Fecal Microbiota and Bile Acid Profiles in Early-Stage Hepatocellular Carcinoma: A Matched Case-Control Study

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INTRODUCTION: Early identification of hepatocellular carcinoma (HCC) is critical to reduce mortality. Diagnostic tools are limited for early disease. Intestinal microbiota may contribute to HCC risk directly and through metabolites, particularly bile acids (BAs), offering potential noninvasive biomarkers. METHODS: This was a case-control study of patients with cirrhosis with or without early-stage HCC, matched based on liver disease severity. Comprehensive analyses of fecal microbiota composition and function were performed. RESULTS: There were 98 patients in the study (49 patients per group). Subjects with HCC were older (median 64 vs 60 years, P < 0.01) and more likely to have hepatitis C (78% vs 43%, P < 0.01). Alpha diversity, beta diversity, and genes and pathways related to BA metabolism did not differ between groups overall, but alpha diversity did differ within the subset of patients with metabolic-associated steatotic liver disease. There was differential abundance of multiple taxa between groups, including higher abundance of Klebsiella pneumoniae in cases. Increased concentration of secondary BA, which are microbiota-dependent, was associated with higher odds of HCC (adjusted odds ratio 2.4, P = 0.02); however, addition of microbial or BA features to a model with clinical data alone did not improve HCC prediction. DISCUSSION: When accounting for liver disease severity, there were limited differences in intestinal microbiota composition and BA metabolism between subjects with or without early-stage HCC. Promising areas for future study of microbiota-based HCC biomarkers were identified, including a focus on the subpopulation of patients with metabolic-associated steatotic liver disease.

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