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

Abstract

Vitamin D deficiency is co-prevalent with various liver diseases including cirrhosis, while the underlying mechanism remains elusive. Vitamin D receptor (VDR) is abundantly expressed in the distal region of small intestine, where the Paneth cells are enriched, suggesting that vitamin D signaling may modulates 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 down regulated expression of Paneth cell fensins in the small intestine, gut dysbiosis, and endotoxinemia. While 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 alpha-defensin 5 (DEFA5) restored the homeostasis of gut microbiota, reduced endotoxemia, relieved liver inflammation, and ameliorated liver fibrosis. Likewise, Cholestyramine, cationic resin that can sequestrate endotoxin in the intestine, attenuated the liver fibrosis as well. Fecal transplant of the microbes derived from the DEFA5-treated donors improved liver fibrosis in the recipient mice. The intestinal Vdrconditional 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 cells functions in the small intestine, leading to gut dysbiosis for liver fibrogenesis.

Sequestration of Intestinal Acidic Toxins by Cationic Resin Attenuates Pancreatic Cancer Progression through Promoting Autophagic Flux for YAP Degradation

“…Furthermore, knockdown of ATGs could restore YAP levels as well (Figure S3C). Endotoxin is known for its promotion of fibrotic stiffness [38,42], and here we noticed that additional treatment with LPS promoted nuclear localization of Yap in Pdx1-Kras mice, in agreement with increased pancreatic fibrosis and sprouting of ductal neoplasia (Figure 3A). The accumulation of Yap in KC mice treated with LPS was also related to increased phosphorylation of mTor and slowed turnover of p62/Sqstm1 and Lc3B, showing impairment of autophagic flux leading to Yap degradation (Figure 3A,B).…”

“…Our previous work demonstrated that oral administration of cationic resin, such as cholestyramine, can sequester intestinal endotoxin (LPS), which consequently reduces systemic inflammation, improves insulin resistance, and relieves fatty liver and liver fibrosis [37,38]. Here, KC mice at 6 weeks of age were fed with or without cholestyramine in chow (3% w/w)-designated KC + CS and KC, respectively-for 14 consecutive weeks.…”

The Role of Vitamin D in Immune System and Inflammatory Bowel Disease

“… 100 Wu et al also reported that antibacterial peptide including defensins and lysozymes produced by Paneth cells were reduced in intestinal VDR conditional knockout mice. 101 After administrating a high-fat-diet plus vitamin D deficient feeding in mice, Paneth cell-specific alpha-defensins such as α-defensin5 (DEF5) and MMP7, were suppressed in the ileum, resulting in increased gut permeability, dysbiosis, and systemic inflammation. 102 A reduction in normal Paneth cells and an increase in abnormal Paneth cells (including disordered, depleted, and diffuse Paneth cells) were also observed in conditional VDR epithelial knockout mice.…”

Vitamin D–VDR Novel Anti-Inflammatory Molecules—New Insights into Their Effects on Liver Diseases

“…A recent study demonstrated the importance of vitamin D 25-hydroxylation in the small intestine in maintaining Paneth cell function [ 162 ]. Deficient hepatic 25-hydroxylation of vitamin D was demonstrated in carbon-tetrachloride-induced liver injury, resulting in the downregulation of defensins expressed in Paneth cells, gut dysbiosis, and endotoxemia [ 162 ]. Intestinal VDR knockout mice showed decreased Paneth cell defensins and lysozyme production, as well as worsening liver injury and fibrogenesis [ 162 ].…”