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Kang DJ, Kakiyama G, Betrapally NS, et al. Rifaximin Exerts Beneficial Effects Independent of its Ability to Alter Microbiota Composition. Clin Transl Gastroenterol. 2016;7(8):e187doi: 10.1038/ctg.2016.44.
Kang, D. J., Kakiyama, G., Betrapally, N. S., Herzog, J., Nittono, H., Hylemon, P. B., Zhou, H., Carroll, I., Yang, J., Gillevet, P. M., Jiao, C., Takei, H., Pandak, W. M., Iida, T., Heuman, D. M., Fan, S., Fiehn, O., Kurosawa, T., Sikaroodi, M., Sartor, R. B., & Bajaj, J. S. (2016). Rifaximin Exerts Beneficial Effects Independent of its Ability to Alter Microbiota Composition. Clinical and translational gastroenterology, 7(8), e187. https://doi.org/10.1038/ctg.2016.44
Kang, Dae J, et al. "Rifaximin Exerts Beneficial Effects Independent of its Ability to Alter Microbiota Composition." Clinical and translational gastroenterology vol. 7,8 (2016): e187. doi: https://doi.org/10.1038/ctg.2016.44
Kang DJ, Kakiyama G, Betrapally NS, Herzog J, Nittono H, Hylemon PB, Zhou H, Carroll I, Yang J, Gillevet PM, Jiao C, Takei H, Pandak WM, Iida T, Heuman DM, Fan S, Fiehn O, Kurosawa T, Sikaroodi M, Sartor RB, Bajaj JS. Rifaximin Exerts Beneficial Effects Independent of its Ability to Alter Microbiota Composition. Clin Transl Gastroenterol. 2016 Aug 25;7(8):e187. doi: 10.1038/ctg.2016.44. PMID: 27560928; PMCID: PMC5543406.
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Clin Transl Gastroenterol. 2016 Aug 25;7(8):e187. doi: 10.1038/ctg.2016.44.

Rifaximin Exerts Beneficial Effects Independent of its Ability to Alter Microbiota Composition.

Clinical and translational gastroenterology

Dae J Kang, Genta Kakiyama, Naga S Betrapally, Jeremy Herzog, Hiroshi Nittono, Phillip B Hylemon, Huiping Zhou, Ian Carroll, Jing Yang, Patrick M Gillevet, Chunhua Jiao, Hajime Takei, William M Pandak, Takashi Iida, Douglas M Heuman, Sili Fan, Oliver Fiehn, Takao Kurosawa, Masoumeh Sikaroodi, R B Sartor, Jasmohan S Bajaj

Affiliations

  1. Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
  2. Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA.
  3. Department of Medicine, University of North Carolina, Division of Gastroenterology and Hepatology, Chapel Hill, North Carolina, USA.
  4. Junshin Clinic Bile Acid Institute, Tokyo, Japan.
  5. Department of Microbiology and Immunology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
  6. Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo, Japan.
  7. West Coast Metabolomics Center, University of California, Davis, California, USA.
  8. School of Pharmaceutical Science, Health Sciences University of Hokkaido, Tobetsu, Japan.

PMID: 27560928 PMCID: PMC5543406 DOI: 10.1038/ctg.2016.44

Abstract

OBJECTIVES: Rifaximin has clinical benefits in minimal hepatic encephalopathy (MHE) but the mechanism of action is unclear. The antibiotic-dependent and -independent effects of rifaximin need to be elucidated in the setting of MHE-associated microbiota. To assess the action of rifaximin on intestinal barrier, inflammatory milieu and ammonia generation independent of microbiota using rifaximin.

METHODS: Four germ-free (GF) mice groups were used (1) GF, (2) GF+rifaximin, (3) Humanized with stools from an MHE patient, and (4) Humanized+rifaximin. Mice were followed for 30 days while rifaximin was administered in chow at 100 mg/kg from days 16-30. We tested for ammonia generation (small-intestinal glutaminase, serum ammonia, and cecal glutamine/amino-acid moieties), systemic inflammation (serum IL-1β, IL-6), intestinal barrier (FITC-dextran, large-/small-intestinal expression of IL-1β, IL-6, MCP-1, e-cadherin and zonulin) along with microbiota composition (colonic and fecal multi-tagged sequencing) and function (endotoxemia, fecal bile acid deconjugation and de-hydroxylation).

RESULTS: All mice survived until day 30. In the GF setting, rifaximin decreased intestinal ammonia generation (lower serum ammonia, increased small-intestinal glutaminase, and cecal glutamine content) without changing inflammation or intestinal barrier function. Humanized microbiota increased systemic/intestinal inflammation and endotoxemia without hyperammonemia. Rifaximin therapy significantly ameliorated these inflammatory cytokines. Rifaximin also favorably impacted microbiota function (reduced endotoxin and decreased deconjugation and formation of potentially toxic secondary bile acids), but not microbial composition in humanized mice.

CONCLUSIONS: Rifaximin beneficially alters intestinal ammonia generation by regulating intestinal glutaminase expression independent of gut microbiota. MHE-associated fecal colonization results in intestinal and systemic inflammation in GF mice, which is also ameliorated with rifaximin.

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