Intestinal REG3 Lectins Protect against Alcoholic Steatohepatitis by Reducing Mucosa-Associated Microbiota and Preventing Bacterial Translocation

Abstract

Summary Approximately half of all deaths from liver cirrhosis, the 10th leading cause of mortality in the United States, are related to alcohol use. Chronic alcohol consumption is accompanied by intestinal dysbiosis and bacterial overgrowth, yet little is known about the factors that alter the microbial composition or their contribution to liver disease. We previously associated chronic alcohol consumption with lower intestinal levels of the antimicrobial-regenerating islet-derived (REG)-3 lectins. Here, we demonstrate that intestinal deficiency in REG3B or REG3G increases numbers of mucosa-associated bacteria and enhances bacterial translocation to the mesenteric lymph nodes and liver, promoting the progression of ethanol-induced fatty liver disease toward steatohepatitis. Overexpression of Reg3g in intestinal epithelial cells restricts bacterial colonization of mucosal surfaces, reduces bacterial translocation, and protects mice from alcohol-induced steatohepatitis. Thus, alcohol appears to impair control of the mucosa-associated microbiota, and subsequent breach of the mucosal barrier facilitates progression of alcoholic liver disease.

Intestinal fungi contribute to development of alcoholic liver disease

“…Although a larger, prospective study is required to confirm data from our retrospective analysis of a human cohort with a relatively small number of patients, our findings support the importance of the mycobiota for patients with alcoholic liver disease. We confirmed that ethanol-induced liver disease is associated with an increase in hepatic F4/80-positive cells (22). CLEC7A is primarily expressed on myeloid cells (18).…”

“…Chronic ethanol administration induced bacterial dysbiosis in mice given vehicle (4,21,22) (Supplemental Figure 2E). Antifungal treatment did not produce major changes in the bacterial composition in isocaloric or ethanol diet-fed mice by comparison of bacterial 16S rRNA data sets (Supplemental Figure 2E).…”

“…We performed deep DNA pyrosequencing of fecal DNA, targeting the hypervariable V4 region of prokaryotic 16S rRNA loci, using a dual indexing strategy on the Illumina MiSeq platform, as previously described (45). Microbial community profiles were generated using species-level (97% similarity) operational taxonomic unitbased (OTU-based) classification and analysis, as previously described by us (22). Sequence data were registered at NCBI under BioProject PRJ-NA317649.…”

The Gut Microbiota and the Hepatologist: Will Our Bugs Prove to be the Missing Link?

“…In a mouse model, intragastric infusion of alcohol led to increased abundance of 2 bacterial phyla, the Bacteroidetes and Verrucomicrobia and a reduced abundance of the phylum Firmicutes , particularly the genus Lactobacillus , compared to control mice [12] . The mice fed alcohol showed downregulation of bactericidal c-type lectins Reg3g in the small intestine; interestingly, treatment with prebiotics partially restored Reg3g expression, decreased bacterial overgrowth and led to a reduction in alcoholic steatohepatitis [13] . Another study elegantly demonstrated that the probiotic Lactobacillus rhamnosus GG prevented alcohol-induced pathogenic changes in the microbiome and the liver [14] .…”

“…Wang et al [13] showed that the administration of alcohol to mice caused intestinal deficiency in Reg3 lectins, which led to an increase in mucosa-associated bacteria, enhanced translocation of gut bacteria to the liver and mesenteric lymph nodes and promoted progression from fatty liver disease to steatohepatitis.…”