The gut-pancreas axis in chronic pancreatitis: Microbiota-endogenous GLP-1 interactions and candidate repair pathways

Chronic pancreatitis (CP) is a progressive fibroinflammatory disorder with limited disease-modifying options. Human CP studies report gut microbial and intestinal-barrier alterations, predominantly in cross-sectional cohorts. This review integrates CP-specific clinical and experimental observations with mechanistic evidence from cell, rodent, and non-CP human studies. Barrier disruption can increase lipopolysaccharide exposure and engage Toll-like receptor 4-associated inflammatory and fibrogenic signaling, whereas microbial and host-derived metabolites regulate enteroendocrine L-cell secretion through defined receptor-mediated and metabolic pathways. Human glucagon-like peptide-1 (GLP-1) studies in CP show heterogeneous responses, while CP trials have not yet connected microbiota-driven GLP-1 changes to disease progression. Evidence for direct pancreatic GLP-1 receptor (GLP-1R) signaling is strongest in β cells; reported immune, stellate-cell, and exocrine effects derive largely from preclinical or pharmacological studies and should not be equated with physiological endogenous GLP-1 exposure. CP-specific animal studies reported attenuated fibrosis or improved barrier and immune endpoints after microbiota-directed interventions, whereas limited human synbiotic trials reported improvements in selected gastrointestinal or perioperative outcomes but did not assess endogenous GLP-1, microbiome engraftment, pancreatic fibrosis, or disease progression. Together, these findings support a biologically coherent and testable microbiota-metabolite-endogenous GLP-1 framework for CP, with causal direction and clinical relevance requiring longitudinal validation. Translation requires microbiome-stratified CP trials incorporating functional microbiome and metabolite profiling; basal and meal-stimulated measurements of active and total GLP-1, together with peptide YY; prespecified clinical outcomes; mediation and treatment-by-biomarker analyses; and long-term safety assessment.