Rifaximin’s therapeutic spectrum: approved indications and experimental insights into emerging uses

Since its 1987 approval, rifaximin has emerged as a gut-targeted, minimally absorbed antibiotic achieving high intestinal levels. Rifaximin works by blocking bacterial RNA polymerase to stop bacterial growth, which helps treat both traveler’s diarrhea and irritable bowel syndrome with diarrhea. It effectively modulates gut microbiota and alleviates dysbiosis-related symptoms. Beyond antimicrobial activity, rifaximin modulates dysbiosis, strengthens the epithelial barrier, and exerts pregnane X receptor (PXR)-mediated anti-inflammatory and anti-angiogenic effects, with implications along the gut–liver and gut–brain axes. These pleiotropic properties support expanding uses in small intestinal bacterial overgrowth (SIBO), inflammatory bowel diseases (IBD), functional dyspepsia, bloating, and lactose intolerance. However, high cost and potential resistance with prolonged exposure highlight the need for antimicrobial stewardship. The aims of this review are to summarize licensed and emerging indications and delineate non-conventional mechanisms. Patient stratification and further controlled clinical studies are required to optimize rifaximin’s precision-medicine potential.