Journal Article

Indole-3-propionic acid inhibits gut dysbiosis and endotoxin leakage to attenuate steatohepatitis in rats

Xin, Feng-Zhi, Li, Yu, Liu, Zhengshuai, Zhou, Da, Liu, Yuxiao, Liu, Xiao-Lin, Pan, Qin, Hu, Zhimin, Zhao, Ze-Hua, Han, Yamei, Ma, Fengguang, Cui, Aoyuan, Gao, Jing, Xue, Yaqian, Fan, Jian-Gao

2019

Overview

Microbial metabolites have emerged as critical components that mediate the metabolic effects of the gut microbiota. Here, we show that indole-3-propionic acid (IPA), a tryptophan metabolite produced by gut bacteria, is a potent anti-non-alcoholic steatohepatitis (NASH) microbial metabolite. Here, we demonstrate that administration of IPA modulates the microbiota composition in the gut and inhibits microbial dysbiosis in rats fed a high-fat diet. IPA induces the expression of tight junction proteins, such as ZO-1 and Occludin, and maintains intestinal epithelium homeostasis, leading to a reduction in plasma endotoxin levels. Interestingly, IPA inhibits NF-κB signaling and reduces the levels of proinflammatory cytokines, such as TNFα, IL-1β, and IL-6, in response to endotoxin in macrophages to repress hepatic inflammation and liver injury. Moreover, IPA is sufficient to inhibit the expression of fibrogenic and collagen genes and attenuate diet-induced NASH phenotypes. The beneficial effects of IPA on the liver are likely mediated through inhibiting the production of endotoxin in the gut. These findings suggest a protective role of IPA in the control of metabolism and uncover the gut microbiome and liver cross-talk in regulating the intestinal microenvironment and liver pathology via a novel dietary nutrient metabolite. IPA may provide a new therapeutic strategy for treating NASH. Fatty liver disease: Bacterial metabolite protects liver by maintaining gut integrity A molecule made by beneficial microbes in the gut helps protect against a severe form of fatty liver disease by preventing bacterial toxins from leaking out of the intestines into the bloodstream. A research team in China led by Yu Li from the Shanghai Institute of Nutrition and Health (CAS) and Jian-Gao Fan from Xinhua Hospital (SJTU) showed in a rat model of non-alcoholic steatohepatitis that indole-3-propionic acid (IPA), a metabolite produced by gut bacteria, helps maintain the integrity of the intestinal inner lining. The more robust intestinal barrier ensures that bacterial toxins do not enter the bloodstream and eventually reach the liver, where they can trigger injury-inducing inflammation. The findings reveal an interaction between the gut microbiome and the liver, and suggest a role for IPA in the treatment of fatty liver disease.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group,생화학분자생물학회
• Subject: 13/51 / 13/95 / 38/1 / 38/23 / 631/443/319/1642/2037 / 692/699/1503/1607/2751 / Animals / Biomedical and Life Sciences / Biomedicine / Collagen / Diet, High-Fat / Digestive system / Disease Models, Animal / Dysbacteriosis / Dysbiosis - drug therapy / Dysbiosis - genetics / Dysbiosis - metabolism / Dysbiosis - microbiology / Endotoxins - metabolism / Epithelium / Gastrointestinal Microbiome - drug effects / Gastrointestinal Microbiome - genetics / Gastrointestinal tract / Gene Expression Regulation - drug effects / High fat diet / Homeostasis / Humans / IL-1β / Indoles / Indoles - pharmacology / Inflammation / Interleukin 6 / Interleukin-1beta / Interleukin-6 - genetics / Intestinal microflora / Intestine / Liver / Liver - drug effects / Liver - injuries / Liver - pathology / Macrophages / Macrophages - drug effects / Medical Biochemistry / Metabolites / Microbiomes / Microbiota / Molecular Medicine / NF-kappa B - genetics / NF-κB protein / Non-alcoholic Fatty Liver Disease - drug therapy / Non-alcoholic Fatty Liver Disease - genetics / Non-alcoholic Fatty Liver Disease - metabolism / Non-alcoholic Fatty Liver Disease - microbiology / Occludin - genetics / Phenotypes / Propionates - pharmacology / Propionic acid / Rats / Stem Cells / Tryptophan / Tryptophan - metabolism / Tumor Necrosis Factor-alpha - genetics / Tumor necrosis factor-α / Zonula occludens-1 protein / Zonula Occludens-1 Protein - genetics / 생화학