Circadian clock at the interface of mucosal immunity, gut microbiota and epithelial barrier in inflammatory bowel disease

Figure 1 Schematic representation of core circadian clock gene networks and their feedback loops in the central and peripheral clocks. This schematic summarizes mechanisms supported by multiple evidence levels (animal models and in vitro/ex vivo studies, with comparatively limited direct human evidence). Human findings, where available, are primarily associative and should not be interpreted as causal. CLOCK: Circadian locomotor output cycles kaput; BMAL1: Brain and muscle ARNT-like 1; PER: Period; CRYα: Cryptochrome α; TNF-α: Tumour necrosis factor-α; IL: Interleukin; REV-ERBα: Reverse erythroblastosis virus α; NLRP3: NOD-like receptor family pyrin domain-containing 3; MCP-1: Monocyte chemoattractant protein-1; CCL2: C-C motif chemokine ligand 2; CCR7: C-C chemokine receptor type 7.

Figure 2 Interactions between circadian clock genes and innate and adaptive immune cells in the intestinal mucosa. Most interactions depicted are derived from experimental immunology studies and preclinical models; clinical evidence mainly reflects observational associations. Translational relevance should therefore be interpreted cautiously. Th: T helper cell; IFN-γ: Interferon-γ; PER2: Period 2; ADAM12: A disintegrin and metalloproteinase 12; CLOCK: Circadian locomotor output cycles kaput; BMAL1: Brain and muscle ARNT-like 1; IL: Interleukin; Foxp3: Forkhead box P3; IBD: Inflammatory bowel disease.

Figure 3 Bidirectional crosstalk between the circadian clock and gut microbiota, including microbial diurnal oscillations and metabolite signaling. The bidirectional clock-microbiota framework is strongly supported by preclinical and mechanistic studies, whereas human interventional evidence remains limited. Future trials incorporating circadian endpoints are needed to validate clinical translation. IBD: Inflammatory bowel disease; SCFA: Short-chain fatty acid; IAA: Indole-3-acetic acid; BMAL1: Brain and muscle ARNT-like 1; PER2: Period 2; AHR: Aryl hydrocarbon receptor.

Figure 4 Integrated model illustrating circadian clock gene networks as multidimensional hubs linking mucosal immunity, gut microbiota, and epithelial barrier function in inflammatory bowel disease. This integrated model combines evidence from human observational studies and experimental systems. Mechanistic links are proposed based on preclinical data, and clinical causality should not be assumed without prospective validation. IBD: Inflammatory bowel disease; DC: Dendritic cell; TNF: Tumour necrosis factor; IL: Interleukin; TLR: Toll-like receptor; NF-κB: Nuclear factor-κB; SCFA: Short-chain fatty acid; AhR: Aryl hydrocarbon receptor; ZO-1: Zonula occludens-1; IEC: Intestinal epithelial cell; Th: T helper cell; IFN-γ: Interferon-γ; Treg: Regulatory T cell; TGF-β: Transforming growth factor-β; CLOCK: Circadian locomotor output cycles kaput; BMAL1: Brain and muscle ARNT-like 1; PER: Period; CRY: Cryptochrome; REV-ERBα: Reverse erythroblastosis virus α; ROR: Retinoic-acid-related orphan receptor; DBP: D-box binding protein; NFIL3: Nuclear factor, interleukin-3.