The gut microbiota regulates mouse biliary regenerative responses

Abstract

17Injury to the biliary epithelium triggers cholangiopathies. However, factors involved in 18 regulating the pathogenesis remains incompletely understood. Here, we report that the 19 gut microbiota is important in regulating hepatobiliary fibroproliferative regenerative 20 process. In helminth Clonorchis sinensis-induced bile duct injury model, wild-type mice 21 showed more extensive peribiliary fibroproliferative responses than non-littermate IL-33-22 deficient mice. However, these reactions could be attenuated by co-housing of the 23 animals together. In the meantime, the relatively fibroproliferative-resistant IL-33-24 deficient mice could become fibroproliferative-responsive especially in large intrahepatic 25 bile duct by antibiotics treatment. Furthermore, microbiota-derived metabolite butyrate 26 was able to inhibit biliary organoid expansion in vitro and temper 3,5-diethoxycarbonyl-27 1,4-dihydrocollidine-induced biliary fibrosis in vivo. Together, our data implies a potential 28 way of management of hepatobiliary diseases by modulating gut microbiota. 29 30 31 3 32 33The biliary tree including intrahepatic and extrahepatic bile ducts (IHBD and EHBD) 34 forms the primary path by which bile is secreted by the liver then transported to the gut. 35Disruption of the epithelial lining of bile ducts triggers hepatobiliary inflammation, 36 fibrosis, and even malignant transformation, which collectively were referred as 37 cholangiopathies. The cholangiopathies account for substantial morbidity and mortality 38 and are often progressive that lead to end-stage liver disease. Despite the severe 39 disease phenotypes, the molecular and cellular effectors and their relationships to 40 cholangiopathies remain poorly defined 1 . 41A number of animal models have been generated to provide in vivo tools to 42 investigate the mechanisms of biliary repair and, eventually, to test the efficacy of 43 innovative treatments 2 . Each of the animal model has its own limitations in translating 44 to human settings. 3,5-Diethoxycarbonyl-1,4-dihydrocollidine (DDC)-feeding in mice 45 recapitulated pathogenic hallmarks of human primary sclerosing cholangitis (PSC) 3 . 46Clonorchis sinensis is a food-borne helminth that naturally cause cholangiopathies 4,5 . 47During progression of biliary injury induced by the worm, a disorganized expansion of 48 bile ducts and recruitment of inflammatory cells known as ductular reaction (DR) 49 become so prominent that not only biliary epithelial but also the peribiliary glands 50 (PBGs), clusters of epithelial cells residing in the submucosal compartment of the bile 51 duct, show hyperplasia and proliferation. PBGs participate in the secretion of neutral, 52 carboxylated, and sulphated mucins into the bile duct lumen. The term adenomatous 53 hyperplasia or chronic proliferative cholangitis has been used to describe this 54 4 phenomenon 6 . What is the underlying molecular and cellular mechanisms of these 55 biliary responses remains incompletely understood. 56The gut microbiota can influence or m...

The role of gut microbiota in liver regeneration

“…And GPR109A activated by butyrate promotes the differentiation of regulatory T cells and IL-10-producing T cells ( 147 ). Also, butyrate is important in the peribiliary fibroproliferative responses and can temper the induced fibrosis, which is beneficial to bile secretion and liver regeneration ( 148 ). Except being an extracellular agonist, butyrate and propionate can inhibit the activity of histone deacetylases in colon cells and immune cells, and thus modulate the differentiation of regulatory T cells ( 149 – 151 ).…”

New insights in the metabolic function related to gut microbiota in the process of liver regeneration

“…The activation of these receptors has been recognized as a crucial component of JNK1-mediated pathways in promoting liver regeneration ( 6 ). In addition, butyrate is important in the regulation of bile secretion and facilitating liver regeneration with detail mechanism undisclosed ( 7 ). Despite the positive result, previous studies have focused more on the important role of gut microbiota’s metabolites as regulatory molecules, but lack of knowledge provided on the role of metabolites as raw materials for metabolic synthesis.…”