Circadian rhythms and microbiota: molecular crosstalk and its implications for health and disease.

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Learn more: PMC Disclaimer | PMC Copyright Notice Biol Direct . 2026 Mar 7;21:47. doi: 10.1186/s13062-026-00748-w Search in PMC Search in PubMed View in NLM Catalog Add to search Circadian rhythms and microbiota: molecular crosstalk and its implications for health and disease Guanlin Wu Guanlin Wu 1 School of Clinical Medicine, Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China Find articles by Guanlin Wu 1, # , Jiayang Zhang Jiayang Zhang 2 School of Basic Medical Sciences, Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China Find articles by Jiayang Zhang 2, # , Shixian Yan Shixian Yan 3 Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011 China Find articles by Shixian Yan 3 , Na Liu Na Liu 4 Neonatology, Weifang Maternal and Child Health Hospital, Weifang, 261000 China Find articles by Na Liu 4 , Weiling Chen Weiling Chen 1 School of Clinical Medicine, Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China Find articles by Weiling Chen 1 , Fenglin Wu Fenglin Wu 1 School of Clinical Medicine, Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China Find articles by Fenglin Wu 1 , Zining Wang Zining Wang 1 School of Clinical Medicine, Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China Find articles by Zining Wang 1 , Junzheng Zhang Junzheng Zhang 1 School of Clinical Medicine, Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China Find articles by Junzheng Zhang 1 , Yuzhe Yang Yuzhe Yang 1 School of Clinical Medicine, Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China Find articles by Yuzhe Yang 1 , Yunshu Deng Yunshu Deng 1 School of Clinical Medicine, Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China Find articles by Yunshu Deng 1 , Xinyu Qiu Xinyu Qiu 1 School of Clinical Medicine, Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China Find articles by Xinyu Qiu 1 , Jiale Liu Jiale Liu 1 School of Clinical Medicine, Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China Find articles by Jiale Liu 1 , Lingqi Shi Lingqi Shi 1 School of Clinical Medicine, Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China Find articles by Lingqi Shi 1 , Xinyu Cui Xinyu Cui 1 School of Clinical Medicine, Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China Find articles by Xinyu Cui 1 , Ruohan Wan Ruohan Wan 5 Department of Cardiac Surgery, Heart Centre of Henan Provincial People’s Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, 451464 China Find articles by Ruohan Wan 5 , Xingjing Li Xingjing Li 6 Department of Hepatobiliary Pancreatic Surgery, Henan Provincial People’s Hospital & People Hospital of Zhengzhou University, Zhengzhou, 450003 China Find articles by Xingjing Li 6 , Yongsheng Han Yongsheng Han 6 Department of Hepatobiliary Pancreatic Surgery, Henan Provincial People’s Hospital & People Hospital of Zhengzhou University, Zhengzhou, 450003 China Find articles by Yongsheng Han 6, ✉ , Guangrui Yang Guangrui Yang 1 School of Clinical Medicine, Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China 2 School of Basic Medical Sciences, Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China Find articles by Guangrui Yang 1, 2, ✉ Author information Article notes Copyright and License information 1 School of Clinical Medicine, Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China 2 School of Basic Medical Sciences, Shanghai University of Medicine & Health Sciences, Shanghai, 201318 China 3 Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011 China 4 Neonatology, Weifang Maternal and Child Health Hospital, Weifang, 261000 China 5 Department of Cardiac Surgery, Heart Centre of Henan Provincial People’s Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, 451464 China 6 Department of Hepatobiliary Pancreatic Surgery, Henan Provincial People’s Hospital & People Hospital of Zhengzhou University, Zhengzhou, 450003 China ✉ Corresponding author. # Contributed equally. Received 2026 Jan 29; Accepted 2026 Feb 25; Collection date 2026. © The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ . PMC Copyright notice PMCID: PMC13081592  PMID: 41794765 Abstract Circadian rhythms, evolutionarily conserved 24-hour oscillations, exert precise regulatory control over microbial communities across host niches including the gastrointestinal tract, oral cavity, urinary bladder, and skin. This bidirectional interplay is critical to host physiology: host circadian clocks shape the composition and functional rhythms of resident microbiota, while microbiota-derived signals reciprocally modulate circadian entrainment and tissue-specific rhythmicity. Circadian disruption from shift work, irregular feeding, light pollution, or sleep deprivation trigger microbial dysbiosis and circadian misalignment, contributing to metabolic diseases, gastrointestinal disorders, neuropsychiatric conditions, cardiovascular diseases, and dermatological or reproductive disorders. Mechanistically, this crosstalk is mediated by rhythmic hormonal secretion, microbial metabolites, epigenetic regulation, and immune signaling. Therapeutic strategies such as time-restricted feeding, probiotics, melatonin, and polyphenol-rich diets show promise in restoring temporal homeostasis. This review synthesizes current evidence on circadian-microbiota interplay, elucidates its roles in physiology and disease, and highlights translational opportunities for chrono-microbiome-based interventions to optimize host health. Supplementary information The online version contains supplementary material available at 10.1186/s13062-026-00748-w. Keywords: Circadian rhythms, Microbiota, Circadian disruption, Therapeutic strategies, Host health Introduction Circadian rhythms are evolutionarily conserved, cell-autonomous oscillations that coordinate physiological processes with approximately 24-hour light/dark cycles [ 1 , 2 ]. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus functions as the central pacemaker, synchronizing peripheral clocks in tissues such as the liver, gut, and skin through neural, hormonal, and metabolic signals [ 3 ]. This hierarchical system orchestrates essential processes, including sleep-wake cycles, neuroendocrine secretion, metabolic pathways, immune responses, and barrier function, ensuring temporal alignment with environmental demands [ 4 – 7 ]. At the molecular level, these rhythms are driven by a transcription-translation feedback loop (TTFL) involving core clock genes—including Bmal1 (Brain and muscle aryl-hydrocarbon receptor nuclear translocator-like 1), Clock (Circadian Locomotor Output Cycles Kaput), Per1/2/3 (Period 1/2/3), Cry1/2 (Cryptochrome 1/2) and Rev-erb (nuclear receptor subfamily 1, group D)—whose oscillatory expression regulates thousands of clock-controlled genes (CCGs) [ 8 , 9 ]. Circadian disruption elicits profound pathophysiological consequences, impairing neurotransmitter and hormone dynamics, altering metabolic homeostasis, and dysregulating immune responses. These disturbances contribute to the development of a range of disorders including obesity, diabetes, cardiovascular disease, neurodegenerative conditions, gastrointestinal dysfunction, and immune deficiencies [ 10 – 14 ]. Notably, circadian misalignment exacerbates systemic imbalances through mechanisms such as aberrant cortisol secretion, disrupted fat metabolism, and impaired cellular repair processes, underscoring its role as a nexus for multifactorial disease pathogenesis [ 15 ]. Accumulating evidence highlights the dual role of the circadian clock as both a coordinator of physiological homeostasis and a modulator of disease susceptibility, emphasizing the necessity of preserving circadian integrity for systemic health. Concurrently, the human microbiota is fundamental to maintaining physiological homeostasis and shaping disease susceptibility through dynamic host-microbe interactions across various body niches [ 16 , 17 ]. For instance, microbial dysbiosis is recognized as a key contributor to immune-mediated diseases, where disrupted microbial communities influence the pathogenesis of autoimmune disorders, chronic inflammation, and allergic conditions by modulating immune and inflammatory pathways [ 18 ]. In cancer biology, the microbiota interacts with host genetics and environmental factors to regulate carcinogenesis, therapeutic efficacy, and disease progression through metabolic and immune modulation [ 19 ]. Similarly, the oral microbiota has systemic implications with its dysbiosis linked to both local and systemic inflammatory diseases [ 20 , 21 ]. The respiratory microbiota functions as a gatekeeper of pulmonary health by maintaining colonization resistance, regulating mucosal immunity, and preserving epithelial homeostasis, with its composition shaped by environmental exposures and host factors [ 22 ], while the gut microbiome exerts profound systemic effects via microbial metabolites, impacting neurodegenerative, cardiovascular, metabolic, and gastrointestinal disorders, while therapeutic interventions like probiotics, fecal microbiota transplantation, and dietary modifications