Gut‒liver‒brain axis signature of cirrhosis-related cognitive impairment is consistent across multi-national cohorts

Cognitive impairment in cirrhosis is associated with an altered gut‒liver‒brain axis, but geographic variations in diet and clinical practices may limit generalizability. We investigated consistency of microbial signatures for cirrhosis-related cognitive impairment across four countries. We enrolled outpatients with cirrhosis from USA, Denmark, Lithuania, and Mexico who underwent Psychometric Hepatic Encephalopathy Score (PHES) testing for covert hepatic encephalopathy (CHE), and stool shotgun metagenomic sequencing. Taxonomic and functional associations with PHES were evaluated after adjustment for MELD, country, demographics, sex, proton pump inhibitor (PPI), lactulose, and rifaximin use. We enrolled 221 patients (median age 58 y, 57.9% men, median MELD 12). Cognitive performance varied by country despite adjustment for clinical covariates. Lithuania demonstrated greater microbial richness and better cognition despite higher MELD, accompanied by distinct dietary patterns including greater yogurt and tea consumption. In the entire cohort, increasing MELD was associated with reduced microbial richness and depletion of commensals. Worse PHES performance, however, showed a distinct microbiome signature with increased Streptococcus abundance independent of MELD, country, PPI use, and HE therapies. Twenty-two microbial pathways were associated with PHES, mostly related to amino-acid biosynthesis and nitrogen metabolism. Of these, ornithine degradation and heme B biosynthesis II were uniquely enriched with worse PHES and CHE, which mapped onto Enterobacteriaceae. We conclude that across four geographically and culturally disparate countries, cirrhosis-related cognitive impairment was associated with consistent microbial compositional and functional alterations distinct from advancing liver disease. These findings support a consistent gut‒liver‒brain axis signature involving oral-gut translocation and altered nitrogen metabolism.