.
important role in .
 

Figure 2.
Molecular mechanisms of liver CYP8B1-CA metabolic axis regulating intestinal epithelial injury repair across organs
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　　In conclusion, this study found that in the state of inflammatory bowel disease, CYP8B1 is abnormally activated and leads to the accumulation of its product CA, which remotely inhibits the self-renewal of ISCs at the base of crypts and prevents intestinal epithelial barrier repair
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The researchers not only proposed that liver FXR and CYP8B1 are expected to become new targets for "enteric disease liver therapy", but also found that FXR agonists can both regulate inflammation and repair the damaged intestinal epithelial barrier, so FXR agonists are expected to become more promising.
IBD treatment drugs
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(Figure 2)
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Researcher Xie Cen of 　　Shanghai Institute of Materia Medica, Associate Researcher He Shijun and Prof.
Frank J.
Gonzalez of the National Institutes of Health are the co-corresponding authors of this study
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Postdoctoral researcher Chen Li of Shanghai Institute of Materia Medica , research assistant Jiao Tingying , Professor Liu Weiwei of Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, and Dr.
Luo Yuhong of National Institutes of Health are the co-first authors of the paper
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This work has received strong support and assistance from researcher Zuo Jianping of Shanghai Institute of Materia Medica, researcher Ding Qiurong and Qin Jun of Shanghai Institute of Nutrition and Health, and researcher Yu Shiyan of Shanghai Jiaotong University Precision Medicine Research Institute
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This work has been funded by the National Key R&D Program, the Strategic Pilot Science and Technology Project of the Chinese Academy of Sciences (Category B), the Shanghai Municipal Science and Technology Major Project, and the National Natural Science Foundation of China
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　　Full text link: 　　(Contributed by: Xie Cen Research Group, Zuo Jianping Research Group; Contributors: Chen Li, Jiao Tingying)