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

Bajaj, Jasmohan S

Betrapally, Naga S

Carroll, Ian

Fan, Sili

Fiehn, Oliver

Gillevet, Patrick M

Herzog, Jeremy

Heuman, Douglas M

Hylemon, Phillip B

Iida, Takashi

Jiao, Chunhua

Kakiyama, Genta

Kang, Dae J

Kurosawa, Takao

Nittono, Hiroshi

Pandak, William M

Sartor, R B

Sikaroodi, Masoumeh

Takei, Hajime

Yang, Jing

Zhou, Huiping

English

Carolina Digital Repository

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

ObjectivesRifaximin 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.MethodsFour 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).ResultsAll 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.ConclusionsRifaximin 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

Sartor, RB

eScholarship - University of California

http://cdr.lib.unc.edu/downloads/6108vg85w

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

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