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

Abstract

Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is a group of chronic relapsing disorders caused by dysregulated mucosal immunity, altered gut microbiota, and impaired epithelial barrier function. There is increasing evidence linking circadian disruptions, such as shift work, jet lag, sleep loss, light misalignment, and irregular eating patterns, to the risk of IBD and associated symptoms and inflammatory activity. The intestinal circadian system is coordinated by the central clock and peripheral clocks in epithelial and immune cells. These oscillators stimulate innate and adaptive immune responses; shape diurnal microbial rhythms and metabolite production; and regulate epithelial tight junctions, mucus production, antimicrobial peptides, and regenerative programs. Microbial metabolites (short-chain fatty acids, bile acids, and tryptophan derivatives) can entrain host clocks, creating a bidirectional immunity-microbiota-barrier network. This minireview synthesizes mechanistic and clinical data on circadian clock gene networks in IBD. It highlights translational opportunities for chronotherapy (e.g., regular meal timing and sleep-light alignment) and discusses why time-of-day optimization of pharmacotherapy for IBD remains exploratory, with limited and heterogeneous evidence across major drug classes (5-aminosalicylic acid, systemic corticosteroids, biologics, and small molecules).

Key Words: Inflammatory bowel disease; Circadian rhythm; Clock genes; Gut microbiota; Epithelial barrier; Chronotherapy; Intestinal homeostasis

Core Tip: Disrupted circadian clock gene networks link mucosal immune imbalance, gut microbiota dysbiosis, and epithelial barrier failure in inflammatory bowel disease. Chronotherapy, particularly behavioral interventions, such as stabilizing sleep-wake schedules and meal timing, is a plausible avenue. However, evidence supporting medication timing in the treatment of IBD remains limited and heterogeneous. Thus, rigorous prospective trials are needed before clinical recommendations can be made.

INTRODUCTION

Inflammatory bowel disease (IBD) is a group of immune-mediated disorders, primarily Crohn’s disease and ulcerative colitis (UC), characterized by chronic intestinal inflammation[1,2]. The pathogenesis of IBD involves multiple mechanisms, including genetic susceptibility, immune dysregulation, gut microbiota imbalance, and environmental triggers[2,3]. In recent years, accelerated lifestyle changes and disrupted sleep patterns have led to an increase in the incidence of IBD, with the patient population becoming increasingly younger[1,2]. This trend of increasing incidence and a younger age of onset is imparting a growing burden on the public health system.

Excessive mucosal immune activation, impaired intestinal epithelial barrier function, and gut microbiota dysbiosis are key drivers of IBD onset and progression[3,4]. The gut microbiota plays a crucial role in maintaining immune balance and epithelial integrity, and its composition and metabolic activity are susceptible to changes in dietary rhythms and sleep schedules[2,5]. Disruption of the intrinsic rhythm of the body amplifies inflammatory signals, leading to intestinal barrier damage and persistent mucosal inflammation.

Against this backdrop, the circadian clock, the core regulator of physiological rhythms, and its clock gene network have been increasingly recognized as being closely linked to the onset and progression of IBD[2,4]. Reexamining the pathogenesis of IBD through the lens of “circadian clock-immune-microbiota-barrier” interactions is warranted. Moreover, further exploration of the integrative roles of core clock genes, such as circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1), and their downstream pathways involved in regulating mucosal immunity, the gut microbiota, and epithelial barrier function, holds promise for establishing a novel mechanistic framework for IBD. Unlike previous reviews that have focused on single cell types or signaling pathways, this narrative minireview integrates mucosal immunity, the gut microbiota, and epithelial barrier function into a unified “clock gene-immunity-microbiota-barrier” framework in the context of IBD.

