Abstract
Background & aims: Chronic pancreatitis (CP) is a progressive fibroinflammatory disease with rising global incidence and no curative therapy. Gut dysbiosis has been associated with CP, but its causal contribution to disease pathogenesis remains unclear. We intended to identify specific pathogenic microbial species that promote CP and to delineate the underlying pathogenic mechanisms.
Methods: Multi-omics analyses were used to identify key microbial signatures in CP patients and mice. Novel pathogenic Escherichia coli strains were isolated and bioengineered for functional studies. In vitro and in vivo assays, along with macrophage-specific knockout mice, adenoviral tools, and pharmacological inhibitors, were employed to dissect host-microbe mechanistic pathways. Therapeutic intervention included administering a screened next-generation probiotic.
Results: Metagenomic sequencing identified HtpG-high-expressing E. coli (HHEC) enrichment as a dominant microbial signature in CP patients. Prevention of HHEC adherence and colonization alleviated CP, whereas recolonization with a new patient-derived HHEC strain PS718 exacerbated it. Mechanistically, E. coli-derived HtpG upregulated protein arginine methyltransferase 5 (PRMT5) in pancreatic macrophages. Pharmacological inhibition of PRMT5 or macrophage-specific deletion of PRMT5 mitigated pancreatic fibrosis and CP progression. PRMT5 methylated Krüppel-like factor 4 (KLF4) at residues R387/R389, stabilizing it, which promoted M2 polarization and pancreatic fibrosis. Therapeutic intervention with Akkermansia muciniphila, which is reduced in CP, suppressed HHEC colonization and ameliorated CP.
Conclusion: These findings provide novel evidence for a pathogenic HHEC-HtpG-macrophage axis in CP, highlighting the potential of microbiota-targeted therapies for the condition.