Rifaximin reduces gut-derived inflammation in severe acute pancreatitis: an experimental animal model and randomized controlled trial

Severe acute pancreatitis (SAP) is characterized by systemic inflammation and intestinal barrier dysfunction and is often associated with gut microbiota dysbiosis. Rifaximin, a gut-specific non-absorbable antibiotic, is known to modulate the gut microbiota. Here, we investigated rifaximin’s effects and mechanisms in SAP using murine models and a single-center, open-label, randomized controlled trial (Chinese Clinical Trial Registry: ChiCTR2100049794). In mice, rifaximin attenuated pancreatic injury and systemic inflammation and altered gut microbiota composition by decreasing mucin-degrading genera such as Akkermansia ( P < 0.05). These protective effects persisted in antibiotic-treated and germ-free mice, suggesting mechanisms not solely dependent on gut microbiota modulation. In patients with predicted SAP ( n = 60), rifaximin significantly reduced systemic inflammation compared with controls. WBC decreased from a median of 11.50 × 10⁹/L (IQR 8.76–15.68) to 8.49 × 10⁹/L (6.93–10.20; P = 0.04) and TNF-α from 15.05 pg/mL (12.73–19.75) to 11.00 pg/mL (8.74–15.40; P = 0.009). However, the incidence of culture-confirmed infection did not differ between the rifaximin and control groups (13.3% vs. 13.3%; RR, 1.00; 95% CI, 0.28–3.63). Adverse events were comparable between groups. Metagenomic analyses revealed suppression of mucin-degrading bacteria (e.g., Akkermansia , Bacteroides fragilis , and Hungatella hathewayi ) ( P < 0.05) and reductions in mucin-degrading carbohydrate-active enzymes, including sialidases and fucosidases. In conclusion, among patients with predicted SAP, rifaximin did not reduce culture-confirmed infectious complications within 90 days after randomization compared with standard care, despite significant improvements in systemic inflammatory markers and selected fecal microbiome features. Larger randomized controlled trials are warranted to validate these findings. IMPORTANCE Although rifaximin has been used to target gut-derived inflammation in other contexts, its role in SAP remains largely unexplored. In this study, rifaximin treatment was associated with reduced pancreatic injury and systemic inflammation in both murine models and patients with predicted SAP. Treatment also led to changes in gut microbial composition, notably a decrease in mucin-degrading taxa. Importantly, similar protective effects were also observed in antibiotic-treated and germ-free mice, indicating that rifaximin may act via microbiota-dependent and host-directed pathways. These findings offer novel insights into the gut-pancreas axis and suggest that rifaximin holds therapeutic potential by modulating gut microbial composition and host inflammatory responses in SAP.