Monoacylglycerol Lipase Inhibitor Mitigates Severe Acute Pancreatitis in Rats by Modulating the Gut Microbiota-Metabolite-Target Gene Interaction Network.

INTRODUCTION

Severe acute pancreatitis (SAP) is characterized by systemic inflammation and gut microbiota dysbiosis. However, the interplay between microbial alterations, host metabolism, and gene expression remains unclear. This study aimed to investigate how monoacylglycerol lipase (MAGL) inhibition by JZL184 alleviates SAP by modulating the gut microbiota- metabolite-target gene network.

METHODS

A rat model of SAP was developed, with rats assigned into three groups for comparison: the Control group (CON), the untreated SAP group (SAP), and the SAP group treated with JZL184. Fecal samples underwent 16S rRNA sequencing to assess microbial diversity and composition. Functional annotation was performed using KEGG pathways. Integrated analyses of intestinal microbiota, metabolomics, and pancreatic transcriptomics (GSE161945) were conducted to construct a microbiota-metabolite-target gene regulatory network, which was validated by qRT-PCR.

RESULTS

SAP rats exhibited decreased Bacteroidetes, increased Proteobacteria, and enrichment of Escherichia-Shigella. JZL184 treatment restored microbial balance, reducing Escherichia-Shigella and enhancing Lactobacillus and Bacteroides. It also suppressed NOD-like receptor and MAPK signaling pathways. Network analysis revealed positive correlations between Escherichia-Shigella, arachidonic acid, and HMOX1 expression, and negative correlations between Lactobacillus, aspartic acid, and ACE expression. qRT-PCR confirmed normalization of ACE expression in JZL184- treated pancreatic tissues.

DISCUSSION: JZL184 mitigated SAP by reshaping microbial composition, reducing pro-inflammatory taxa, restoring beneficial microbes, and altering key metabolites. These changes collectively modulated inflammatory pathways, including MAPK and NOD-like receptor signaling. The therapeutic benefit may also be mediated through the microbial control of metabolites that influence gene expression.

CONCLUSION

JZL184 effectively mitigates SAP by reshaping the gut microbiota-metabolite-gene network, suppressing pathogenic bacteria and inflammatory pathways while restoring beneficial microbes and metabolic homeostasis. These findings support MAGL inhibition as a promising microbiota- targeted therapeutic strategy for SAP.