LITERATURE SEARCH STRATEGY AND STUDY SELECTION

We conducted a narrative literature review using a predefined search and selection approach. PubMed, Web of Science Core Collection, CNKI, and Wanfang Data were searched from their inception until January 22, 2026. The search terms had a combination of controlled vocabulary (MeSH in PubMed) and free-text keywords, and were adapted for each database (including Chinese search strings for CNKI and Wanfang Data). They covered: (1) IBD; (2) Circadian rhythms/clock genes/chronotherapy; and (3) Key domains relevant to this minireview (mucosal immunity, gut microbiota/metabolites, and epithelial barrier function). The complete database-specific search strategies (including Chinese search strings for CNKI and Wanfang Data) are provided in Supplementary material. Records retrieved from all databases were exported and de-duplicated using Zotero. The titles and abstracts were screened first, followed by a full-text assessment, independently by two reviewers (Yu KX and Lu ZJ). Disagreements were resolved by consensus. To reduce selection bias, we prioritized human studies directly linking circadian measures to IBD phenotypes, well-established IBD models demonstrating causal clock-immune/microbiota/barrier mechanisms, and translational studies reporting circadian endpoints or time-of-day-dependent interventions. When multiple studies reported the same results, we preferentially cited primary studies and those with higher-quality designs.

CIRCADIAN CLOCK

Mammals possess an endogenous timing system with an approximately 24-hour cycle, commonly referred to as the circadian clock. This system coordinates physiological and behavioral rhythms, aligning body functions with day-night changes to preserve homeostasis[5]. Within this network, the suprachiasmatic nucleus of the hypothalamus serves as the central pacemaker. As the “master clock”, it receives photic input from the retina, integrates temporal information, and transmits rhythmic signals to peripheral tissues via autonomic and neuroendocrine pathways, thereby synchronizing metabolic and behavioral rhythms throughout the body[1-3,5].

Peripheral clocks are widely distributed across organs, including in the gastrointestinal tract, liver, and immune cells. Although these clocks can oscillate autonomously, their phases are generally aligned using signals from the central clock. Meal timing and the metabolic status of the gut microbiota are regarded as “secondary timing cues” that locally adjust peripheral clock phases, ensuring that rhythmic gene expression is coordinated with tissue-specific functions[2,4,5].

At the molecular level, the circadian rhythm system is driven by a highly conserved transcription-translation feedback loop. The core components of this loop include the clock genes CLOCK, BMAL1, period (PER), and cryptochrome (CRY)[5]. CLOCK and BMAL1 form a heterodimer that functions as the primary positive regulatory complex. This complex binds to E-box elements in the promoters of target genes, driving the rhythmic transcription of PER and CRY[1,5]. As PER and CRY proteins accumulate in the cytoplasm and become phosphorylated, they translocate into the nucleus and interact with the CLOCK-BMAL1 complex, thereby suppressing their own transcription. This negative feedback loop generates a self-sustaining oscillatory system with a period of approximately 24 hours[4-6].

Beyond this core circuit, the circadian system is regulated by multiple layers of auxiliary mechanisms. Retinoic-acid-related orphan receptor alpha (RORα) and reverse erythroblastosis virus alpha (REV-ERBα) competitively bind to ROR response elements in the BMAL1 promoter, exerting activating and inhibitory effects, respectively, at the transcriptional level. REV-ERBα also inhibits nuclear factor-κB signaling and NOD-like receptor family pyrin domain-containing 3 inflammasome activity. This suggests close cross-talk between circadian networks and immune-inflammatory pathways[1,4,6]. Additionally, D-box binding protein and nuclear factor, interleukin (IL)-3 act at D-box regulatory elements within the PER and ROR genes. D-box binding protein promotes, and nuclear factor, IL-3 suppresses the transcription of these genes. A dynamic balance between these factors is critical for the precision and stability of the circadian cycle[1,3,7].

Recent studies have revealed novel functions of circadian genes in intestinal immune regulation. In a prospective observational cohort (49 IBD patients and 19 healthy controls[4]), the expression levels of core clock genes in the peripheral blood in patients with UC were found to be inversely associated with inflammatory marker levels. Moreover, PER2, CRY1, and CRY2 levels were found to be lower in patients with elevated fecal calprotectin levels (> 250 mg/kg[4]), but they returned toward control levels during remission. These clinical data are associative and do not establish causality.