show promise in restoring microbial balance [ 23 – 26 ]. Furthermore, microbiota in the urinary and reproductive tracts and skin are essential for urogenital and cutaneous health, respectively, where dysbiosis in the urinary tract and genital microbiota associates with urinary pathologies and infertility in both sexes, potentially influenced by sexual transmission dynamics and modifiable through probiotic interventions [ 27 , 28 ]. Moreover, skin microbiota maintains cutaneous barrier function through context-dependent interactions that regulate epithelial homeostasis, pathogen resistance, and local immunity, with imbalances linked to various dermatological conditions [ 29 ]. Collectively, these findings underscore the microbiota’s pervasive influence on human physiology and disease across multiple organ systems. The intricate interplay between microbial communities, host factors, and environmental exposures unlocks novel therapeutic opportunities for disease management, which can be achieved through targeted microbial modulation, personalized nutrition, and ecological restoration strategies. Despite significant advances in understanding circadian biology and host-microbiota interactions independently, their reciprocal relationship between circadian disruption and microbial dysregulation remains critically underexplored. While it is established that circadian rhythms govern physiological processes and that microbiota imbalances contribute to diverse pathologies, the mechanistic links connecting circadian misalignment to microbial perturbations—and their combined impact on systemic disease—remain poorly defined. Emerging evidence suggests that circadian oscillations may temporally regulate microbial community structure and function through rhythmic hormonal secretion, feeding-fasting cycles, and immune activity, thereby influencing microbial metabolite production and host-microbe signaling [ 30 – 33 ]. Conversely, dysbiotic microbiota may disrupt peripheral clock gene expression, amplifying circadian dysfunction in a bidirectional feedback loop. This review synthesizes current evidence to address key knowledge gaps: (1) how circadian disturbances reshape microbial ecosystems across mucosal and epithelial interfaces; (2) the role of microbial-derived signals in modulating circadian clock entrainment and tissue-specific rhythmicity; and (3) the translational potential of chrono-microbiome-based therapeutics to mitigate diseases rooted in circadian-microbial crosstalk. By systematically delineating these cross-regulatory interactions, we aim to provide novel insights into how circadian and microbial homeostasis interdepend, while proposing integrative strategies—including chrono-targeted probiotics, timed nutrient delivery, and environmental rhythm resynchronization—to restore host-microbe temporal harmony and optimize clinical outcomes. The impact of host circadian rhythm alterations on gut microbiota diurnal rhythmicity in physiology and disease The gut microbiota is a complex community indispensable for host physiological homeostasis [ 34 ]. Notably, both its microbial composition and functional activity exhibit pronounced diurnal (time-of-day–dependent) rhythmicity, which is tightly synchronized with host circadian rhythms [ 35 ]. This temporal coordination is critical for maintaining metabolic balance and its disruption disproportionately alters gut microbial ecosystems, thereby amplifying systemic physiological disturbances. Emerging evidence highlights the tripartite interplay between diet, circadian rhythms, and gut microbiota in shaping host physiology [ 36 – 38 ]. Dietary interventions, particularly concerning meal timing and nutrient composition, simultaneously regulate circadian clock alignment and microbial community dynamics [ 39 – 42 ]. Time-restricted feeding/eating (TRF/TRE) exemplifies this synergy, restoring microbial balance and synchronizing microbial diurnal rhythms with host circadian oscillations, thereby optimizing metabolic, hormonal and immune-inflammatory responses [ 41 , 42 ]. Specific microbial taxa demonstrate circadian-dependent fluctuations in abundance and metabolite production (e.g., short-chain fatty acids), which can reinforce peripheral circadian rhythmicity via nuclear receptor signaling [ 39 , 42 ]. Conversely, circadian misalignment coupled with erratic eating patterns disrupts microbial diversity and metabolic output, driving dysbiosis-associated pathologies such as metabolic syndrome, cardiovascular disease, and neuropsychiatric disorders [ 39 , 40 , 43 ]. Consequently, chrono-aligned nutrition is positioned as a promising therapeutic strategy to harmonize host-microbe temporal coordination [ 40 , 41 , 43 ]. Collectively, these insights underscore the therapeutic potential of dietary timing and composition in maintaining circadian and microbial homeostasis. Circadian rhythm disturbances profoundly reshape gut microbiota, exacerbating neuropsychiatric disease progression via the microbiota-gut-brain axis. For example, in epilepsy, circadian-driven dysbiosis aggravates seizure susceptibility through bidirectional gut-brain interactions [ 44 ]. In Alzheimer’s disease (AD), pathogenesis is linked to circadian-synchronized microbial shifts, marked by pathobiont expansion, depletion of beneficial taxa, and gut barrier dysfunction that amplify neuroinflammation and neurodegeneration [ 45 ]. Aging-associated blood-brain barrier (BBB) deterioration is further accelerated by circadian-microbiota interactions [ 46 ]. Psychiatric disorders like depression and schizophrenia also demonstrate circadian-aligned microbial dysbiosis, where rhythm-modulated metabolites disrupt neuroendocrine signaling [ 47 ]. Mechanistically, circadian disruption alters microbial responses to feeding/fasting cycles, exacerbating metabolic-endocrine imbalances [ 48 , 49 ]. Therefore, therapeutic strategies targeting microbial rhythmicity, such as timed dietary interventions, show promise for neuropsychiatric conditions [ 49 ]. Together, these findings highlight circadian regulation of the microbiota as a critical determinant of neuropsychiatric health and a promising target for therapeutic intervention. Furthermore, circadian-microbiota interactions extend to metabolic and infectious diseases through epigenetic and metabolite-mediated mechanisms. Gut microbes bidirectionally communicate with host circadian clocks via histone modifications and metabolite signaling (e.g., butyrate, bile acids), regulating metabolic homeostasis, immune responses, and endocrine function [ 50 , 51 ]. At the molecular level, gut microbiota–derived metabolites interact with core clock genes, such as Bmal1, Clock, Per, and Cry, thereby influencing metabolic homeostasis [ 52 ]. Dysregulation of this microbiota–circadian axis has been implicated in the pathogenesis of obesity, type 2 diabetes mellitus (T2DM) pathogenesis, and other metabolic disorders, where circadian-microbiota misalignment impairs glucose regulation, insulin sensitivity, and lipid metabolism [ 30 , 51 – 54 ]. Microbial metabolites synchronize peripheral circadian clocks, while polyphenols exert cardioprotective effects by modulating both microbiota composition and circadian gene expression [ 53 , 54 ]. In infectious contexts, circadian-microbiota crosstalk influences antiviral immunity and hepatitis B-related cirrhosis progression through metabolic-immune pathway modulation [ 55 , 56 ]. Collectively, these findings advocate for chronotherapeutic strategies to restore circadian-microbiota synchrony across metabolic, immune, and infectious disease paradigms. Gram-negative bacteria within the gut microbiota are a major source of lipopolysaccharides (LPS), which can translocate into the systemic circulation under conditions of intestinal barrier dysfunction and microbial dysbiosis [ 57 , 58 ]. Elevated circulating LPS acts as a potent inflammatory mediator and has been implicated in the development of insulin resistance and metabolic dysfunction through activation of innate immune signaling pathways [ 59 , 60 ]. In parallel, LPS exerts neurotoxic effects by promoting amyloid-β aggregation, neuroinflammation, and neuronal dysfunction, thereby contributing to the pathogenesis of Alzheimer’s disease and related neurodegenerative disorders [ 57 , 58 ]. Accumulating evidence identifies Sirtuin 1 (SIRT1) as a central molecular regulator linking metabolic homeostasis, immune function, and circadian rhythm control [ 60 , 61 ]. LPS has been shown to functionally suppress SIRT1 activity, leading to impaired insulin signaling, chronic inflammation, and disruption of circadian clock regulation in both central and peripheral tissues [ 59 , 62 ]. Given that SIRT1 directly modulates core clock components and coordinates peripheral circadian oscillations, its inhibition contributes to circadian desynchrony and multi-organ dysfunction [ 60 , 61 ]. In the central nervous system, SIRT1 repression exacerbates amyloid-β accumulation, mitochondrial dysfunction, and neuroinflammatory responses, thereby accelerating neurodegenerative processes [ 57 , 58 ]. Lifestyle factors, including diet composition, physical activity, sleep