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Complement receptor of immunoglobulin superfamily (CRIg) is expressed on liver macrophages and directly binds complement component C3b or Gram-positive bacteria to mediate phagocytosis. CRIg plays important roles in several immune-mediated diseases, but it is not clear how its pathogen recognition and phagocytic functions maintain homeostasis and prevent disease. We previously associated cytolysin-positive Enterococcus faecalis with severity of alcohol-related liver disease. Here, we demonstrate that CRIg is reduced in liver tissues from patients with alcohol-related liver disease. CRIg-deficient mice developed more severe ethanol-induced liver disease than wild-type mice; disease severity was reduced with loss of toll-like receptor 2. CRIg-deficient mice were less efficient than wild-type mice at clearing Gram-positive bacteria such as Enterococcus faecalis that had translocated from gut to liver. Administration of the soluble extracellular domain CRIg-Ig protein protected mice from ethanol-induced steatohepatitis. Our findings indicate that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of liver disease.

ObjectiveAntimicrobial C-type lectin regenerating islet-derived 3 gamma (REG3G) is suppressed in the small intestine during chronic ethanol feeding. Our aim was to determine the mechanism that underlies REG3G suppression during experimental alcoholic liver disease.DesignInterleukin 22 (IL-22) regulates expression of REG3G. Therefore, we investigated the role of IL-22 in mice subjected to chronic-binge ethanol feeding (NIAAA model).ResultsIn a mouse model of alcoholic liver disease, we found that type 3 innate lymphoid cells produce lower levels of IL-22. Reduced IL-22 production was the result of ethanol-induced dysbiosis and lower intestinal levels of indole-3-acetic acid (IAA), a microbiota-derived ligand of the aryl hydrocarbon receptor (AHR), which regulates expression of IL-22. Importantly, faecal levels of IAA were also found to be lower in patients with alcoholic hepatitis compared with healthy controls. Supplementation to restore intestinal levels of IAA protected mice from ethanol-induced steatohepatitis by inducing intestinal expression of IL-22 and REG3G, which prevented translocation of bacteria to liver. We engineered Lactobacillus reuteri to produce IL-22 (L. reuteri/IL-22) and fed them to mice along with the ethanol diet; these mice had reduced liver damage, inflammation and bacterial translocation to the liver compared with mice fed an isogenic control strain and upregulated expression of REG3G in intestine. However, L. reuteri/IL-22 did not reduce ethanol-induced liver disease in Reg3g-/- mice.ConclusionEthanol-associated dysbiosis reduces levels of IAA and activation of the AHR to decrease expression of IL-22 in the intestine, leading to reduced expression of REG3G; this results in bacterial translocation to the liver and steatohepatitis. Bacteria engineered to produce IL-22 induce expression of REG3G to reduce ethanol-induced steatohepatitis.

Alterations of gut microbes play a role in the pathogenesis and progression of many disorders including liver and gastrointestinal diseases. Both qualitative and quantitative changes in gut microbiota have been associated with liver disease. Intestinal dysbiosis can disrupt the integrity of the intestinal barrier leading to pathological bacterial translocation and the initiation of an inflammatory response in the liver. In order to sustain symbiosis and protect from pathological bacterial translocation, antimicrobial proteins (AMPs) such as a-defensins and C-type lectins are expressed in the gastrointestinal tract. In this review, we provide an overview of the role of AMPs in different chronic liver disease such as alcoholic steatohepatitis, non-alcoholic fatty liver disease, and cirrhosis. In addition, potential approaches to modulate the function of AMPs and prevent bacterial translocation are discussed.