CIRCADIAN CLOCK AND IBD

Circadian clock and innate immunity

Innate immune cells are essential for maintaining intestinal homeostasis and defending against pathogenic invasion. By modulating the periodic expression of core clock genes, the circadian system precisely regulates the rhythmic function of innate immune cells, including macrophages and neutrophils[1,2]. Macrophages are key effector cells of innate immunity. They exhibit circadian variations in phagocytic activity, migratory behavior, and the secretion of inflammatory mediators (e.g., tumor necrosis factor-α and IL-1β). These rhythms depend on dynamic regulation by clock genes[2,3]. At the molecular level, the CLOCK-BMAL1 complex binds to E-box elements in the promoters of inflammation-related genes, thereby driving rhythmic transcription. In contrast, REV-ERBα functions as a negative regulator by associating with the promoter regions of NOD-like receptor family, pyrin domain-containing 3 inflammasome core genes, thereby inhibiting inflammasome assembly and excessive IL-1β release at night and helping to prevent exaggerated nocturnal inflammation[2,6].

Regulatory circuits linking the circadian clock to intestinal inflammation may be perturbed in IBD. Observational evidence in human cohorts has reported altered expression levels of core clock genes in peripheral blood cells and/or intestinal tissues in patients with IBD compared with controls. Some studies have further noted an inverse relationship between clock-gene expression levels and inflammatory marker levels in patients with UC during remission[4]. Because most available clinical datasets are single-center and cross-sectional, these associations should be considered hypothesis-generating as they do not establish causality[1,2]. At the behavioral level, circadian misalignment may also interact with intestinal inflammation. For example, sleep disruption has been associated with IBD-related outcomes and changes in circadian rhythm gene expression in a human study[8]. In parallel, chemokine pathways that recruit monocytes/macrophages (e.g., C-C motif chemokine ligand 2, also known as monocyte chemoattractant protein-1) are upregulated in inflamed mucosa and may contribute to sustained inflammatory cell infiltration, providing a plausible mechanistic bridge between clock disruption and immune-cell trafficking[2].

Neutrophil recruitment to the gut and its bactericidal function, which represents the first line of defense against invading pathogens, are also under circadian control. Circulating neutrophil counts peak during periods of increased activity, and this fluctuation depends on glucocorticoid signaling regulated by the central clock via the sympathetic-adrenal cortex axis. This governs the rhythmic release of neutrophils from the bone marrow[1,3]. In patients with IBD, persistent neutrophil infiltration is commonly observed in the intestinal mucosa, reflecting potential disruption of this rhythmic regulation. Mutations in clock genes or environmental circadian misalignment can impair neutrophil chemotaxis and bactericidal capacity, while abnormally activating neutrophils during the resting phase. This leads to excessive release of reactive oxygen species and proteases, further damaging the epithelial barrier[2,7]. Moreover, neutrophil trafficking is driven by an intrinsic circadian program. BMAL1 regulates C-X-C motif chemokine ligand 2 to induce C-X-C chemokine receptor 2-dependent diurnal changes in neutrophil transcriptional and migratory properties, whereas C-X-C chemokine receptor 4 antagonizes this process[9]. In a cohort of healthy volunteers (n = 12[9]), neutrophil markers also displayed diurnal variation, supporting conservation across species.

Dendritic cells (DCs) are also affected by the clock during antigen presentation and immune modulation. Studies have shown that DC migration from the intestinal lamina propria to the mesenteric lymph nodes peaks mainly during the host’s resting phase, and this rhythmic process depends on the BMAL1-mediated temporal regulation of migration-related genes, such as C-C motif chemokine receptor 7[2,3]. The disruption of circadian rhythms distorts DC migration patterns, hindering the timely presentation of intestinal antigens to T cells, and thereby weakening communication between the innate and adaptive immune systems[2,3]. However, direct evidence for robust diurnal oscillations of mucosal DC-derived cytokines in patients with IBD remains limited. Mechanistic links between circadian regulation, antigen presentation, and downstream effector T-cell programs [including T helper 1 (Th1) and Th17-associated responses] are supported mainly by experimental and translational studies[6,10].

In summary, the circadian system participates in the temporal regulation of innate immune cells by modulating the expression of core clock genes. The disruption of this rhythmic system is closely associated with the development and persistence of chronic intestinal inflammation (Figure 1). The abovementioned mechanisms are supported predominantly by data from animal models and cellular experiments. Evidence in humans is largely observational; therefore, clinical causality and therapeutic impact remain to be confirmed in prospective studies.

