Bmal1 Mediates P. Gingivalis-Driven Inflammatory Bowel Disease

This study investigates how the periodontal pathogen Porphyromonas gingivalis exacerbates inflammatory bowel disease (IBD), specifically examining whether its virulence factors disrupt peripheral circadian entrainment in intestinal epithelial cells, thereby amplifying BMAL1 degradation and CLOCK-mediated MYD88/NF-κB hyperactivation. By delineating the spatiotemporal interplay between microbial-driven circadian dysregulation, paracellular permeability defects (via ZO-1/occludin suppression), and mucosal immunity imbalance, this research establishes a chronopharmacological framework for targeting the BMAL1-MYD88-NF-κB axis to mitigate pathogen-accelerated IBD progression. 1. Clinical IBD tissues underwent circadian protein and P. gingivalis detection via WB/RT-PCR. 2. DSS-treated mice with biweekly P. gingivalis gavage were evaluated for colitis (HE staining), cytokines (IHC/ELISA), and BMAL1-clock interactions (qRT-PCR/WB). 3. Light-disrupted mice ± DSS colitis (4 cohorts) were compared for circadian-IBD crosstalk. 4. P. gingivalis-infected NCM460 cells with BMAL1 modulation were profiled via transcriptomics. 1. P. gingivalis accelerated IBD progression in murine models by disrupting intestinal barrier integrity, concurrent with circadian rhythm dysregulation marked by suppressed BMAL1 expression. 2. Circadian-disordered mice exhibited heightened DSS sensitivity, with the circadian-disordered colitis cohort showing exacerbated weight loss, intestinal inflammation, cytokine overexpression, and barrier hyperpermeability versus rhythm-stable controls. 3. BMAL1 knockdown liberated CLOCK to bind MYD88’s promoter, driving TLR4/NF-κB activation via MYD88 upregulation. This cascade reduced ZO-1/occludin expression, impairing epithelial barrier function and amplifying IBD severity. P. gingivalis exacerbates intestinal barrier dysfunction via BMAL1 downregulation-driven CLOCK/MYD88/NF-κB signaling.