Modulation of the Metabiome by Rifaximin in Patients with Cirrhosis and Minimal Hepatic Encephalopathy

Authors

Jasmohan S. Bajaj, Virginia Commonwealth UniversityFollow
Douglas M. Heuman, Virginia Commonwealth UniversityFollow
Arun J. Sanyal, Virginia Commonwealth UniversityFollow
Phillip B. Hylemon, Virginia Commonwealth UniversityFollow
Richard K. Sterling, Virginia Commonwealth UniversityFollow
R. Todd Stravitz, Virginia Commonwealth UniversityFollow
Michael Fuchs, Virginia Commonwealth UniversityFollow
Jason M. Ridlon, Virginia Commonwealth UniversityFollow
Kalyani Daita, Virginia Commonwealth UniversityFollow
Pamela Monteith, Virginia Commonwealth University
Nicole A. Noble, Virginia Commonwealth UniversityFollow
Melanie B. White, Virginia Commonwealth UniversityFollow
Andmorgan Fisher, George Mason University
Masoumeh Sikaroodi, George Mason University
Huzefa Rangwala, George Mason University
Patrick M. Gillevet, George Mason University

Document Type

Article

Original Publication Date

2013

Journal/Book/Conference Title

PLOS ONE

Volume

8

DOI of Original Publication

10.1371/journal.pone.0060042

Comments

Originally Published at http://dx.doi.org/10.1371/journal.pone.0060042

Date of Submission

November 2014

Abstract

Hepatic encephalopathy (HE) represents a dysfunctional gut-liver-brain axis in cirrhosis which can negatively impact outcomes. This altered gut-brain relationship has been treated using gut-selective antibiotics such as rifaximin, that improve cognitive function in HE, especially its subclinical form, minimal HE (MHE). However, the precise mechanism of the action of rifaximin in MHE is unclear. We hypothesized that modulation of gut microbiota and their end-products by rifaximin would affect the gut-brain axis and improve cognitive performance in cirrhosis. Aim To perform a systems biology analysis of the microbiome, metabolome and cognitive change after rifaximin in MHE.

Methods

Twenty cirrhotics with MHE underwent cognitive testing, endotoxin analysis, urine/serum metabolomics (GC and LC-MS) and fecal microbiome assessment (multi-tagged pyrosequencing) at baseline and 8 weeks post-rifaximin 550 mg BID. Changes in cognition, endotoxin, serum/urine metabolites (and microbiome were analyzed using recommended systems biology techniques. Specifically, correlation networks between microbiota and metabolome were analyzed before and after rifaximin.

Results

There was a significant improvement in cognition(six of seven tests improved,pVeillonellaceaeand increase inEubacteriaceae was observed. Rifaximin resulted in a significant reduction in network connectivity and clustering on the correlation networks. The networks centered onEnterobacteriaceae, Porphyromonadaceae and Bacteroidaceae indicated a shift from pathogenic to beneficial metabolite linkages and better cognition while those centered on autochthonous taxa remained similar.

Conclusions

Rifaximin is associated with improved cognitive function and endotoxemia in MHE, which is accompanied by alteration of gut bacterial linkages with metabolites without significant change in microbial abundance.

Trial Registration

ClinicalTrials.gov NCT01069133

Rights

© 2013 Bajaj et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Is Part Of

VCU Internal Medicine Publications