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.

Circadian rhythms and adaptive immunity

Stable functioning of the adaptive immune system is vital for intestinal immune homeostasis. Circadian rhythms exert a profound influence on the onset and progression of IBD by shaping the differentiation and functional rhythms of T, B, and regulatory immune cell subsets[1,3].

The activation and differentiation of T cells are tightly regulated by the circadian clock. Among helper T cell subsets, the Th1/Th17 balance shows dynamic circadian fluctuations. Experimental studies have indicated that the CLOCK-BMAL1 complex binds to the E-box element in the promoter of RORγt, a key transcription factor in Th17 cells. This may provide a promising approach to inhibit its activity and significantly reduce the proportion of Th17 cells during the night[2]. In a cross-sectional study, PER2 expression levels in peripheral-blood CD4+ T cells were found to be reduced in patients with active UC (n = 20)[7] compared with its levels in healthy controls (n = 22)[7], as determined using quantitative reverse transcription-polymerase chain reaction. Flow cytometry also showed a reduced percentage of PER2+ CD4+ T cells in the active UC (n = 8)[7] vs control (n = 8) group[7]. In the inflamed colonic mucosa of patients with active UC, PER2 levels are inversely correlated with the UC Endoscopic Index of Severity score (r = -0.702, P < 0.01), Mayo score (r = -0.699, P < 0.01), and C-reactive protein levels (r = -0.556, P < 0.01)[7]. However, these associations are observational and do not establish causality[7]. Further studies have demonstrated that PER2 binds to the promoter region of a disintegrin and metalloproteinase 12 and inhibits its transcription. Loss of PER2 leads to overexpression of a disintegrin and metalloproteinase 12, which promotes Th1 differentiation and interferon-γ production, thereby amplifying inflammatory responses[1,7]. BMAL1 also modulates Th22 cell function by regulating circadian fluctuations in IL-22 levels. Higher daytime levels of IL-22 promote epithelial repair; however, this rhythmic regulation is disrupted in IBD, resulting in insufficient IL-22 secretion and a weakened intestinal epithelial barrier[11].

Likewise, the immunosuppressive activity of regulatory T cells (Tregs) shows pronounced circadian dependence, primarily governed by BMAL1-mediated periodic regulation of forkhead box P3 (Foxp3) transcription[3]. Through the “BMAL1-Foxp3-IL-10” signaling axis, the circadian clock influences Treg proliferation and migration and cytokine secretion. Under normal conditions, a daytime decline in BMAL1 expression levels reduces Foxp3 activity and Treg-mediated suppression, allowing the body to respond more robustly to stimuli associated with food intake. At night, BMAL1 levels increase, enhancing Foxp3 activity and promoting Treg accumulation in the intestinal mucosa, thereby maintaining immune tolerance[3]. However, the available evidence suggests that circadian control of the BMAL1-Foxp3-IL-10 axis may be perturbed in inflammatory settings. In humans, the findings are primarily associative and heterogeneous, whereas mechanistic links are better supported by experimental models[3,6].

B cell development and antibody secretion also follow circadian dynamics, particularly in the context of mucosal immunity. Peripheral blood B-cell counts typically show a “high during the day, low at night” rhythm, which is closely linked to transcriptional regulation by core clock genes. The CLOCK-BMAL1 heterodimer binds to E-box sequences in metabolic genes, such as glucose transporter 1 in B cells, modulating energy metabolism, and thereby influencing B-cell proliferation and survival[3,7]. In B-cell-specific BMAL1-knockout mice, antigen-specific IgG and secretory IgA levels are markedly decreased, and their circadian oscillations are lost, indicating that the circadian clock is crucial for sustaining the rhythmicity of humoral immunity[3,7]. Consistent with this, rhythmic intestinal IgA responses help maintain host-commensal mutualism, and disruption of this program can compromise local antibody-mediated defense systems and exacerbate intestinal inflammation[12].

