Cited by 430Liver Disease and TransplantationGut microbiota and healthGastrointestinal motility and disorders

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

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Bajaj, Jasmohan S., Heuman, Douglas M., Sanyal, Arun J., Hylemon, Phillip B., Sterling, Richard K., Stravitz, R. Todd, Fuchs, Michael, Ridlon, Jason M., Daita, Kalyani, Monteith, Pamela, Noble, Nicole A., White, Melanie B., Fisher, Andmorgan, Sikaroodi, Masoumeh, Rangwala, Huzefa, Gillevet, Patrick M.·2013·PLoS ONE

DOI 10.1371/journal.pone.0060042PMC PMC3615021

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Abstract

UNLABELLED: 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, p<0.01) and endotoxemia (0.55 to 0.48 Eu/ml, p = 0.02) after rifaximin. There was a significant increase in serum saturated (myristic, caprylic, palmitic, palmitoleic, oleic and eicosanoic) and unsaturated (linoleic, linolenic, gamma-linolenic and arachnidonic) fatty acids post-rifaximin. No significant microbial change apart from a modest decrease in Veillonellaceae and increase in Eubacteriaceae was observed. Rifaximin resulted in a significant reduction in network connectivity and clustering on the correlation networks. The networks centered on Enterobacteriaceae, 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.

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Background
Rifaximin Treatment in Hepatic Encephalopathy
Bass, N. M., Mullen, K. D., Sanyal, A., Poordad, F., Neff, G., Leevy, C. B., Sigal, S., Sheikh, M. Y., Beavers, K., Frederick, T., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0907893 · Cited by 1,300
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Authors: Bajaj, J. S., Heuman, D. M., Sanyal, A. J., Hylemon, P. B., Sterling, R. K., Stravitz, R. T., Fuchs, M., Ridlon, J. M., Daita, K., Monteith, P., Noble, N. A., White, M. B., Fisher, A., Sikaroodi, M., Rangwala, H., & Gillevet, P. M.
Affiliations: Virginia Commonwealth University (US)
George Mason University (US)
Corresponding author: Bajaj, Jasmohan S.
ORCID: Bajaj, Jasmohan S.
Sanyal, Arun J.
Hylemon, Phillip B.
Sterling, Richard K.
Stravitz, R. Todd
Fuchs, Michael
Ridlon, Jason M.
White, Melanie B.
Fisher, Andmorgan
Sikaroodi, Masoumeh
Rangwala, Huzefa
Gillevet, Patrick M.
Venue: PLoS ONE
Publisher: Public Library of Science (PLoS)
Published: 2013-04-02
Volume: 8
Issue: 4
Pages: e60042
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0060042
PMC: PMC3615021
OpenAlex: W2138196119
Cited by: 430
References: 46
Citations by year: 2026: 19 · 2025: 27 · 2024: 34 · 2023: 34 · 2022: 25 · 2021: 40 · 2020: 31 · 2019: 37 · 2018: 45 · 2017: 27 · 2016: 31 · 2015: 43 · 2014: 25 · 2013: 9
FWCI: 22.45
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: PLoS ONE (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, other-oa)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
VCU Scholars Compass (Virginia Commonwealth University) (submittedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Figshare (submittedVersion, cc-by)
Funders: National Institutes of Health (UL1TR000058)
University of California, Davis
National Institute on Alcohol Abuse and Alcoholism (R01AA020203, RO1AA020203)
National Institute of Diabetes and Digestive and Kidney Diseases (RO1AA020203, RO1DK087913, R01DK087913)
National Center for Complementary and Alternative Medicine (RO1AA020203)
National Center for Advancing Translational Sciences
National Center for Complementary and Integrative Health (U01AT004428)
Topics: Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
Keywords: rifaximin, minimal hepatic encephalopathy, liver cirrhosis, gut microbiota, gut-brain axis, endotoxemia, cognitive function, serum metabolomics, urine metabolomics, fatty acids, Veillonellaceae, Enterobacteriaceae, Bacteroidaceae, Porphyromonadaceae
MeSH terms: Rifaximin, Cognition, Female, Hepatic Encephalopathy, Humans, Liver Cirrhosis, Male, Middle Aged, Rifamycins, Gastrointestinal Tract, Metagenome, Metabolomics, Metabolome

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

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