Front Immunol. 2026 Sep 16;17:1932634. doi: 10.3389/fimmu.2026.1932634. eCollection 2026.
ABSTRACT
Clinical outcomes in hypertriglyceridemia-associated acute pancreatitis remain highly heterogeneous. Despite comparable lipid burdens, patients may experience anything from mild interstitial edema to fulminant necrotizing disease, a divergence that current models struggle to explain. Hypertriglyceridemia-associated acute pancreatitis (HTG-AP) now accounts for roughly one in nine acute pancreatitis cases worldwide, but serum triglyceride levels alone do not explain the significant East-West mortality gap (4.1% versus 1.0%). Emerging evidence shifts the focus away from the pancreas itself and toward a gut-pancreas co-metabolic circuit. Within this circuit, microbial metabolites engage host receptors and determine whether local injury escalates into systemic disease. In this review, we examine four interconnected axes that form The mechanistic backbone of this circuit: LPS-TLR4-lysophosphatidylcholine, short-chain fatty acid-GPR43/HDAC, tryptophan-aryl hydrocarbon receptor, and bile acid-FXR/TGR5-recognizing that direct HTG-AP-specific evidence is currently strongest for the LPS-TLR4-LPC axis, while the other three axes are supported by evidence from AP broadly and await HTG-AP-specific validation. We critically examine the cross-talk among these pathways and apply the Bradford Hill criteria to assess the validity of current causal inferences in the gut-pancreas axis. From a translational perspective, we introduce the concept of "functional metabolite guilds" (metabolite clusters sharing protective endpoints) to inform and streamline future postbiotic formulation designs. We also outline a co-metabolic stratification logic to guide patient selection in future trials. The ultimate goal is to move beyond descriptive microbiome catalogs toward precision interventions that match metabolic deficits with guild-based restoration strategies.
PMID:42819668 | PMC:PMC13624473 | DOI:10.3389/fimmu.2026.1932634