Collectively, the circadian clock maintains intestinal immune homeostasis through multiple mechanisms by fine-tuning T cell differentiation and B cell-mediated humoral responses. When this rhythmic system is disturbed, immune tolerance is impaired, cytokine secretion is dysregulated, and inflammatory signals are continuously amplified, creating a permissive environment for the initiation and progression of chronic inflammatory diseases (Figure 2). Most evidence for circadian regulation of T/B-cell programs derives from experimental models, while clinical findings mainly reflect cross-sectional associations. Thus, translation to patient management requires larger, well-controlled human studies.

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.

The circadian clock and the gut microbiota

As core components of the intestinal microecosystem, the structural composition and metabolic activity of the gut microbiota exhibit pronounced rhythmic oscillations within a 24-hour cycle. This dynamic equilibrium, which is maintained by bidirectional coordination between the host circadian clock and the microbial communities, is easily perturbed. Once disrupted, it is associated with dysbiosis, which has been implicated in the development of IBD[4,5,13].

The host circadian clock modulates diurnal rhythms through multiple mechanisms. The central clock primarily influences nutrient availability in the intestinal lumen via rhythmic feeding behavior, indirectly shaping the circadian distribution of microbial taxa. At the same time, local endogenous clocks in the gut, including circadian gene networks in epithelial and immune cells, are equally critical for preserving microbial homeostasis. Studies have shown that the epithelial clock regulates the rhythmicity of cell proliferation and barrier renewal. BMAL1 and CRY2 act synergistically to control stem cell proliferation and differentiation, with CRY2 maintaining rhythmic cell regeneration via the signal transducer and activator of transcription 3 signaling pathway[4,14]. When the local intestinal clock is disrupted, the epithelial renewal rhythms become disordered, delaying barrier repair. This delay allows the luminal contents and the microbiota to penetrate the submucosa and trigger inflammatory responses[4,14]. Compared to whole-body circadian rhythms, the tissue-specific features of the local intestinal clock more precisely account for dynamic microbial changes and provide a theoretical basis for future interventions that aim to “rebuild local rhythms”.

Microbial metabolites, in turn, provide feedback to the host circadian clock, forming a closed-loop regulatory system with the following sequence: “Host rhythm, microbiota, metabolites, host rhythm”. Short-chain fatty acids are among the most characteristic signaling molecules in this context. Their intestinal concentrations display clear circadian patterns, peaking at night and decreasing during the day. Butyrate enhances clock gene expression via histone deacetylase inhibition and epigenetic regulation, including increased histone acetylation at core clock loci[2,15]. Propionate promotes phase alignment within the suprachiasmatic nucleus by activating the G protein-coupled receptor 41 signaling pathway[2,5]. In a parallel, double-blind, placebo-controlled randomized trial, 36 patients with mild-to-moderate active UC were randomized 1:1 to sodium butyrate 600 mg/day (one capsule daily) for 12 weeks (n = 18)[13] or placebo (rice-starch capsules, n = 18)[13]. Compared with placebo, butyrate reduced fecal calprotectin (change, -133.82 ± 155.62 vs 51.58 ± 95.57; P < 0.001) and high-sensitivity C-reactive protein [change -0.36 (-1.57, -0.05) vs 0.48 (-0.09, 4.77); P < 0.001] levels, increased the expression levels of several circadian genes (CRY1: 2.22 ± 1.59 vs 0.63 ± 0.49, P < 0.001[13]; CRY2: P = 0.001; PER1: P = 0.005; BMAL1: P = 0.003), and improved sleep quality (Pittsburgh Sleep Quality Index score change, -2.94 ± 3.50 vs 1.16 ± 3.61; P < 0.001)[13]. Evidence suggests that rhythmic microbial metabolism provides a direct interface between the gut microbiota and mucosal immunity. Daily variation in the production of short-chain fatty acids, particularly butyrate, may influence macrophage inflammatory programs by biasing polarization toward a less pro-inflammatory phenotype and reducing pro-inflammatory cytokine output, which is consistent with the overall attenuation of mucosal inflammation observed in colitis settings[2,16]. In parallel, microbial tryptophan metabolism generates indole derivatives that engage aryl hydrocarbon receptor (AhR)-related signaling in the gut. Together with the intrinsic clock regulation of group 3 innate lymphoid cells, this axis has been associated with IL-22-dependent barrier support and a restrained inflammatory tone[11,16].