regularity, and circadian alignment, critically regulate SIRT1 activity and downstream metabolic and circadian pathways [ 59 , 61 ]. Collectively, these findings support the LPS–SIRT1 axis as a key mechanistic pathway through which gut microbiota dysbiosis interfaces with circadian disruption and contributes to metabolic and neurodegenerative disease progression. Although numerous studies have reported strong associations between environmental or host circadian disruption, alterations in gut microbiota composition, and disease development, direct evidence demonstrating a causal role for disrupted diurnal microbiome rhythmicity remains limited. In most cases, changes in microbial rhythmicity are inferred from observational or correlative data, underscoring the need for functional approaches to establish a direct link between altered microbial temporal dynamics and disease phenotypes. Moreover, many reported microbiota alterations may occur secondary to shifts in feeding behavior, hormonal rhythms, or host metabolic status, rather than reflecting direct clock-driven effects on the microbiome. Circadian rhythm modulation within the digestive system Human shift work Rotational shift work in male security personnel induces gut microbiota alterations linked to circadian disruption, characterized by increased abundances of Blautia , Bifidobacterium , Dialister , and Ruminococcus gnavus , elevated fecal short-chain fatty acids (SCFAs) correlating with intestinal permeability (serum zonulin), and exacerbated dysbiosis in high-sugar consumers [ 63 ], suggesting microbiota-mediated metabolic dysfunction and circadian-metabolic axis dysregulation as precursors to long-term cardiometabolic risks. Similarly, shift work combined with alcohol consumption disrupts the diurnal oscillation of SCFAs, contributing to intestinal barrier dysfunction [ 64 ]. Taken together, these findings implicate circadian disruption–induced microbial alterations as a mechanistic link between shift work and increased vulnerability to chronic metabolic disorders (Fig. 1 and Supplementary Table 1 ). Fig. 1. Open in a new tab Impact of circadian disruption on gut microbiota and digestive health. Circadian disruption leads to shifts in gut microbiota composition, which subsequently impair digestive health through multiple biological pathways, as elaborated below: (1) Shift work and circadian disruptions in humans. Disrupted light-dark cycles impact gut microbiota (e.g., Bilophila , Lactobacillus ), resulting in altered gut permeability and inflammation, affecting overall health. (2) Light-dark cycle perturbations in animal models. Animal studies demonstrate that circadian misalignment triggers microbial alterations (e.g., Lactobacillus johnsonii ), which affect gut health and contribute to metabolic disorders. (3) TRF and dietary interventions. TRF and other dietary interventions restore circadian rhythm balance, modulate gut microbial communities (e.g., Firmicutes , Bacteroidetes ), and improve metabolic health by enhancing gut barrier integrity and regulating immune responses. (4) Liver-microbiota crosstalk. Circadian disruptions induced by a high-fat diet (HFD) or high-cholesterol diet perturb hepatic circadian rhythms, which in turn drive changes in gut microbiota (e.g., Firmicutes , Bacteroidetes ). These microbial shifts further disrupt metabolic processes and impair liver function. (5) Immune and disease implications. Sleep restriction and circadian misalignment elicit gut microbial changes (e.g., Akkermansia , Lactobacillus ), which trigger immune dysregulation and contribute to the pathogenesis of diseases such as colorectal cancer, colitis, and enteritis. (6) Host-microbe co-regulation. Circadian disturbances disrupt the symbiotic host-microbiota relationship (e.g., alterations in Firmicutes and Proteobacteria ), thereby compromising gut barrier function, nutrient absorption, and immune homeostasis Light-dark cycle perturbations in animal models Environmental light perturbations profoundly reshape host-microbiota interactions. For instance, chronic jet lag significantly alters the gut microbiome and mycobiome in mice fed a high-fat and high-fructose diet (HFFD)—specifically reducing the abundances of Akkermansia , Lactococcus , Prevotella , Clostridium , and Bifidobacterium , while elevating those of Aspergillus and Blumeria —thereby accelerating the progression of metabolic dysfunction-associated fatty liver disease (MAFLD) [ 65 ]. Abnormal light-dark cycles or phase shifts disrupt microbial composition (e.g., increasing Ruminococcus torques, decreasing Lactobacillus johnsonii), impair barrier integrity, and increase susceptibility to inflammation and irritable bowel syndrome (IBS) [ 66 – 68 ]. Conversely, interventions like intermittent photoperiods can enhance circadian rhythmicity and improve metabolic health by modulating the microbiota [ 69 ]. Furthermore, dim light at night (dLAN) reshapes colonic microbiota in mice, correlating with metabolic dysfunction and weight gain, highlighting the role of light pollution in obesity [ 70 ]. Short-light cycles alter Per2 expression and microbial diversity, affecting SCFA production and gut inflammation, particularly in Per2 knockout mice [ 71 ]. These findings collectively link circadian light disruption to metabolic, inflammatory, and gastrointestinal disease risk (Fig. 1 and Supplementary Table 2 ). Time-restricted feeding and dietary interventions Feeding timing has emerged as a critical zeitgeber linking circadian rhythms to gut microbial dynamics. Disruption of eating–fasting cycles, such as during shift work or irregular meal timing, leads to microbial dysbiosis and circadian misalignment, thereby increasing susceptibility to metabolic and inflammatory disorders [ 72 ]. Time-restricted feeding (TRF) and specific dietary components are powerful modulators of the circadian-microbiota-metabolism axis. TRF restores hepatic metabolic rhythms, mitigates dysbiosis, and prevents conditions like gallstones and colitis in mouse models [ 73 ]. Restricted feeding synchronized with the intestinal circadian clock mitigates colitis in IL-10 knockout mice by restoring rhythmic immune cell recruitment and microbial oscillations (notably Lachnospiraceae and Oscillospiraceae ), thereby improving survival and preventing inflammatory bowel disease (IBD) progression [ 74 ]. Besides, it also attenuates high-fat diet (HFD)-induced obesity and steatosis by enhancing microbial oscillations [ 75 ]. In contrast, daytime restricted feeding disrupts hepatic circadian gene expression and bile acid profiles, leading to an expansion of Firmicutes and a reduction in Verrucomicrobia —alterations closely linked to metabolic perturbations [ 76 ]. Conversely, night-restricted feeding (NRF) synchronizes gut microbiota-serotonin rhythmicity, thereby improving intestinal health in rabbits [ 77 ]. Beyond feeding regimens, dietary bioactives exert similar regulatory effects: oat fiber supplementation in HFD-fed mice modulates circadian rhythms via microbiota-derived SCFAs, upregulating hepatic clock gene expression and ameliorating lipid metabolism [ 78 ]. Green tea polyphenols promote the enrichment of Bacteroidetes while inhibiting Firmicutes , thus alleviating circadian rhythm dysfunction [ 79 ]. Oolong tea polyphenols (OTP) reverse constant darkness-induced disruptions in both gut microbiota composition and hepatic clock gene expression [ 80 , 81 ]. Similarly, ripened Pu-Erh tea (RPT) restores microbiota balance and bile acid metabolic homeostasis in circadian-disrupted mice [ 82 ]. Collectively, these findings underscore that both dietary timing and bioactive nutrients are powerful regulators of the circadian–microbiota–metabolism axis, offering prophylactic and therapeutic strategies for preventing and treating metabolic and inflammatory diseases (Fig. 1 and Supplementary Table 3 ). Liver-microbiota crosstalk The hepatic circadian clock and gut microbiota engage in persistent crosstalk to orchestrate host metabolism [ 83 ]. Pharmacological activation of the circadian nuclear receptor REV-ERBα by SR9009 alleviates diet-induced nonalcoholic steatohepatitis in mice by time-dependently modulating of gut microbiota—specifically by increasing Akkermansia and decreasing Desulfovibrionaceae )—alongside enhanced gut barrier integrity, ameliorated hepatic inflammation, and improved insulin sensitivity [ 84 ]. Conversely, HFD drives PPARγ-mediated reprogramming of hepatic circadian rhythms via microbiota, an effect that is abrogated by antibiotic administration [ 85 ]. Circadian disruption exacerbates nonalcoholic fatty liver disease (NAFLD) in mice by altering gut microbiota diversity, marked by a pronounced elevation in the Firmicutes/Bacteroides ratio and concomitant perturbations in hepatic lipid metabolism, highlighting the critical role of circadian rhythmicity in the pathogenesis of metabolic diseases [ 86 ]. Antibiotic depletion of Gram-positive bacteria impairs hepatic circadian rhythms and metabolic functions [ 87 ]. Acetaminophen-induced liver injury exhibits diurnal variation influenced by microbial metabolites, and this injury can be mitigated by antibiotic-induced