Paneth Cell Dysfunction Mediates Alcohol-related Steatohepatitis Through Promoting Bacterial Translocation in Mice: Role of Zinc Deficiency.

摘要: Background and aims Microbial dysbiosis is associated with alcohol-related hepatitis (AH), the mechanisms yet to be elucidated. The present study aimed determine effects of alcohol zinc deficiency on Paneth cell (PC) antimicrobial peptides, α-defensins, define link between PC dysfunction AH. Approach results Translocation pathogen-associated molecular patterns (PAMPs) was determined in patients severe AH a mouse model alcoholic steatohepatitis. composition function were examined mice. α-defensin investigated α-defensin-deficient Synthetic human 5 (HD5) orally given alcohol-fed mice test therapeutic potential. role evaluated acute chronic models deprivation. Hepatic inflammation PAMP translocation lipocalin-2 (LCN2) chemokine (C-X-C motif) ligand 1 (CXCL1) elevation Antibiotic treatment, lipopolysaccharide injection mice, vitro experiments showed that PAMPs, but not alcohol, directly induced LCN2 CXCL1. Chronic feeding caused systemic reduction Knockout functional α-defensins synergistically affected alcohol-perturbed bacterial gut barrier exaggerated liver damage. Administration HD5 effectively altered cecal microbial composition, especially increased Akkermansia muciniphila, reversed alcohol-induced deleterious effects. Zinc-regulated homeostasis at multiple levels, dietary effect bactericidal activity. Conclusions Taken together, suggests mediated by involved pathogenesis administration may represent promising approach for treating