Furthermore, the engagement of microbiota-derived tryptophan metabolites (including indole derivatives such as indole-3-acetic acid) with AhR signaling has been linked to mucosal immune regulation and may interface with circadian programs in the gut. In IBD, dysbiosis and inflammatory stress may disrupt this microbiota-metabolite-AhR axis; however, direct evidence for consistent alterations of specific indole metabolites (e.g., indole-3-acetic acid) in humans remains limited and largely associative[11,16].

Taken together, the relationship between the host circadian clock and the gut microbiota is not a one-way process but a dynamic, continuously adjusting equilibrium. The host circadian system shapes the microbial structure and function through central signaling, local cellular clocks, and metabolic regulation, whereas microbial metabolites modulate host rhythms. Clarifying and targeting this bidirectional regulatory network may serve as a promising strategy for future circadian-based therapeutics against IBD. The bidirectional clock-microbiota links are strongly supported by preclinical and mechanistic studies, whereas human interventional evidence remains limited and heterogeneous, warranting rigorous trials with circadian endpoints.

Circadian rhythms and the intestinal barrier

The integrity of the intestinal barrier is fundamental for gut homeostasis, and the circadian rhythm system plays a crucial role in its temporal regulation. Circadian rhythms influence both the structure and function of intestinal epithelial cells and participate in processes such as cell proliferation, tissue repair, and mucus secretion. When these rhythms are disrupted, the barrier becomes more susceptible to injury, which is a key mechanism underlying the onset and progression of IBD[1,7,17].

Within the intestinal barrier, the rhythmic expression of tight junction proteins is especially important. Proteins such as occludin, claudin-1, and zonula occludens-1 in epithelial cells show regular circadian fluctuations in their mRNA and protein levels, typically peaking during the active phases to facilitate adaptation to feeding and environmental stimuli[1,3,7]. At the molecular level, the CLOCK-BMAL1 heterodimer recognizes and binds to E-box elements in target gene promoters, thereby promoting the rhythmic transcription of occludin and claudin-1. PER2 regulates the localization and assembly of zonula occludens-1 on cell membranes through direct interactions[1,3]. Animal experiments have confirmed that the intestinal epithelium-specific deletion of BMAL1 abolishes the rhythmic expression of tight junction proteins, markedly increases intestinal permeability, and increases susceptibility to dextran sulfate sodium-induced colitis, as evidenced by severe mucosal damage and inflammatory cell infiltration[6].

The renewal and repair of intestinal epithelial cells are tightly governed by circadian rhythms. Under physiological conditions, the proliferation of intestinal epithelial stem cells is most active during the resting phase, when PER2 levels decline, relieving the inhibition of cyclin D1 and promoting entry into S phase[3,4]. BMAL1 simultaneously limits excessive proliferation during daytime by regulating the rhythmic expression of p21[18]. Circadian clock disturbances disrupt normal stem cell proliferation patterns, impair G1/S transition, and delay epithelial regeneration. Circadian disruptions, including sleep loss, have been associated with impaired intestinal epithelial homeostasis in experimental models[14]. In addition, epithelial autophagy is under clock control. BMAL1 binds to the promoters of genes such as autophagy-related protein 5 and microtubule-associated protein 1 light chain 3, enhancing nighttime autophagy to remove damaged organelles and pathogens. In addition, epithelial autophagy appears to be under circadian regulation and may contribute to mucosal stress adaptation. Circadian disruption in IBD-related contexts may blunt this homeostatic program and aggravate epithelial injury[2,3].