Objective: Chronic ethanol consumption is known to cause alcohol-associated liver disease, which poses a global health concern as almost a quarter of heavy drinkers develop severe liver damage. Alcohol-induced liver disease ranges from a mild, reversible steatotic liver to alcoholic steatohepatitis and irreversible liver fibrosis and cirrhosis, ultimately requiring liver transplantation. While ethanol consumption is associated with dysregulated lipid metabolism and altered cholesterol homeostasis, the impact of dyslipidemia and pre-existing hypercholesterolemia on the development of alcohol-associated liver disease remains to be elucidated. Design: To address the influence of systemic dyslipidemia on ethanol-induced liver disease, chronic-binge ethanol feeding was applied to female C57BL/6J (wild type) mice and mice deficient for the low-density lipoprotein receptor (Ldlr-/-), which display a human-like lipoprotein profile with elevated cholesterol and triglyceride levels in circulation. Respective control groups were pair-fed an isocaloric diet. Results: Chronic-binge ethanol feeding did not alter systemic lipid levels in wild type mice. While increased systemic cholesterol levels in Ldlr-/- mice were not affected by ethanol feeding, chronic-binge ethanol diet aggravated elevated plasma triglyceride levels in Ldlr-/- mice. Despite higher circulatory triglyceride levels in Ldlr-/- mice, hepatic lipid levels and the development of hepatic steatosis were not different from wild type mice after ethanol diet, while hepatic expression of genes related to lipid metabolism (Lpl) and transport (Cd36) showed minor changes. Immunohistochemical assessment indicated a lower induction of infiltrating neutrophils in the livers of ethanol-fed Ldlr-/- mice compared to wild type mice. In line, hepatic mRNA levels of the proinflammatory genes Ly6g, Cd11b, Ccr2, Cxcl1 and F4/80 were reduced, indicating less inflammation in the livers of Ldlr-/- mice which was associated with reduced Tlr9 induction. While systemic ALT and hepatic MDA levels were not different, Ldlr-deficient mice showed accelerated liver fibrosis development after chronic-binge ethanol diet than wild type mice, as indicated by increased levels of Sirius Red staining and higher expression of pro-fibrotic genes Tgfb, Col1a1 and Col3a1. Ldlr-/- and wild type mice had similar plasma ethanol levels and did not show differences in the hepatic mRNA levels of Adh1 and Cyp2e1, important for ethanol metabolism. Conclusion: Our results highlight that chronic-binge ethanol feeding enhances systemic dyslipidemia in Ldlr-/- mice which might accelerate the development of hepatic fibrosis, independent of hepatic lipid levels. [ABSTRACT FROM AUTHOR]

Bile salt export pump (Bsep) (Abcb11)−/− mice are protected from acquired cholestatic injury due to metabolic preconditioning with a hydrophilic bile acid (BA) pool with formation of tetrahydroxylated bile acids (THBAs). We aimed to explore whether loss of Bsep and subsequent elevation of THBA levels may have immunomodulatory effects, thus improving liver injury in the multidrug resistance protein 2 (Mdr2) (Abcb4)−/− mouse. Cholestatic liver injury in Mdr2−/−Bsep−/− double knockout (DKO), Mdr2−/−, Bsep−/−, and wild‐type mice was studied for comparison. Mdr2−/− mice were treated with a THBA (3α,6α,7α,12α‐Tetrahydroxycholanoic acid). RNA/protein expression of inflammatory/fibrotic markers were investigated. Serum BA‐profiling was assessed by ultra‐performance liquid chromatography tandem mass spectrometry. Hepatic immune cell profile was quantified by flow cytometric analysis (FACS). In vitro, the THBA effect on chenodeoxycholic acid (CDCA)–induced inflammatory signaling in hepatocyte and cholangiocytes as well as lipopolysaccharide (LPS)/interferon‐γ (IFN‐γ)–induced macrophage activation was analyzed. In contrast to Mdr2−/−, DKO mice showed no features of sclerosing cholangitis. Sixty‐seven percent of serum BAs in DKO mice were polyhydroxylated (mostly THBAs), whereas Mdr2−/− mice did not have these BAs. Compared with Mdr2−/−, DKO animals were protected from hepatic inflammation/fibrosis. THBA feeding in Mdr2−/− mice improved liver injury. FACS analysis in DKO and Mdr2−/− THBA‐fed mice showed changes of the hepatic immune cell profile towards an anti‐inflammatory pattern. Early growth response 1 (EGR1) protein expression was reduced in DKO and in Mdr2−/− THBA‐fed mice compared with Mdr2−/− control mice. In vitro, THBA‐reduced CDCA induced EGR1 protein and mRNA expression of inflammatory markers in hepatocytes and cholangiocytes. LPS/IFN‐γ–induced macrophage activation was ameliorated by THBA. THBAs repress EGR1‐related key pro‐inflammatory pathways. Conclusion: THBA and their downstream targets may represent a potential treatment strategy for cholestatic liver diseases. [ABSTRACT FROM AUTHOR]