Short-chain fatty acids alleviate acute pancreatitis by targeting IL-17A to inhibit inflammation and restore intestinal barrier function.

BACKGROUND & AIMS: Acute pancreatitis (AP) is a life-threatening inflammatory disease with a rising incidence in which intestinal barrier dysfunction and bacterial translocation contribute to severe disease progression. Short-chain fatty acids (SCFAs), key microbial metabolites, have been linked to intestinal health, however, their role in AP and the underlying mechanisms remain unclear. This study aimed to investigate whether SCFAs alleviate AP by restoring intestinal barrier function and modulating inflammation, with a focus on the gut microbiota and the interleukin-17A (IL-17A) pathway. METHODS: Mouse AP models were induced using caerulein, and mice were treated with exogenous mixed SCFAs, IL-17A/IL-17RA inhibitors, or recombinant IL-17A (rIL-17A). Germ-free mice, antibiotic-treated mice, and fecal microbiota transplantation (FMT) were used to assess the role of the gut microbiota. Fecal SCFA levels, pancreatic/intestinal histopathology, barrier function markers (Occludin, claudin-1, and D-lactate), inflammatory cytokines, and the IL-17A pathway were analyzed via GC-MS, immunohistochemistry, Western blotting, RNA sequencing, and 16S rRNA gene sequencing. RESULTS: Fecal SCFA levels were reduced in AP mice. Exogenous mixed SCFAs ameliorated pancreatic injury, decreased serum amylase/lipase and proinflammatory cytokines (IL-1β, TNF-α, and IFN-γ), and restored intestinal barrier integrity (increased villus length, mucus layer thickness, and tight junction proteins). The protective effects of SCFAs were abrogated in germ-free or antibiotic-treated mice, but FMT from SCFA-treated donors recapitulated these benefits, supporting a contribution of the gut microbiota to SCFA-mediated protection. 16S rRNA sequencing revealed that SCFAs increased Bifidobacterium pseudolongum (B. pseudolongum) abundance, and B. pseudolongum supplementation alone mitigated AP severity. RNA sequencing and functional assays revealed that SCFAssuppressed the intestinal IL-17A/IL-17RA pathway, reducing the Th17 cell proportion and IL-17A-driven inflammation. The inhibition of IL-17A or IL-17RA mimicked the protective effects of SCFAs, whereas rIL-17A exacerbated AP, which was reversed by SCFAs. CONCLUSION: SCFAs alleviate AP by improving intestinal barrier integrity and suppressing inflammation, with the gut microbiota contributing, at least in part, to these protective effects. These effects involve gut microbiota remodeling, enrichment of B. pseudolongum, and attenuation of the IL-17A/IL-17RA-related signaling. These findings support a microbiota-associated SCFA-IL-17A regulatory axis in AP and suggest that IL-17A-related signaling warrants further investigation as a potential therapeutic target.