alterations to the gut microbiota [ 88 ]. Conditional deletion of hepatic Npas2 remodels the microbiota Bacteroides and induces metabolic stress [ 89 ]. Collectively, these studies underscore the pivotal role of liver-gut circadian crosstalk as a promising therapeutic target for metabolic liver diseases (Fig. 1 and Supplementary Table 4 ). Immune and disease implications Disruptions in light-dark cycles induce circadian misalignment in mice, perturbing both hypothalamic and hepatic circadian clocks. This dysregulation, in turn, reshapes gut microbiome composition by depleting beneficial taxa such as Limosilactobacillus and Faecalibacterium , while impairing metabolic and immune functions, promoting systemic inflammation, and facilitating the onset of metabolic diseases [ 90 ]. Furthermore, intestinal circadian clock disruption accelerates colorectal cancer (CRC) progression via the expansion of pathogenic Fusobacterium and Bacteroides expansion and impairment of the intestinal barrier [ 91 ]. Histone deacetylase 3 (HDAC3) regulates tuft cell biogenesis and intestinal immune rhythms through transforming growth factor-β (TGF-β), with these processes synchronized by the microbiota [ 92 ]. Circadian misalignment also exacerbates dextran sulfate sodium-induced colitis by reducing microbial diversity and increasing pro-inflammatory taxa including Alloprevotella and Streptococcus [ 93 ]. Conversely, butyrate—a microbiota-derived SCFA—modulates immune responses in Sjögren’s syndrome by inducing the generation of IL-10-producing B cells via circadian-clock-related genes such as Rorα and Rev-erbα, thereby alleviating inflammation and ameliorating symptoms in NOD/ShiLtJ mice [ 94 ]. The gut microbiota also plays a crucial role in coordinating diurnal rhythms of intestinal innate immunity. Segmented filamentous bacteria (SFB) exhibit rhythmic mucosal attachment, which regulates antimicrobial protein expression in synchrony with the day-night cycle and enhances resistance to enteric pathogens such as Salmonella [ 95 ]. Diurnal feeding cycles modulate small intestinal epithelial cell immune responses, microbiome composition, and intestinal barrier function [ 96 ]. Disruption of circadian rhythms—caused by aberrant dietary timing or circadian misalignment—can exacerbate inflammatory disorders such as Crohn’s disease [ 96 ]. Notably, targeted therapeutic interventions can harness this circadian-microbiota axis. Edible bird’s nest (EBN) supplementation enriches beneficial taxa including Akkermansia and Lactobacillus , improving glucose and lipid metabolic homeostasis via circadian modulation [ 97 ]. Melatonin has been shown to restore microbiota disrupted by sleep restriction or HFD, enhancing microbial diversity and reducing inflammation [ 98 , 99 ]. Additionally, miRNA-10a-5p sustains triglyceride and microbiota rhythmicity, supporting insulin sensitivity through the regulation of Lachnospiraceae abundance and butyrate production [ 100 ]. These findings highlight the intricate interplay between circadian rhythms and the gut microbiota in the maintenance of immune and metabolic homeostasis, offering promising avenues for chronotherapeutic strategies targeting inflammatory and metabolic diseases (Fig. 1 and Supplementary Table 5 ). Host-microbe co-regulation Circadian rhythms not only govern host physiology but also profoundly shape the temporal organization of the gut microbiota [ 101 ]. Emerging evidence highlights a bidirectional interplay in which host circadian clocks regulate microbial composition and function, while microbial-derived signals reciprocally modulate circadian entrainment and peripheral clock gene expression [ 72 , 101 ]. The gut microbiota exhibits pronounced diurnal oscillations at both compositional and functional levels, and these rhythmic fluctuations extend to microbial metabolites, including short-chain fatty acids and bile acids, which act as key mediators synchronizing peripheral circadian clocks in host tissues [ 102 ]. Under homeostatic conditions, host circadian behaviors exert minimal selective pressure on the gut microbiota, however, they are pivotal for mediating gut microbiota recovery following antibiotic exposure [ 103 ]. Loss of intestinal epithelial Bmal1 disrupts microbial circadian rhythmicity—particularly within the Lachnospiraceae and Odoribacteraceae families—impairs immune gene expression, and compromises gastrointestinal immune homeostasis, thereby highlighting the indispensable role of the intestinal circadian clock in sustaining microbial function and mucosal immunity [ 104 ]. Bmal1 deletion abolishes microbiota rhythmicity, accompanied by sex-specific alterations in microbial community composition [ 105 ]. Beyond the gut, ruminal microbiota exhibit melatonin-regulated circadian rhythms that fine-tune microbial fermentation processes and host metabolic homeostasis [ 106 ]. In humans, sleep deprivation disrupts duodenal secretion of human defensin 5 (HD5) and perturbs gut microbiota composition, leading to reduced SCFA production and subsequent metabolic and immune dysregulation [ 107 ]. Notably, sulforaphane (SFN) supplementation ameliorates microbiota dysbiosis and improves hepatic function in circadian-disrupted mice [ 108 ]. Altogether, these observations emphasize that the integrity of the host and tissue-specific circadian clocks is indispensable for preserving microbial rhythmicity, metabolic equilibrium, and immune resilience (Fig. 1 and Supplementary Table 6 ). Impact of circadian rhythms modulations on neurological and psychiatric systems Sleep and circadian regulation of gut-brain axis Recent studies have further extended the circadian–microbiota paradigm to sleep and neuropsychiatric disorders. Circadian rhythm disruption induces gut microbial dysbiosis, which in turn modulates the gut–brain axis through neuroactive metabolites, immune signaling, and hormonal pathways, contributing to insomnia and related conditions [ 101 , 109 ]. In murine models, 72-hour rapid eye movement sleep deprivation (REM-SD) induces physiological stress and neuroinflammation, accompanied by circadian disruption and gut microbial dysbiosis [ 110 ]—phenotypes that mirror the distinct microbial signatures observed in human prodromal Parkinson’s disease (PD) and REM sleep behavior disorder (RBD). These parallels implicate gut-brain axis alterations in the early stages of neurodegeneration [ 111 ]. Complementary human studies further demonstrate that circadian misalignment, induced via simulated sleep-wake cycle disruption, drives functional remodeling of gut microbial communities [ 112 ]. Additionally, sleep-associated metabolic reprogramming exhibits brain-region specific patterns, involving circadian-modulated metabolites critical for neurodevelopment [ 113 ]. Notably, light exposure emerges as a critical environmental modulator of microbial stability, as photoperiod abnormalities directly disrupt microbial equilibrium through circadian entrainment mechanisms [ 114 ]. These findings collectively emphasize the role of sleep quality and circadian integrity in shaping microbial-host metabolic crosstalk. Individual chronotypes further influence microbiome dynamics, a factor that may inform the development of personalized therapeutic interventions [ 115 ]. The tripartite interaction between light-regulated circadian rhythms, sleep architecture, and gut microbial ecology thus underscores their combined impact on neurological health and systemic homeostasis (Fig. 2 and Supplementary Table 7 ). Fig. 2. Open in a new tab Circadian disruption and its impact on neuropsychiatric health via gut microbiota. Disruptions in circadian rhythms alter gut microbiota, which subsequently affects neuropsychiatric health via the gut–brain axis. (1) Sleep and circadian regulation. Circadian disruptions (e.g., acute sleep deprivation, REM sleep behavior disorder, and sleep-wake cycle shifts) trigger microbial changes (e.g., Firmicutes , Bacteroides , Lactobacillus ), which impair intestinal barrier function, disrupt metabolic homeostasis, and compromise brain health. hese perturbations further contribute to systemic consequences, including increased cardiovascular risk, metabolic disorders, and neurodegenerative diseases. (2) Microbiota-mediated mechanisms. Disruptive factors such as microbial depletion, shift work, and activity-based anorexia (ABA) alter the composition of gut microbiota (e.g., Lactobacillus, Bifidobacterium), leading to intestinal barrier dysfunction, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and aberrant expression of circadian clock genes. These changes subsequently result in diverse adverse health outcomes, including impaired stress response, liver injury-associated brain dysfunction, and anorexia-related behaviors. (3) Therapeutic interventions. Interventions such as antibiotic administration, polystyrene nanoplastic exposure, and surgical interventions modulate microbial balance (e.g., Akkermansia , Bacteroides ) and ameliorate gut-brain axis function. Specifically, these interventions enhance intestinal barrier integrity, regulate circadian rhythm homeostasis, and suppress neuroinflammation—ultimately improving cognitive