Gut Microbiota of Subjects with Severe Cirrhosis Is Impacted by Rifaximin and Is Associated with Disease Severity: A Randomized Clinical Trial

Severe cirrhosis represents an unmet medical need, as no therapy can reverse disease progression. Increasing evidence implicates gut dysbiosis in the pathophysiology of cirrhosis, highlighting the gut microbiome as a source of biomarkers and therapeutic targets. Although rifaximin reduces complications in advanced cirrhosis, its impact on gut microbial communities and antibiotic resistance remains poorly understood. This multicenter trial (NCT03069131) evaluated the effect of rifaximin on 12-month survival and complication incidence in patients with severe cirrhosis. We characterized longitudinal changes in gut microbial composition in 21 rifaximin-treated patients and 21 controls using 16S rRNA gene sequencing combined with culture-based approaches. Associations between bacterial profiles and disease severity were used to identify microbial signatures linked to clinical outcomes, including overall survival and spontaneous bacterial peritonitis incidence. We identified several bacterial groups associated with disease severity, overall survival, and spontaneous bacterial peritonitis. Rifaximin treatment was associated with reduced microbial richness, decreased abundance of taxa typically enriched in advanced cirrhosis (e.g., Escherichia, Streptococcus, Veillonella), and increased concentrations of rifaximin-resistant E. coli. Altogether, these findings support the potential of microbiota-derived signatures to reflect clinical status, improve patient stratification, and guide future investigations aimed at clarifying their mechanistic relevance.