Linkage of gut microbiome with cognition in hepatic encephalopathy

Abstract

Hepatic encephalopathy (HE) has been related to gut bacteria and inflammation in the setting of intestinal barrier dysfunction. We aimed to link the gut microbiome with cognition and inflammation in HE using a systems biology approach. Multitag pyrosequencing (MTPS) was performed on stool of cirrhotics and age-matched controls. Cirrhotics with/without HE underwent cognitive testing, inflammatory cytokines, and endotoxin analysis. Patients with HE were compared with those without HE using a correlation-network analysis. A select group of patients with HE (n = 7) on lactulose underwent stool MTPS before and after lactulose withdrawal over 14 days. Twenty-five patients [17 HE (all on lactulose, 6 also on rifaximin) and 8 without HE, age 56 ± 6 yr, model for end-stage liver disease score 16 ± 6] and ten controls were included. Fecal microbiota in cirrhotics were significantly different (higher Enterobacteriaceae, Alcaligeneceae, and Fusobacteriaceae and lower Ruminococcaceae and Lachnospiraceae) compared with controls. We found altered flora (higher Veillonellaceae), poor cognition, endotoxemia, and inflammation (IL-6, TNF-α, IL-2, and IL-13) in HE compared with 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. We concluded that cirrhosis, especially when complicated with HE, is associated with significant alterations in the stool microbiome compared with healthy individuals. Specific bacterial families (Alcaligeneceae, Porphyromonadaceae, Enterobacteriaceae) are strongly associated with cognition and inflammation in HE.

Gut Microbiota, Inflammation and Hepatic Encephalopathy: A Puzzle with a Solution in Sight

“…15 In the previous report, Bajaj et al have convincingly demonstrated that lactulose withdrawal does not exert a very significant effect on the composition of the fecal microbiome except for a reduction in Faecalibacterium sp. 14 These observations suggest that gut bacterial function, rather than a change in the microbiome composition, may be responsible for the effects of lactulose. 15 Authors hypothesized that cirrhotic patients with HE controlled on daily lactulose can be withdrawn from therapy without cognitive deterioration and those who did experience an episode of HE recurrence have different metabiome interactions than those who remained recurrence-free.…”

Microbiome alterations observed in liver diseases present opportunities for potential fecal transplantation

“…A similarly organized 2011 study did not use CDR, however, it did correlate decreased microflora diversity in patients with cirrhosis compared to controls. Diversity was even less in decompensated cirrhotic patients with hepatic encephalopathy (10). The pathology associated with altered CDR is thought to be secondary to reduced production of fatty acids which function to reduce colonic inflammation and reduce intestinal permeability to endotoxins (11).…”

Probiotics and Liver Disease

“…22 Changes in microbiota have also been implicated in causation of hepatic encephalopathy, but the reports are conflicting. [23][24][25] However, the weight of evidence suggests some relationship between changes in microbiota and cognition. Changes in gut microbiota may also have a role in the pathogenesis of other complications of cirrhosis (eg, spontaneous bacterial peritonitis, hepatorenal syndrome, and cirrhotic …”