function, restoring metabolic homeostasis, and reducing inflammation and neurodegenerative risk Microbiota-mediated mechanisms in neuropsychiatric disorders The gut microbiota has emerged as a critical mediator of interactions between circadian rhythms and neuropsychiatric disorders, with mechanistic insights spanning multiple pathological contexts. Experimental evidence demonstrates that microbial communities drive circadian-timed dysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis under stress and exacerbate cognitive deficits following hepatic ischemia-reperfusion injury (HIRI) through neuroinflammatory pathways [ 116 ]. Notably, circadian disruption amplifies AD-related neurodegeneration through microbiota-dependent inflammatory cascades—highlighting the therapeutic potential of intestinal barrier stabilization to mitigate cognitive decline [ 117 ]. Furthermore, translational models such as activity-based anorexia (ABA) reveal sex-specific dysregulation of the circadian-microbiome-gut-brain axis, providing mechanistic insights into how malnutrition-induced circadian fragmentation sustains neuropsychiatric comorbidities [ 118 ]. These findings collectively position the microbiota as a dynamic interface linking circadian integrity to neurocognitive outcomes, with disruptions in microbial-circadian crosstalk exacerbating neuroinflammation, metabolic dyshomeostasis, and disease progression across diverse neurological and psychiatric conditions (Fig. 2 and Supplementary Table 8 ). Therapeutic interventions Several therapeutic and environmental interventions demonstrate the critical interplay between pharmacological agents, dietary components, and environmental factors in modulating the microbiota-circadian-neuropsychiatric axis. Pharmacological approaches such as Dendrobium officinale polysaccharide (DOP) ameliorate circadian disruption-associated cognitive impairment by restoring microbiota composition and enhancing intestinal barrier integrity, highlighting microbiota-gut-brain axis mechanisms in neuroprotection [ 119 ]. Conversely, antibiotic-mediated microbiome depletion disrupts cerebral metabolic cycles, revealing gut-brain crosstalk as a regulator of both metabolic homeostasis and circadian dynamics [ 120 ]. Environmental neurotoxins like polystyrene nanoplastics (PS-NPs) induce gut-brain axis-mediated circadian interference and neurotoxicity, though these effects are reversible through melatonin and probiotic interventions [ 121 ]. Dietary interventions further reinforce this tripartite interaction: polyphenols, (including oolong tea derivatives) attenuate circadian disruption-induced cognitive decline via microbiota modulation and neuroinflammatory suppression [ 122 ], while cyclocarya paliurus flavonoids (CPF) restore circadian rhythmicity by synchronizing gut microbial communities with cellular clock machinery [ 123 ]. Green tea polyphenols (GTP) similarly enhance microbial homeostasis and rescue circadian-associated metabolites, reinforcing diet-microbiota synchronization as a therapeutic strategy [ 124 ]. Importantly, the integration of photic circadian circuits with microbial signaling into neuroimmune-metabolic networks emphasizes how environmental cues, such as light cycles and pollutant exposure, systemically shape health outcomes [ 32 ]. Collectively, these findings position microbiota-circadian interactions as a central nexus for therapeutic innovation, where pharmacological, nutritional, and environmental interventions converge to mitigate neuropsychiatric dysregulation through axis-targeted mechanisms (Fig. 2 and Supplementary Table 9 ). Circadian rhythms modulations in metabolic processes Dietary interventions Capsaicin ameliorates metabolic disorders in HFFD-fed mice by restoring gut microbiota diurnal rhythmicity, enhancing microbial oscillations, and regulating glucose metabolism-related genes [ 125 ]. Similarly, oat β-glucan (GLU) alleviates metabolic syndrome in HFD-fed mice by reinstating circadian clock genes (Bmal1, Clock, Cry1), restoring gut microbiota oscillations, and promoting GLP-1 secretion via SCFA-mediated G protein-coupled receptor activation [ 126 , 127 ]. Ellagic acid modulates hepatic circadian signaling (NPAS2 upregulation) and reshapes microbiota composition to mitigate alcohol-related liver injury [ 128 ]. ω-3 polyunsaturated fatty acids (PUFAs) mitigate HFFD-induced circadian microbiota dysbiosis, restoring diurnal microbial fluctuations and SCFA production to improve lipid metabolism [ 129 ]. Conversely, reversed feeding patterns (day-night inversion) exacerbate HFD-induced obesity and lipid dysregulation by reducing gut microbial diversity and enriching inflammation-associated bacteria [ 130 ]. Collectively, these findings underscore the therapeutic potential of dietary and nutrient-based interventions in restoring circadian–microbiota alignment to counteract diet-induced metabolic disorders (Fig. 3 and Supplementary Table 10 ). Fig. 3. Open in a new tab Metabolic consequences of circadian disruption and microbial imbalance. Alterations in circadian rhythms can disrupt the composition of gut microbiota, thereby influencing metabolic health through multiple mechanisms. The key pathways and implications are detailed below: (1) Dietary interventions. Shifts in the light-dark cycle, high-fat diet (HFD), and alcohol-related diseases disrupt microbial communities (e.g., Firmicutes , Bacteroidetes , Lachnospiraceae ), leading to alterations in metabolic processes such as glucose metabolism, lipid metabolism, and insulin sensitivity. (2) Metabolic dysfunction. Circadian misalignment (e.g., shift work, jet lag) and genetic clock dysfunction disrupt gut microbial rhythmicity, precipitate gastrointestinal diseases, and contribute to metabolic syndrome, obesity, and insulin resistance. (3) Host metabolic regulation. Circadian disturbances alter microbial composition (e.g., Bacteroides , Lachnospiraceae ) and perturb gut microbiota-host crosstalk, impacting processes including glucagon-like peptide-1 (GLP-1) secretion, trimethylamine (TMA) production, and lipid absorption. These disruptions contribute to metabolic dysregulation, including obesity, insulin resistance, and glucose homeostasis. (4) Disease-specific interactions and clinical implications. circadian rhythm disruptions associated with diseases (e.g., type 2 diabetes, inflammatory bowel disease) alter microbial composition (e.g., Lachnospiraceae , Akkermansia ) and host metabolic processes, accelerating disease progression. (5) Therapeutic synchronization of circadian-microbial axis. Interventions such as time-restricted feeding (TRF) and HFD adjustment realign circadian rhythms, modulate microbial balance, and regulate metabolic processes—ultimately improving outcomes related to obesity and insulin resistance Circadian disruption and metabolic dysfunction Chronic exposure to glucocorticoids—commonly used for inflammatory and autoimmune conditions—has been shown to disrupt intrinsic circadian rhythmicity in rats, with far-reaching consequences including aberrant lipid accumulation, profound alterations in microbial community structure, and subsequent metabolic imbalance [ 131 ]. Beyond pharmacological interventions, genetic ablation of core circadian clock genes or environmental perturbations that induce circadian misalignment similarly promote weight gain and glucose intolerance in mice. Mechanistically, these phenotypes are linked to perturbed rhythmicity of SCFA-producing bacteria, key metabolites that regulate energy homeostasis and glucose metabolism [ 132 ]. Translating to human populations, night shift work, a prevalent environmental circadian disruptor, induces a shift in the gut microbial composition characterized by reduced Bacteroidetes abundance and increased Firmicutes levels, a dysbiotic profile consistently associated with elevated risks of metabolic disorders (e.g., obesity, type 2 diabetes) and gastrointestinal pathologies [ 133 ]. Complementing these findings, Sleep deprivation in humans disrupts the circadian oscillation of bile acids—critical mediators of lipid digestion and gut microbial signaling—further establishing a link between environmental stressors, circadian misalignment, and metabolic dysregulation [ 134 ]. Notably, the pathogenic effects of circadian disruption on metabolism are transmissible via fecal microbiota transplantation, underscoring the microbiota as a central mediator of circadian-metabolic crosstalk [ 135 ]. Together, these preclinical and clinical observations highlight that both environmental insults and genetic defects in circadian clock machinery can reshape the temporal dynamics of gut microbial communities, thereby perturbing host metabolic pathways and increasing susceptibility to chronic metabolic and gastrointestinal diseases in a transmissible manner (Fig. 3 and Supplementary Table 11 ). Microbial metabolites and host metabolic regulation Diurnal secretion of glucagon-like peptide-1 (GLP-1)—a key incretin hormone that enhances insulin secretion, suppresses glucagon release, and regulates satiety—is tightly dependent on the gut microbiota, with emerging evidence indicating that circadian rhythm