{
  "abstract": "Background Circadian rhythm disruption (CRD) is an emerging environmental risk factor for Crohn’s disease (CD), but its pathogenic interplay with gut microbiota and host metabolism remains poorly understood.Methods To investigate whether and how CRD exacerbates CD by impairing host ketogenesis. We established a murine model combining chronic circadian disruption (CRD) with 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis, followed by multi-omics analyses (single-cell RNA sequencing, 16S rRNA sequencing, and metabolomics). Mechanistic insights were validated through antibiotic depletion, fecal microbiota transplantation (FMT), bone marrow-derived macrophage (BMDM) assays, and epithelial-specific 3-hydroxy-3-methylglutaryl coenzyme A synthase 2 (HMGCS2) knockout mice.Results Clinical Evidence Associates Circadian Gene Dysregulation with Inflammation in CD Patients ( IDDF2026-ABS-0519 Figure 1). CRD significantly aggravated TNBS-induced colitis, amplifying both inflammation and tissue damage. Single-cell RNA sequencing revealed that CRD suppressed epithelial ketogenesis, reducing β-hydroxybutyrate (BHB) levels, while simultaneously promoting type I interferon-driven macrophage PANoptosis. Exogenous BHB supplementation reversed the CRD-exacerbated colitis phenotype. Epithelial-specific HMGCS2 knockout abrogated the detrimental effects of CRD. Mechanistically, BHB inhibited macrophage PANoptosis by suppressing JAK/STAT signaling via the HCAR2-cAMP axis. CRD markedly depleted BHB-producing commensals such as Lactobacillus murinus and Muribaculum intestinale. Reconstitution of these microbes attenuated colitis severity and suppressed macrophage PANoptosis.Conclusions Circadian disruption exacerbates CD by impairing the gut microbiota-ketone axis, which in turn promotes macrophage PANoptosis and sustains intestinal inflammation. Targeting this axis may represent a novel therapeutic strategy for managing circadian-related disease progression ( IDDF2026-ABS-0519 Figure 2).Abstract IDDF2026-ABS-0519 Figure 1Abstract IDDF2026-ABS-0519 Figure 2",
  "authors": [
    {
      "affiliations": [
        "The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China"
      ],
      "name": "Chongyang Huang"
    },
    {
      "affiliations": [
        "The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China"
      ],
      "name": "Zelong Lin"
    },
    {
      "affiliations": [
        "Guangzhou First People’s Hospital, China"
      ],
      "name": "Huishi Tan"
    }
  ],
  "title": "IDDF2026-ABS-0519 Circadian disruption exacerbates crohn’s disease by promoting macrophage panoptosis and impairing microbiota-dependent ketogenesis",
  "uid": "ef6ac7d8-f052-5f3e-ae34-e585010b2156"
}