Epidemiology of the gut-liver axis and hepatocellular carcinoma risk in a multiethnic liver cirrhosis cohort: defining the role of bacteria, metabolites, and glycoproteins

PROJECT SUMMARY Hepatocellular carcinoma (HCC) is the most common type of liver cancer in adults in which most cases develop in patients with liver cirrhosis. The incidence and mortality of HCC is rising and showing widening disparities, with the Latinx population having the greatest increase over the last decade. Latinxs represent 19%

of the total U.S. population, comprise the largest racial/ethnic group in California (CA, 40%), and are notably underrepresented in current research into biomarkers for HCC. Notably, HCC in U.S. born Latinxs from Mexico is double that of Mexican-born individuals, underscoring the importance of social, behavioral, and

environmental risk factors on hepatocarcinogenesis. In our preliminary research using the Microbiome, Microbial Markers, and Liver Disease (M3LD) Study, a multicenter prospective cohort of individuals with liver cirrhosis recruited across CA, we published the first-in-human evidence showing a role for the gut-liver axis in

HCC risk. We identified a duodenal microbe (Alloprevotella), circulating metabolites (methionine and methionine sulfoxide), and bile acid (taurocholic acid) that were associated with subsequent diagnosis of HCC. We found a Latinx ethnicity-specific microbiome composition in participants with cirrhosis, and we showed that

dietary factors previously associated with reduced HCC risk (healthy eating index, coffee, fiber, and protein) were associated with Latinx ethnicity and significant microbial differences in participants with cirrhosis at risk of HCC. Based on these preliminary results, this study proposes to expand the M3LD cohort by enrolling ~1000

participants with liver cirrhosis enriching for the Latinx population, who will be followed prospectively for HCC development. We will collect duodenal biopsy and blood specimens, clinical data, and epidemiological data. We will characterize the duodenal barrier and identify novel bacteria and glycans, and probe for microbial-

related serum immune markers and metabolites. The overall goal is to apply a rigorous experimental design that will reveal mechanisms that influence HCC risk in the Latinx population, ultimately leading to the identification of novel biomarkers for risk assessment and targets for HCC prevention, and a disparity

reduction.