disruption concurrently impairs glucose metabolic homeostasis and blunts insulin secretory capacity [ 136 ]. Gut microbiota-derived SCFAs, such as butyrate, entrain intestinal epithelial circadian rhythms through histone deacetylase (HDAC) inhibition, phase-shifting core clock genes (Bmal1, Per2) and influencing host metabolism and immunity [ 137 ]. Translating these preclinical observations to clinical settings, butyrate supplementation in patients with ulcerative colitis has been shown to upregulate the expression of circadian clock genes (Cry1, Cry2, Per1, Bmal1), reduces inflammation, and improves sleep quality [ 138 ]. Beyond intestinal epithelia, microbial metabolites such as SCFAs exert systemic effects by modulating circadian clock gene expression in extraintestinal tissues, coordinating nutrient uptake, lipid metabolism, and energy homeostasis [ 139 , 140 ]. The microbiota further influences lipid metabolism via the microbiota-NFIL3 axis, which controls the rhythmicity of intestinal epithelial clock genes, thereby modulating intestinal lipid absorption and systemic fat storage [ 141 ]. Additionally, mechanistic studies have also identified that inhibition of the gut microbial CutC enzyme improves glucose tolerance by restoring circadian control over phosphatidylcholine metabolism [ 142 ]. Similarly, the microbiota regulates diurnal host metabolic rhythms through modulation of HDAC3 activity in intestinal epithelia, which directly influences the expression of core clock genes [ 140 ]. The microbiota-dendritic cell (DC)-group 3 innate lymphoid cells (ILC3) axis—integrating retinoic acid and circadian transcription factors including REV-ERBα and NFIL3—promotes fat storage, and inhibition of RUNX1 has been proposed as a potential strategy to counteract obesity driven by circadian disruption [ 143 ]. Additionally, the absence of the microbiota disrupts sex-specific metabolic rhythms, accompanied by alterations in sexual maturation and growth hormone signaling [ 144 ]. Overall, these insights reveal that microbial metabolites and circadian clocks are tightly interwoven in regulating host metabolism, immunity, and development, positioning the microbiota–circadian axis as a critical determinant of health and disease (Fig. 3 and Supplementary Table 12 ). Disease-specific interactions and clinical implications Type 2 diabetes disrupts the diurnal oscillations of gut microbial taxa—including Ruminococcaceae and Lachnospiraceae —and impairs GLP-1 sensitivity, thereby exacerbating insulin resistance [ 145 ]. In db/db mice, a well-established model of T2D, the loss of diurnal rhythmicity in key commensal genera such as Akkermansia and Bifidobacterium is associated with altered levels of histidine and trimethylamine N-oxide (TMAO), metabolites that contribute to impaired glucose homeostasis [ 146 ]. Maternal HFD exposure induces sex-specific metabolic and microbiota rhythmicity disturbances in offspring, with males being particularly susceptible [ 147 ]. Urolithin A enhances clock genes (Bmal1, Per2) and tight junction proteins, thereby alleviating IBD [ 148 ]. Additionally, circadian oscillations modulate the severity of hepatic ischemia-reperfusion injury in diabetic mice, suggesting that microbiota-dependent temporal regulation contributes to diabetes-related liver damage [ 149 ]. From a clinical perspective, breastfeeding promotes the rhythmic development of Bifidobacterium in infants, whereas formula feeding supplemented with galacto-oligosaccharides (GOS) sustains bifidobacterial abundance—both of which support long-term metabolic health [ 150 ]. Collectively, these findings emphasize that circadian–microbiota interactions not only shape metabolic outcomes across the lifespan but also hold translational potential for the prevention and management of metabolic and inflammatory diseases (Fig. 3 and Supplementary Table 13 ). Therapeutic synchronization of circadian-microbial axis Melatonin synchronizes hepatointestinal lipid homeostasis under conditions of constant light exposure, reinstating the expression of core clock genes and normalizing gut microbiota composition to alleviate HFD-induced obesity [ 151 ]. Similarly, the melatonergic agonist agomelatine enhances SCFA production and improves metabolic profiles by reestablishing disrupted circadian rhythmicity [ 152 ]. In human studies, TRF improves key metabolic markers and augments microbiota diversity, particularly enriching taxa such as Prevotellaceae and Bacteroidaceae , via upregulation of Sirtuin 1 (SIRT1) [ 153 ]. These findings highlight the promising potential of circadian-aligned interventions, such as melatonin supplementation and TRF, in restoring metabolic balance and enhancing microbiota diversity. Such strategies offer novel, translatable approaches for the management of metabolic disorders (Fig. 3 and Supplementary Table 14 ). Circadian coordination of gut microbiota across residual systems The gut microbiota plays a pivotal role not only in maintaining digestive health but also in engaging in bidirectional crosstalk with multiple physiological systems, thereby modulating disease pathogenesis and overall host health [ 154 ]. Disruptions to circadian rhythmicity can induce profound alterations in the composition and functional capacity of the gut microbiota, which in turn exert far-reaching effects on systemic processes beyond the gastrointestinal tract—including cancer, cardiovascular diseases, reproduction, orthopedic disorders, and skin health (Fig. 4 and Supplementary Table 15 ). This emerging area of research underscores the interconnectedness of the circadian regulated gut microbiome and other physiological processes, emphasizing the necessity of adopting a holistic approach to studying health and disease mechanisms. Fig. 4. Open in a new tab The influence of gut microbiota on systems beyond the digestive, neurological, and metabolic domains. Gut microbiota not only plays a critical role in digestive, neurological, and metabolic health but also exerts significant effects on other organ systems, including the cardiovascular, respiratory, genital, skin, and musculoskeletal systems. Circadian rhythm disruptions—such as those induced by abnormal light exposure and dietary alterations—trigger shifts in microbial communities, which in turn lead to microbial imbalances in these extrapulmonary and extraintestinal systems. These microbial perturbations contribute to the development of conditions including cardiovascular diseases, immune dysfunction, and impaired muscle metabolism. Specifically, alterations in microbial composition modulate the function of the skin and respiratory tract, thereby influencing immune responses, inflammatory processes, and the regulation of various physiological pathways. Collectively, these findings underscore the broader systemic implications of circadian regulation of the gut microbiota The aggravation or recurrence of numerous respiratory diseases may be rooted in circadian rhythm disturbances [ 91 ]. Gu et al. demonstrated that disturbances in the circadian rhythms of resting activity are associated with an increased incidence of chronic respiratory diseases [ 92 ]. Additionally, various respiratory allergic diseases exhibit diurnal fluctuations, which are closely related to the regulation of circadian rhythms [ 93 ]. Although the direct interplay between respiratory microbiota and circadian rhythms remains underexplored, emerging evidence implicates circadian disruption in elevating respiratory disease susceptibility through gut microbiota dysregulation. Notably, TRF profoundly modulates the gut microbiome, metabolome, and their diurnal rhythmicity in lung cancer models. Specifically, TRF promotes the enrichment of beneficial bacterial taxa (e.g., Lactobacillus , Bacillus , Bifidobacterium ), reprograms metabolic pathways associated with immune responses and inflammation, and enhances tumor suppression—thus offering a promising non-pharmacological intervention strategy for lung cancer [ 155 ]. Sleep fragmentation (SF) in obese mice on an obesogenic diet (OBD) disrupts gut microbiome, increasing the Firmicutes/Bacteroidetes ratio and causing inflammation. These alterations impair cardiac repair following myocardial infarction (MI) and exacerbate acute heart failure outcomes [ 156 ]. Circadian rhythms influence gut microbial composition, and their disruption compromises post-MI cardiac repair. Conversely, TRF during the wake phase (dark cycle) improves heart failure outcomes by restoring functional capacity of beneficial gut microbial taxa [ 157 ]. In salt-sensitive rats, diurnal rhythms of blood pressure (BP) and gut microbiota are tightly synchronized. High salt intake disrupts both microbial community structure and BP rhythmicity, with downstream detrimental effects on renal function—highlighting the potential of targeting diurnal gut microbiota fluctuations as a strategy to manage hypertension [ 158 ]. Additionally, high-salt diet-induced hypertension disrupts the gut microbiome, leading to kidney and colon inflammation, but calcitriol supplementation restores gut barrier function and alleviates hypertension-related damage by modulating microbial composition [ 159 ]. These findings highlight the intricate interplay between circadian rhythms, gut microbiota, and the cardiovascular system, suggesting that targeting microbial rhythmicity could yield novel therapeutic approaches for managing hypertension, enhancing cardiac repair, and attenuating inflammation. Long-term exposure to constant darkness in rats mimics circadian dysrhythmia, exacerbating dyslipidemia associated with polycystic ovary syndrome (PCOS). However, supplementation with Limosilactobacillus reuteri ameliorates these PCOS-related symptoms by modulating the microbiota-metabolome, reducing Clostridium and Ruminococcaceae UCG-010, and regulating the GALR1–NR1D1–SREBP1 pathway in the liver [ 160 ]. Conversely, continuous light exposure in Sprague-Dawley rats induces PCOS-like reproductive and metabolic perturbations, including increased Parasutterella abundance and impaired glucose metabolism. This circadian disruption also triggers significant alterations in gut microbial composition, characterized by reduced levels of Corynebacterium , Odoribacter , and Acinetobacter , which correlate closely with hormonal and metabolic disturbances [ 161 ]. Gut microbial metabolites, specifically 3-(4-hydroxyphenyl) propionic acid (4-OH-PPA) and 3-phenylpropionic acid (PPA) produced by Clostridium sporogenes, modulate the circadian rhythms in mouse fibroblast cells by affecting the oscillations of clock genes Per2 and Bmal1, influencing both the amplitude and phase of the rhythm and linking gut microbiota with circadian gene expression regulation [ 162 ]. Additionally, disruption of circadian rhythms in mice exposed to continuous light impairs oocyte quality and embryonic development via dysregulation of bile acid metabolism and the vitamin D axis. Depletion of bile acids such as lithocholic acid (LCA) reduces intestinal vitamin D absorption—a process critical for maintaining oocyte quality—with melatonin or vitamin D3 supplementation restoring these parameters and improving reproductive outcomes [ 163 ]. Collectively, these findings underscore the critical role of gut microbiota and circadian rhythm synchronization in regulating reproductive health. They further highlight the potential for microbiota-targeted and circadian-based interventions to mitigate reproductive and metabolic dysfunctions associated with conditions like PCOS and infertility. Butyrate supplementation mitigates weight gain in diet-induced obesity by modulating the gut microbiome, particularly increasing Firmicutes , while activating the muscle circadian clock and enhancing histone acetylation to promote fatty acid oxidation, thereby contributing to anti-obesity effects [ 164 ]. In mice with collagen-induced arthritis, gut microbial circadian rhythms are altered and gut barrier integrity is disrupted; notably, rhythmic gene expression in the colon and microbial metabolites (including tryptophan derivatives) lose their oscillatory patterns, highlighting the profound impact of inflammatory disease on circadian gut function [ 165 ]. Dietary timing influences rheumatoid arthritis (RA) inflammatory rhythms through gut microbiota oscillations. Parabacteroides distasonis responds to nutritional cues by releasing glycitein, which modulates the SIRT5-NF-κB signaling axis to attenuate inflammation in RA [ 166 ]. Dysfunctional circadian rhythms in mice promote colorectal cancer metastasis by increasing the accumulation of myeloid-derived suppressor cells (MDSCs) in the lungs, a process facilitated by the gut microbiota and its metabolite taurocholic acid (TCA)—which enhances glycolytic metabolism in MDSCs [ 167 ]. Together, these findings highlight the critical role of circadian rhythms and gut microbiota in regulating metabolic and muscular function, suggesting that targeting these interconnected pathways could provide novel strategies for managing obesity, alleviating inflammatory conditions, and impeding cancer progression. Sleep restriction disrupts skin barrier function and gut microbial circadian rhythms in mice, triggering oxidative stress, skin inflammation, and circadian misalignment of the skin’s biological clock. However, melatonin supplementation restores the skin’s circadian clock, improves barrier function, and enhances the gut microbiota’s circadian rhythms, particularly Bacteroides and propionic acid production. Propionic acid acts via GPR43 signaling pathways to improve skin health, highlighting melatonin’s mediation through gut microbiota in counteracting the effects of sleep deprivation on the skin [ 168 ]. Circadian regulation of extragastrointestinal microbiota in physiology and disease Research on the relationship between circadian rhythms and microbiota has predominantly focused on the gut microbiome, with comparatively less attention devoted to microbial communities inhabiting other body sites. However, recent investigations have begun to illuminate the substantial impact of circadian rhythms on microbiota residing in diverse organs, including the oral cavity, urinary bladder, and skin (Fig. 5 and Supplementary Table 16 ). Fig. 5. Open in a new tab Extragastrointestinal microbiota and circadian regulation in health and disease. Circadian rhythms play a pivotal role in regulating microbiota across diverse extragastrointestinal systems, including the skin, oral cavity, and urinary bladder. Disruptions to these rhythms—such as late-night eating or altered light exposure—induce microbial dysbiosis at these body sites. In the oral cavity, such disruptions promote inflammatory pathways associated with periodontal disease. In the skin, circadian misalignment elevates oxidative stress and impairs barrier function, contributing to skin aging and dermatological conditions. In the urinary bladder, circadian disruption triggers changes in microbial diversity, increasing the risk of infections and diseases such as bladder cancer. Collectively, these findings underscore the systemic influence of circadian rhythms on microbiota across multiple organ systems These studies underscore the crucial role of circadian regulation in modulating microbial populations and their associated functions, influencing not only local physiological processes but also broader health outcomes. While research investigating the interplay between non-gut microbiota and circadian rhythms remains relatively limited, these emerging findings already provide valuable insights into how circadian disruptions can alter microbial diversity and functionality—perturbations that may contribute to the pathogenesis of various health conditions. This growing body of work demonstrates the importance of understanding circadian regulation beyond the gut microbiota, pointing to the broader implications for health and disease. The oral cavity, a vital part of the human microbiome, harbors a complex microbial ecosystem of symbiotic, mutualistic, and potentially pathogenic microorganisms that form biofilms to maintain oral stability, promote health, and prevent disease [ 169 ]. Accumulating evidence demonstrates that the oral microbiota exhibits intrinsic circadian rhythms governed by the host’s internal biological clock. When disrupted by factors such as shift work or jet lag, these rhythms alter the oral microbial community structure and perturb functional pathways related to sulfur metabolism, peroxisomal function, and fatty acid metabolism [ 170 ]. Notably, a human study revealed that the salivary microbiome displays distinct circadian rhythmicity, with significant diurnal oscillations in key genera including Streptococcus and Prevotella . These fluctuations are shaped by host physiological changes: morning microbial profiles are enriched for metabolic functions, while evening communities prioritize environmental response pathways—highlighting the pivotal role of circadian rhythms in regulating oral microbial dynamics [ 171 ]. Circadian misalignment induced by a forced desynchrony protocol significantly alters the oral microbiota, affecting microbial population structures and functional pathways related to metabolism and immunity, leading to an increase in pro-inflammatory genera such as Fusobacterium and Porphyromonas , which are closely linked to periodontal disease and other inflammatory conditions [ 170 ]. Complementing these findings, a randomized crossover trial showed that the timing of food intake modulates the diurnal rhythms of the human salivary microbiota. Late eating inverts daily microbial diversity patterns and increases pro-inflammatory bacterial taxa, which may exert adverse effects on systemic metabolism, thereby establishing a link between dietary timing and metabolic disease risk [ 172 ]. These findings underscore the importance of circadian rhythms in maintaining oral microbiome balance, suggesting that disruptions to these rhythms can significantly impact oral health and contribute to the development or progression of inflammatory diseases. Traditional perspectives have long held that the urinary tract, excluding the urethral opening, is devoid of microorganisms in the absence of urinary tract infections. However, advancing research has challenged this paradigm, confirming the presence of microorganisms