IDDF2024-ABS-0363 Bifidobacterium pseudolongum-generated acetate mitigates severe acute pancreatitis through the suppression of GPR43-mediated macrophage pyroptosis

<h3>Background</h3> Recent studies have highlighted the role of the gut microbiota and their metabolites in the progression of severe acute pancreatitis (SAP). We aimed to identify specific beneficial bacterial species that could be used prophylactically to prevent SAP. <h3>Methods</h3> We performed shotgun metagenomic sequencing in stool samples of SAP mice. Biological functions of <i>Bifidobacterium pseudolongum</i> on SAP was examined in mice by administration of caerulein. Fecal samples of germ-free mice and <i>B. pseudolongum</i>-conditioned media (B.p CM) were collected for non-targeted and targeted metabolomic profiles. THP-1 cells were co-cultured with B.p CM or candidate metabolites. <h3>Results</h3> The abundance of <i>B. pseudolongum</i> was significantly reduced in mice with SAP. Oral gavage of <i>B. pseudologum</i> profoundly protects against pancreatic necrosis and local and systemic inflammation. Incubation of THP-1 cells with B.p CM suppressed LPS-induced pyroptosis and the expression of inflammatory cytokines. Acetate was identified as the critical metabolite generated from <i>B. pseudolongum</i> in B.p CM, an observation that was confirmed in germ-free mice. Acetate also inhibited inflammatory responses in THP-1 cells and improved pancreatic damage in vivo. The destructions of the gut barrier and defensins have been restored by <i>B. pseudolongum</i> treatment. Moreover, the pancreatic protection of <i>B. pseudolongum</i> was diminished by the GPR43 inhibitor. Mechanistically, <i>B. pseudolongum</i> suppressed the NLRP3/GSDMD signaling pathway, which was reversed after GPR43 inhibitor administration. <h3>Conclusions</h3> <i>B. pseudolongum</i> protected against SAP by secreting the anti-inflammatory metabolite acetate, which modulated GPR43/NLRP3/GSDMD signaling pathway and suppressed macrophage pyroptosis. <i>B. pseudolongum</i> holds potential as a probiotic for the prevention of SAP.