Source 1Virginia Commonwealth University and McGuire VAMC.

Background/aims: Hepatic encephalopathy (HE) has been related to gut bacteria and inflammation in the setting of intestinal barrier dysfunction. We proposed to link the gut microbiome with cognition and inflammation in HE using a systems biology approach.

Methods: Multi-tag pyrosequencing(MTPS) was performed on stool of cirrhotics and age-matched controls. Cirrhotics with/without HE underwent cognitive testing, inflammatory cytokines, and endotoxin analysis. HE patients were compared to those without HE using a correlation network analysis. A select group of HE patients (n=7) on lactulose underwent stool MTPS before and after lactulose withdrawal over 14 days.

Results: 25 patients [17 HE (all on lactulose, 6 also on rifaximin) and 8 no HE, age 56±6 years, MELD 16±6] and 10 controls were included. Fecal microbiota in cirrhotics were significantly different (higher Enterobacteriaceae, Alcaligeneceae, Fusobacteriaceae and lower Ruminococcaceae and Lachnospiraceae) compared to controls. We found altered flora (higher Veillonellaceae), poor cognition, endotoxemia and inflammation (IL-6, TNF-α, IL-2 and IL-13) in HE compared to cirrhotics without HE. In the cirrhosis group, Alcaligeneceae and Porphyromonadaceae were positively correlated with cognitive impairment. Fusobacteriaceae, Veillonellaceae and Enterobacteriaceae were positively and Ruminococcaceae negatively related to inflammation. Network analysis comparison showed robust correlations(all p<1E-5) only in the HE group between the microbiome, cognition and IL-23, IL-2 and IL-13. Lactulose withdrawal did not change the microbiome significantly beyond Fecalibacterium reduction.

Conclusions: Cirrhosis, especially when complicated with HE, is associated with significant alterations in the stool microbiome compared to healthy individuals. Specific bacterial families (Alcaligeneceae, Porphyromonadaceae, Enterobacteriaceae) are strongly associated with cognition and inflammation in HE.