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Updated: Mar 15, 2026
Quantitative Polymerase Chain Reaction-based Analyses of Murine Intestinal Microbiota After Oral Antibiotic Treatment
Published on: November 17, 2018
Rifaximin Exerts Beneficial Effects Independent of its Ability to Alter Microbiota Composition
Dae J Kang1, Genta Kakiyama1, Naga S Betrapally2
1Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.
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.
Insights
Rifaximin reduces ammonia generation independently of gut bacteria by regulating intestinal glutaminase expression. It also lessens inflammation and improves gut function in minimal hepatic encephalopathy models.
Area of Science:
- Gastroenterology and Hepatology
- Microbiome Research
- Pharmacology
Background:
- Minimal hepatic encephalopathy (MHE) is associated with altered gut microbiota and ammonia production.
- Rifaximin is a non-absorbable antibiotic used to treat MHE, but its precise mechanisms of action remain unclear.
- Understanding rifaximin's effects, both antibiotic-dependent and -independent, is crucial for optimizing MHE management.
Purpose of the Study:
- To investigate the mechanisms of rifaximin in minimal hepatic encephalopathy (MHE).
- To differentiate between antibiotic-dependent and -independent effects of rifaximin on the gut.
- To assess rifaximin's impact on ammonia generation, intestinal barrier, and inflammation in an MHE model.
Main Methods:
- Germ-free (GF) mice and humanized mice (colonized with MHE patient microbiota) were used, with some groups receiving rifaximin.
- Measurements included ammonia generation markers (serum ammonia, cecal glutamine, intestinal glutaminase), systemic inflammation (cytokines), intestinal barrier integrity (FITC-dextran, tight junction proteins), and microbiota function (endotoxemia, bile acid metabolism).
Main Results:
- Rifaximin reduced ammonia generation in GF mice by increasing intestinal glutaminase expression, independent of microbiota.
- Humanized microbiota induced systemic and intestinal inflammation, which was significantly reduced by rifaximin.
- Rifaximin improved microbiota function by decreasing endotoxemia and altering bile acid metabolism, without changing microbial composition.
Conclusions:
- Rifaximin effectively reduces intestinal ammonia generation through microbiota-independent regulation of glutaminase.
- MHE-associated microbiota contributes to inflammation, which can be ameliorated by rifaximin.
- Rifaximin demonstrates beneficial effects on both ammonia generation and inflammation in MHE, highlighting its multifaceted therapeutic role.
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