Better nutrition, better barrier: Short-peptide-based enteral nutrition maintains intestinal microenvironment to reduce bacterial translocation in severe acute pancreatitis

Enteral nutrition (EN) is recommended for treating severe acute pancreatitis (SAP), as it helps to reduce infection originating from intestinal bacterial translocation. However, the optimal EN type remains undetermined. This study aimed to evaluate the efficacy of short-peptide-based enteral nutrition (SPEN) versus intact-protein-based enteral nutrition (IPEN) in SAP, and to investigate the mechanism of action. A retrospective analysis was conducted to assess the impacts of SPEN versus IPEN on SAP patients. A murine SAP model was established to evaluate the effects of SPEN versus IPEN on intestinal microenvironment and bacterial translocation. Multi-omics analyses (microbiome, metabolome, transcriptome, single-cell RNA sequencing) were performed. Compared to IPEN, SPEN reduced hospital stay (OR = 0.186, 95% CI 0.070-0.492) and infection (OR = 0.281, 95% CI 0.108-0.729) in SAP patients. SPEN attenuated intestinal barrier damage and bacterial translocation in SAP mice. Then we first found that SPEN mitigated SAP-induced flagellated bacteria proliferation via restoring gut luminal microenvironmental homeostasis, thus reducing intestinal flagellin (the ligand of Toll-like receptor 5, TLR5). The excessive infiltration and activation of lamina propria dendritic cell (LPDC) were ameliorated by SPEN after SAP. Although TLR5 deficiency on LPDC reduced bacterial translocation after SAP, the effects of SPEN were abolished in TLR5-deficient models. SPEN reduced intestinal flagellated bacteria abundance in SAP patients. SPEN protects the intestinal barrier thereby reducing bacterial translocation after SAP via inhibiting the activation of TLR5 on LPDC by flagellin. Our findings may provide a novel perspective for treating enterogenous infection after SAP.