in the lower urinary tract and establishing their significant association with host health status [ 27 ]. Furthermore, emerging evidence indicates that the bladder microbiota is functionally linked to circadian rhythms. A key study demonstrated that the microbiota influences the transcriptome and weight of the urinary bladder in mice, with the absence of microbiota in germ-free (GF) mice leading to changes in circadian genes (e.g., Per1, Per2), immune-related genes, and extracellular matrix (ECM) components, resulting in a significant reduction in bladder weight and size (up to 25%) compared to mice housed with normal microbiota (specific pathogen-free, SPF), suggesting a critical role for the bladder microbiota in regulating urinary bladder physiology via circadian-associated pathways [ 173 ]. In healthy women, consistent late bedtimes significantly compromise key skin physiological traits, including hydration, elasticity, and barrier function, while increasing transepidermal water loss (TEWL) and sebum content, and reducing skin microbiome diversity, with notable alterations in the abundance of Pseudomonas and decreases in Streptococcus , Stenotrophomonas , Acinetobacter , Haemophilus , and Neisseria , correlating with skin health degradation [ 174 ]. Sleep loss negatively affects cutaneous regeneration and the effectiveness of nocturnal dermatological treatments by disrupting circadian rhythms, impairing skin hydration, increasing oxidative stress, and compromising barrier function, which impacts drug absorption, skin repair, and leads to sleep disturbance-induced inflammation and dysbiosis in the skin microbiome. Collectively, these perturbations ultimately diminish the effectiveness of dermatological interventions [ 175 ]. These findings emphasize the critical link between circadian rhythms and skin health, suggesting that disturbances to sleep patterns and microbial rhythmicity can impair skin function, hinder tissue regeneration, and reduce the efficacy of dermatological treatments. Summary and perspectives This review provides an in-depth analysis of the intricate crosstalk between circadian rhythms and microorganisms, with a focus on circadian oscillation patterns of microbial communities colonizing the intestine, oral cavity, respiratory tract, and urinary tract, as well as their multifaceted impacts on host physiology and disease pathogenesis. It underscores the pivotal role of circadian regulation: the composition and functional activity of the microbiota are tightly orchestrated by the host’s biological clock, and circadian misalignment may precipitate the onset and progression of diverse disorders, including obesity, diabetes mellitus, and cardiovascular diseases. It should be noted that although gut microbial communities display robust diurnal oscillations, whether these rhythms fulfill the strict definition of endogenous, self-sustained circadian rhythms remains to be fully established, as most studies assess microbial rhythmicity under host- and environment-driven conditions. Future research should further elucidate how circadian rhythms shape the compositional and functional dynamics of distinct microbial communities across various body niches, while unraveling the mechanistic underpinnings through which this bidirectional interplay modulates host health and disease susceptibility. A major limitation in the current literature is the lack of direct causal evidence linking disrupted diurnal gut microbiome rhythmicity to disease development. While numerous studies have reported associations between circadian disruption—arising from shift work, modern lifestyle, or host clock dysfunction—and microbial dysbiosis in metabolic, immune, and neurodegenerative diseases, most of these findings remain correlative in nature. To establish causality, functional studies, such as fecal microbiota transplantation experiments using time-resolved or rhythmically distinct donor microbiota, are critically needed. Such approaches would allow direct testing of whether altered microbial rhythmicity is sufficient to drive disease phenotypes or modulate disease severity. Addressing this gap will be essential for advancing our mechanistic understanding of circadian–microbiota interactions. In particular, future studies should clarify the relative dominance of the central SCN clock versus tissue-specific peripheral clocks in regulating microbial rhythmicity, as this hierarchy is likely context-dependent. Moreover, emerging evidence suggests that microbial metabolites may, under certain conditions, feed back to modulate peripheral clock function, highlighting the bidirectional complexity of host–microbiota temporal crosstalk. Such mechanistic insights will inform the rational development of chronobiology-based microbiota-targeted therapies—an approach that may hold particular promise for metabolic and inflammatory disorders, where clinically feasible interventions such as TRF and melatonin are already available. Collectively, these considerations highlight that future chrono-microbiome research should not only aim to establish causality but also account for individual variability—including chronotype, sex-specific differences, and genetic variation in clock genes—which may shape microbial rhythmicity and determine therapeutic responsiveness. Such insights will be critical for advancing personalized chrono-microbiome interventions. Electronic supplementary material Below is the link to the electronic supplementary material. Supplementary Material 1 (95.8KB, docx) Acknowledgements Not applicable. Abbreviations 4-OH-PPA (4-hydroxyphenyl) propionic acid ABA Activity-based anorexia AD Alzheimer’s disease ALT Alanine aminotransferase AMH Anti-Müllerian hormone AMP Adenosine monophosphate AST Aspartate aminotransferase BBB Blood-brain barrier Bmal1 Brain and muscle aryl-hydrocarbon receptor nuclear translocator-like 1 Clock Circadian Locomotor Output Cycles Kaput Per1/2/3 (Period 1/2/3) Cry1/2 Cryptochrome 1/2) Rev-erb Nuclear receptor subfamily 1, group D BP Blood pressure CCGs Clock-controlled genes CPF Cyclocarya paliurus flavonoids CRC Colorectal cancer CRP C-reactive protein CRY Cryptochrome DC Dendritic cell dLAN Dim light at night DOP Dendrobium officinale polysaccharide ECM Extracellular matrix EBN Edible bird’s nest FD4 Fluorescein isothiocyanate-dextran 4 GF Germ-free GLP-1 Glucagon-like peptide-1 GLU Oat β-glucan GOS Galacto-oligosaccharides GPR43 G protein-coupled receptor 43 GTP Green tea polyphenols HD5 Human defensin 5 HDAC Histone deacetylase HFD High-fat diet HFFD High-fat and high-fructose diet HIRI Hepatic ischemia-reperfusion injury HPA Hypothalamic-pituitary-adrenal IBD Inflammatory bowel disease IBS Irritable bowel syndrome IL Interleukin ILC3 Group 3 innate lymphoid cells IMP Inosine monophosphate LCA Lithocholic acid LDL-C Low-density lipoprotein cholesterol LPS Lipopolysaccharide MAFLD Metabolic dysfunction-associated fatty liver disease MDSCs Myeloid-derived suppressor cells MHC Major histocompatibility complex miRNA MicroRNA NAFLD Nonalcoholic fatty liver disease NASH Nonalcoholic steatohepatitis NFIL3 Nuclear factor interleukin-3 regulated NF-kB Nuclear factor kappa B NRF Night-restricted feeding OBD Obesogenic diet OTP Oolong tea polyphenols PCOS Polycystic ovary syndrome PD Parkinson’s disease PER Period circadian regulator PPA Phenylpropionic acid PPARγ Peroxisome proliferator-activated receptor gamma PS-NPs Polystyrene nanoplastics RBD REM sleep behavior disorder REM-SD Rapid eye movement sleep deprivation REV-ERBα/β Nuclear receptor subfamily 1 group D member 1/2 RPT Ripened Pu-Erh tea SCFAs Short-chain fatty acids SCN Suprachiasmatic nucleus SF Sleep fragmentation SFN Sulforaphane SIRT1 Sirtuin 1 SREBP Sterol regulatory element-binding protein T2DM Type 2 diabetes mellitus TEER Transepithelial electrical resistance TEWL Transepidermal water loss TGF-β Transforming growth factor beta TLR2 Toll-like receptor 2 TMA Trimethylamine TMAO Trimethylamine N-oxide TNF-α Tumor necrosis factor-alpha TRF/E Time-restricted feeding/eating TTFL Transcription-translation feedback loop UCG Uncultured genus ZO-1 Zonula occludens-1 ZT Zeitgeber time Author contributions All authors have participated in the writing, reviewing and editing of the manuscript. All authors have read and agreed to publish this version of the manuscript. Funding This study was funded by the National Natural Science Foundation of China (32171165), the Opening Fund of NHC Key Laboratory of Chronobiology (Sichuan University) (NHCC-2025-01) and the Institute for Mechanisms and Prevention of Chronic Diseases (A1-0200-25-201007-3). Data availability No datasets were generated or analysed during the current study. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable Competing interests The authors declare no competing interests. Footnotes Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Guanlin Wu and Jiayang Zhang contributed equally to this work. Contributor Information Yongsheng Han, Email: [email protected]. Guangrui Yang, Email: [email protected]. References 1. Huang WY, et al. Circadian rhythms, sleep, and metabolism. 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