The role of pathobionts in alcoholic liver disease

Alcohol use disorder and alcohol-related liver disease are a major cause of morbidity and mortality among Veterans. Chronic alcoholism is associated with changes in the intestinal microbiota, increased intestinal permeability, and elevated systemic levels of bacterial products. Results from our laboratory indicate that intestinal pathobionts contribute to alcohol-related liver disease. Using an unbiased approach by metagenomic sequencing we found significantly more virulence factors in fecal metagenomes from patients with alcoholic hepatitis than patients with alcohol use disorder or non-alcoholic controls. The presence of the virulence factor kpsM encoded in the genome of Escherichia coli (E. coli), is independently associated with mortality in patients with alcoholic hepatitis. E. coli kpsM is involved in the synthesis and expression of the polysialic acid capsule. Our preliminary data further shows that E. coli kpsM escapes phagocytosis by Kupffer cells. A subsequent increase in hepatic inflammation contributes to the development of ethanol-induced liver disease. This is supported by additional data demonstrating that colonization of gnotobiotic mice with feces from a patient with alcoholic hepatitis positive for E. coli kpsM exacerbates ethanol-induced liver disease. We hypothesize that pathobiontic kpsM-positive E. coli are an important etiological factor in the modulation of hepatic inflammation and the development of alcohol-related liver disease. Our experimental approach is to correlate specific virulence-related genes in the gut metagenomes with clinical outcomes of Veterans with alcohol-related liver disease (Aim 1). We will investigate the molecular mechanism of how kpsM-positive E. coli contribute to alcohol-related liver disease in vivo and in cultured liver cells (Aim 2). Using a precision-microbiome approach, we will test the hypothesis that targeted manipulation of alcohol-associated dysbiosis can ameliorate ethanol- induced liver disease (Aim 3). We believe these studies will provide novel insights into the contribution of the microbiota to alcohol-related liver disease. Innovative and novel strategies will be developed to prevent or ameliorate alcohol-related liver disease in Veterans.