title: Rifaximin Exerts Beneficial Effects Independent of its Ability to Alter Microbiota Composition.
abstract: OBJECTIVE
  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.
authors: Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
authors: Dae J
authors: DJ
authors: Kang
authors: Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
authors: Genta
authors: G
authors: Kakiyama
authors: Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA.
authors: Naga S
authors: NS
authors: Betrapally
authors: Department of Medicine, University of North Carolina, Division of Gastroenterology and Hepatology, Chapel Hill, North Carolina, USA.
authors: Jeremy
authors: J
authors: Herzog
authors: Junshin Clinic Bile Acid Institute, Tokyo, Japan.
authors: Hiroshi
authors: H
authors: Nittono
authors: Department of Microbiology and Immunology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
authors: Phillip B
authors: PB
authors: Hylemon
authors: Department of Microbiology and Immunology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
authors: Huiping
authors: H
authors: Zhou
authors: Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA.
authors: Ian
authors: I
authors: Carroll
authors: Department of Microbiology and Immunology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
authors: Jing
authors: J
authors: Yang
authors: Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA.
authors: Patrick M
authors: PM
authors: Gillevet
authors: Department of Microbiology and Immunology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
authors: Chunhua
authors: C
authors: Jiao
authors: Junshin Clinic Bile Acid Institute, Tokyo, Japan.
authors: Hajime
authors: H
authors: Takei
authors: Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
authors: William M
authors: WM
authors: Pandak
authors: Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo, Japan.
authors: Takashi
authors: T
authors: Iida
authors: Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
authors: Douglas M
authors: DM
authors: Heuman
authors: West Coast Metabolomics Center, University of California, Davis, California, USA.
authors: Sili
authors: S
authors: Fan
authors: West Coast Metabolomics Center, University of California, Davis, California, USA.
authors: Oliver
authors: O
authors: Fiehn
authors: School of Pharmaceutical Science, Health Sciences University of Hokkaido, Tobetsu, Japan.
authors: Takao
authors: T
authors: Kurosawa
authors: Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA.
authors: Masoumeh
authors: M
authors: Sikaroodi
authors: Department of Medicine, University of North Carolina, Division of Gastroenterology and Hepatology, Chapel Hill, North Carolina, USA.
authors: R B
authors: RB
authors: Sartor
authors: Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
authors: Jasmohan S
authors: JS
authors: Bajaj