Disruption of the circadian rhythm induces acute pancreatitis via amino acid metabolism-mediated macrophage infiltration.

BACKGROUND: Circadian rhythms play a key role in regulating physiological processes, including inflammatory responses. Disruption of these rhythms has been associated with a variety of inflammatory diseases, but it is not known whether disrupted circadian rhythms directly trigger pancreatitis. METHODS: We conducted a population-based cohort study using data from the UK Biobank to assess the association between circadian rhythm disruption and the risk of pancreatitis. In addition a mouse model of circadian rhythm disruption was generated by exposing mice to continuous light. Expression levels of circadian rhythm genes, inflammatory factors and digestive enzyme levels were analyzed using real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Hematoxylin and eosin staining and immunohistochemical staining were introduced to assess histopathological changes and macrophage infiltration. RNA sequencing (RNA-seq) was performed to identify differentially-expressed genes as well as the mechanisms involved. In addition, we investigated whether administration of melatonin could alleviate this disorder. RESULTS: This population-based study revealed that individuals with disrupted circadian rhythms are at a significantly higher risk of developing pancreatitis. In our circadian rhythm disorder mouse model, the incidence of acinar vacuolization increased with exposure to light. This was accompanied by a significant rise in intrapancreatic trypsin levels as well as serum digestive enzyme levels and activity. Interestingly, increased infiltration of M1-type macrophages was observed in the circadian rhythm disorder group. RNA-seq analysis indicated that under conditions of continuous light exposure, there was a significant enrichment of gene expression related to amino acid metabolism in pancreatic tissue, particularly genes involved in the glycine, serine, and threonine metabolic pathways. The use of the threonine dehydrogenase (TDH) inhibitor QC1 effectively promoted the polarization of RAW264.7 cells towards the M2-type macrophage phenotype. Furthermore, treatment with melatonin inhibited the expression of TDH in pancreatic tissue, reduced the levels of inflammatory cytokines, and promoted the M2 polarization of macrophages, thus relieving the circadian disruption-induced pancreatic disorder. CONCLUSIONS: Our study establishes a link between circadian disruption and an elevated risk of pancreatitis and suggests a potential therapeutic effect of melatonin treatment.