Impaired 25-hydroxylation of vitamin D in liver injury suppresses intestinal Paneth cell defensins, leading to gut dysbiosis and liver fibrogenesis

Vitamin D deficiency is coprevalent with various liver diseases, including cirrhosis, whereas the underlying mechanism remains elusive. Vitamin D receptor (VDR) is abundantly expressed in the distal region of the small intestine, where the Paneth cells are enriched, suggesting that vitamin D signaling may modulate the intestinal Paneth cells and their production of defensins to restrain microbiome growth in the small intestine. In this study, we found that in carbon tetrachloride-induced liver injury, hepatic 25-hydroxylation of vitamin D was impaired, leading to downregulated expression of Paneth cell defensins in the small intestine, gut dysbiosis, and endotoxinemia. Although intraperitoneal injection of endotoxin (lipopolysaccharides) alone did not elicit liver fibrosis, it exacerbated the carbon tetrachloride-initiated liver fibrogenesis. Oral gavage of synthetic Paneth cell α-defensin 5 (DEFA5) restored the homeostasis of the gut microbiota, reduced endotoxemia, relieved liver inflammation, and ameliorated liver fibrosis. Likewise, cholestyramine, a cationic resin that can sequestrate endotoxin in the intestine, attenuated liver fibrosis as well. Fecal transplant of the microbes derived from the DEFA5-treated donors improved liver fibrosis in the recipient mice. The intestinal Vdr conditional knockout mice exhibited reduction of Paneth cell defensins and lysozyme production and worsened liver injury and fibrogenesis. Thus, liver injury impairs synthesis of 25(OH)VD₃, which consequently impedes the Paneth cell functions in the small intestine, leading to gut dysbiosis and liver fibrogenesis. NEW & NOTEWORTHY Vitamin D deficiency is coprevalent with various liver diseases, indicating the role of vitamin D in maintaining liver homeostasis. In this study, we observed that the hepatic 25-hydroxylation of VD is critical for intestinal innate immunity through VD signaling in the small intestine for maintaining Paneth cell functions. Conversely, failure of biogenesis of VD in the liver impairs intestinal immunity, leading to gut dysbiosis and endotoxemia, which promotes liver fibrogenesis.