The mucus layer is another critical component of the intestinal barrier, where the circadian clock exerts precise regulation. Mucin 2 (MUC2), the main structural protein in the mucus layer, exhibits circadian rhythms in both its expression and secretion[3,4]. This regulation is primarily mediated by two pathways. First, the CLOCK-BMAL1 complex binds directly to the E-box element in the MUC2 promoter, driving its rhythmic transcription. Second, REV-ERBα indirectly modulates MUC2 secretion by influencing the autophagy rhythm of goblet cells[1,2,7]. Under normal circumstances, autophagic activity in goblet cells increases at night, facilitating the clearance of abnormal MUC2 particles and ensuring the quality of mucus secreted during the day. PER2-deficient mice lose this rhythm, leading to intracellular accumulation of MUC2 and impaired mucus-barrier integrity and structural disruption of the mucus layer[1]. In models of experimental colitis, intestinal epithelial clock disruption is associated with reduced goblet-cell differentiation (MUC2+ cells)[17], which may weaken the mucus barrier, increase bacterial-epithelial contact, and promote inflammatory responses[6].

Overall, the circadian clock is central to the maintenance of intestinal barrier homeostasis. Rhythmic disruption not only compromises epithelial defense mechanisms, but is also closely associated with persistent inflammation, impaired mucosal repair, and disease recurrence in patients with IBD. These observations suggest that the restoration of rhythmic regulation may be a key direction for future precision therapies (Figure 3). Most of these conclusions come from animal studies and lab tests on gut cells. We have fewer direct data from human gut tissue samples. So, the evidence is stronger for how the clock works in the gut, not for proving it helps IBD patients. Figure 4 provides an overview of how circadian clock gene networks interact with mucosal immunity, the gut microbiota, and epithelial barrier function to shape the pathogenesis of IBD.

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.

CONCLUSION

Collectively, the dynamic interplay between the host circadian clock and the intestinal microenvironment helps maintain homeostasis through coordinated immune and metabolic pathways. Disruption of rhythmic regulation across this network can contribute to barrier impairment and inflammatory progression in patients with IBD[4,5,13]. Accumulating evidence implicates core clock components (e.g., CLOCK and BMAL1) and downstream pathways in shaping mucosal immune responses, the oscillations of microbes and their metabolites, and epithelial barrier programs, while microbial metabolites can, in turn, modulate host clocks, together forming a bidirectional “clock gene-immunity-microbiota-barrier” framework[2,15-17]. By contrast, evidence that time-of-day dosing improves IBD outcomes remains limited and heterogeneous, and routine timing changes are not currently supported for major drug classes (5-aminosalicylic acid, systemic corticosteroids, biologics, and small molecules).

Key limitations of the current literature include predominantly observational human data with potential confounding and reverse causality, substantial disease and sampling heterogeneity (UC vs Crohn’s disease; site and timing of specimen collection), and feasibility/adherence constraints for timed interventions. Therefore, well-controlled prospective studies with standardized circadian endpoints are needed before clinical recommendations can be made.

Several translational challenges must be addressed to move chronotherapy for IBD from mechanistic plausibility to actionable clinical guidance. First, circadian misalignment is not uniform across patients. Chronotype and real-world rest-activity rhythms vary widely, which may modify inflammatory and microbiota-related phenotypes and thereby influence who is most likely to benefit from circadian-aligned interventions[19]. Second, adherence and feasibility are major barriers. Sustained changes in sleep-light schedules and meal timing require patient-specific plans and objective monitoring, especially when symptoms fluctuate or when work schedules impose “social jet lag”[2,6,8]. Third, the current interventional evidence remains heterogeneous across modalities (behavioral, dietary, and pharmacologic timing) and is often limited by small sample sizes, variable endpoints, and inconsistent circadian measurements[2,6,13]. Future studies should, therefore: (1) Stratify participants by chronotype or actigraphy-derived circadian metrics; (2) Incorporate standardized circadian endpoints alongside conventional IBD outcomes (symptoms, biomarkers, endoscopy); and (3) Test pragmatic, patient-centered chronotherapy packages (e.g., light-sleep alignment plus regular meal timing) with digital adherence support, to identify scalable and clinically meaningful time-based strategies for intestinal homeostasis in patients with IBD[2,6].

What can clinicians do now?

Behavioral strategies (stable sleep-wake schedules, appropriate levels of light exposure, and regular meal timing) may help reduce circadian misalignment in patients with IBD[2,6]. Clinicians can screen for circadian disruptions (e.g., shift work, jet lag, sleep loss, and irregular eating patterns) and provide basic counseling.