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Rifaximin Exerts Beneficial Effects Independent of its Ability to Alter Microbiota Composition.
Kang, Dae J; Kakiyama, Genta; Betrapally, Naga S; Herzog, Jeremy; Nittono, Hiroshi; Hylemon, Phillip B; Zhou, Huiping; Carroll, Ian; Yang, Jing; Gillevet, Patrick M; Jiao, Chunhua; Takei, Hajime; Pandak, William M; Iida, Takashi; Heuman, Douglas M; Fan, Sili; Fiehn, Oliver; Kurosawa, Takao; Sikaroodi, Masoumeh; Sartor, R B; Bajaj, Jasmohan S.
Afiliação
  • Kang DJ; Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
  • Kakiyama G; Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
  • Betrapally NS; Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA.
  • Herzog J; Department of Medicine, University of North Carolina, Division of Gastroenterology and Hepatology, Chapel Hill, North Carolina, USA.
  • Nittono H; Junshin Clinic Bile Acid Institute, Tokyo, Japan.
  • Hylemon PB; Department of Microbiology and Immunology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
  • Zhou H; Department of Microbiology and Immunology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
  • Carroll I; Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA.
  • Yang J; Department of Microbiology and Immunology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
  • Gillevet PM; Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA.
  • Jiao C; Department of Microbiology and Immunology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
  • Takei H; Junshin Clinic Bile Acid Institute, Tokyo, Japan.
  • Pandak WM; Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
  • Iida T; Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo, Japan.
  • Heuman DM; Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
  • Fan S; West Coast Metabolomics Center, University of California, Davis, California, USA.
  • Fiehn O; West Coast Metabolomics Center, University of California, Davis, California, USA.
  • Kurosawa T; School of Pharmaceutical Science, Health Sciences University of Hokkaido, Tobetsu, Japan.
  • Sikaroodi M; Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA.
  • Sartor RB; Department of Medicine, University of North Carolina, Division of Gastroenterology and Hepatology, Chapel Hill, North Carolina, USA.
  • Bajaj JS; Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
Clin Transl Gastroenterol ; 7(8): e187, 2016 Aug 25.
Article em En | MEDLINE | ID: mdl-27560928
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-1ß, IL-6), intestinal barrier (FITC-dextran, large-/small-intestinal expression of IL-1ß, 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.

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2016 Tipo de documento: Article