Decreased Paneth cell alpha-defensins promote fibrosis in a choline-deficient L-amino acid-defined high-fat diet-induced mouse model of nonalcoholic steatohepatitis via disrupting intestinal microbiota

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease characterized by fibrosis that develops from fatty liver. Disruption of intestinal microbiota homeostasis, dysbiosis, is associated with fibrosis development in NASH. An antimicrobial peptide alpha-defensin secreted by Paneth cells in the small intestine is known to regulate composition of the intestinal microbiota. However, involvement of alpha-defensin in NASH remains unknown. Here, we show that in diet-induced NASH model mice, decrease of fecal alpha-defensin along with dysbiosis occurs before NASH onset. When alpha-defensin levels in the intestinal lumen are restored by intravenous administration of R-Spondin1 to induce Paneth cell regeneration or by oral administration of alpha-defensins, liver fibrosis is ameliorated with dissolving dysbiosis. Furthermore, R-Spondin1 and alpha-defensin improved liver pathologies together with different features in the intestinal microbiota. These results indicate that decreased alpha-defensin secretion induces liver fibrosis through dysbiosis, further suggesting Paneth cell alpha-defensin as a potential therapeutic target for NASH.

Automated summary

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease characterized by fibrosis that develops from fatty liver. Dysbiosis, the disruption of intestinal microbiota homeostasis, is associated with fibrosis development in NASH. The decrease of fecal alpha-defensin, an antimicrobial peptide secreted by Paneth cells, and dysbiosis occur before NASH onset. Restoration of alpha-defensin levels improves liver fibrosis and resolves dysbiosis, suggesting Paneth cell alpha-defensin as a potential therapeutic target for NASH.