Linkage of gut microbiome with cognition in hepatic encephalopathy

Div. of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth Univ. and McGuire VA Medical Ctr., 1201, Broad Rock Blvd., Richmond, VA 23249, USA.
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.74). 09/2011; 302(1):G168-75. DOI: 10.1152/ajpgi.00190.2011
Source: PubMed

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.

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    ABSTRACT: Some evidence has shown benefits of probiotics in the management of minimal hepatic encephalopathy (MHE). We evaluated the efficacy of a multistrain probiotic compound, alone and in combination with lactulose, in the treatment of MHE. This study has two parts. First, consecutive adult patients with MHE were randomized to receive lactulose (30-60 mL/day) + probiotic (200 million colony forming units of seven bacteria species/day) (Gp-LPr) or lactulose + placebo (Gp-L). In second part, a non-randomized group of patients received probiotic alone (Gp-Pr). Medication duration was for 2 weeks and patients were followed-up for another 8 weeks. Improvement in MHE status was assessed by psychometric hepatic encephalopathy score (PHES). Development of overt encephalopathy, hospitalization, and death were considered as secondary outcomes. Sixty patients (80% male, mean age 38.4 ± 9.6 years) completed the intervention. PHES significantly improved after medication in all the three groups (Gp-LPr: -3.8 ± 3.9 to -1.6 ± 3.0; Gp-L: -4.8 ± 4.1 to -1.6 ± 2.9; and Gp-Pr: -4.9 ± 3.7 to -2.1 ± 2.5, P < 0.001). After 8 weeks follow-up, improvement was maintained in Gp-LPr and Gp-Pr, but there was deterioration in those who did not receive probiotics (Gp-L: PHES score reversed to -4.8 ± 4.2). Two patients (one each in Gp-L and Gp-Pr) experienced overt encephalopathy. One patient was hospitalized due to worsening of ascites (Gp-LPr) and one due to spontaneous bacterial peritonitis (Gp-L). Side effects were mild and not significantly different among the groups. Lactulose and probiotics are effective for the treatment of MHE; however, probiotics, but not lactulose, have long-term effects. More studies are required before suggesting probiotics for the standard treatment of MHE.
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    ABSTRACT: Several studies revealed that gut microbiota are associated with various human diseases, e.g., metabolic diseases, allergies, gastroenterological diseases, and liver diseases. The liver can be greatly affected by changes in gut microbiota due to the entry of gut bacteria or their metabolites into the liver through the portal vein, and the liver-gut axis is important to understand the pathophysiology of several liver diseases, especially non-alcoholic fatty liver disease and hepatic encephalopathy. Moreover, gut microbiota play a significant role in the development of alcoholic liver disease and hepatocarcinogenesis. Based on these previous findings, trials using probiotics have been performed for the prevention or treatment of liver diseases. In this review, we summarize the current understanding of the changes in gut microbiota associated with various liver diseases, and we describe the therapeutic trials of probiotics for those diseases.
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