How Disrupted Body Clocks Affect Gut Bacteria and Movement, Leading to Constipation

The homeostasis of the Chrono-Microbiota-Motility axis, as depicted in Figure 1, is central to maintaining normal intestinal physiological function, especially regular motility. This homeostasis relies on the precise and dynamic coordination among its three major internal components—the host circadian rhythm system, the gut microbiota, and the intestinal motility system. The core mechanism lies in temporal synchronization. This principle dictates that the rhythmic activity of the gut microbiota must align with the host's own biological clock. Together, they jointly drive and regulate the periodic changes in intestinal motility. This synchronization ensures that key physiological processes, such as digestion, absorption, and defecation, occur efficiently within optimal time windows. The intestinal motility system is a complex network comprising the enteric nervous system (ENS), interstitial cells of Cajal (ICCs), and smooth muscle cells. It does not merely execute commands passively. Instead, this system exhibits its own intrinsic rhythmicity and actively integrates temporal signals from both the host and the microbiota. It thus serves as the crucial effector that ensures the coordinated function of the entire axis.

There is a complex and precise bidirectional regulatory relationship between the host circadian rhythm system and the gut microbiota. The host's circadian system includes a central clock in the suprachiasmatic nucleus and peripheral clocks in organs like the intestine. These clocks collectively create a rhythmic environment for the gut microbiota. They achieve this by regulating key physiological processes, including body temperature, hormone secretion (e.g., cortisol and melatonin), immune responses, and intestinal epithelial cell renewal (6, 7). This rhythmic environment selects and shapes the composition and function of the gut microbiota, leading to significant 24-h periodic fluctuations in the abundance of many key microbial groups and their metabolites [e.g., short-chain fatty acids (SCFAs), secondary bile acids] (8). The rhythmic activities of these microbial communities form the basis for the normal function of the Chrono-Microbiota-Motility axis.

On the other hand, the gut microbiota and its metabolites can also regulate the host's biological clock in reverse, forming a feedback loop. SCFAs produced by the microbiota, especially butyrate, are not only the primary energy source for colon epithelial cells but can also directly affect the expression rhythm of core clock genes in intestinal cells through epigenetic modifications (e.g., histone acetylation) (9, 10). This "temporal signal" from microorganisms can fine-tune or even partially reset peripheral biological clocks, synchronizing them with the metabolic rhythms of the microbiota. When this synchronization is maintained, the intestinal motility system receives consistent, coordinated rhythmic commands from both host and microbiota (4). SCFAs produced by the microbiota at specific times can stimulate enterochromaffin cells (EC cells) to release 5-hydroxytryptamine (5-HT), which is a key neurotransmitter for initiating intestinal peristaltic reflexes and high-amplitude propulsive contractions (HAPCs) (11, 12). Therefore, a microbiota that is temporally synchronized with the host is a direct executor and amplifier for ensuring rhythmic intestinal motility and regular defecation.

Gut jet lag refers to the state of desynchronization between the host's biological clock and the gut microbiota rhythm, which is the core manifestation of the Chrono-Microbiota-Motility axis dysregulation. Modern lifestyles, such as irregular eating times (e.g., skipping breakfast, late-night eating) and excessive exposure to artificial light at night (especially blue light), are the primary external driving factors leading to gut jet lag (5, 13). These factors, directly or indirectly, disrupt the originally coordinated temporal signals between the host and microbiota, triggering a cascade of reactions that ultimately lead to FC.

Irregular eating times are the most direct factor disrupting microbiota rhythms. The composition and metabolic activity of the gut microbiota are highly dependent on the host's nutrient intake. When eating times are inconsistent with the "feeding window" expected by the host's biological clock, the microbiota receives chaotic temporal signals. For example, extensive eating at night, when the body should typically be in a fasting and repair state, forces bacteria active during the day and responsible for digesting carbohydrates and proteins to start working at the wrong time, while those adapted to the nocturnal environment are inhibited. This "misaligned" metabolic activity not only alters the day-night rhythm of the microbiota but also leads to dysregulation in the production rhythm of its metabolites (such as SCFA), thereby affecting intestinal motility (5, 13).

Nocturnal artificial light exposure, on the other hand, acts through a more indirect but equally powerful mechanism. Light is the strongest signal synchronizing the host's central biological clock. Nighttime light, especially blue light from electronic screens, inhibits the pineal gland's secretion of melatonin. Melatonin is not only a key hormone regulating sleep but also an important "temporal signal" that conveys "darkness" information to peripheral biological clocks throughout the body, including the intestine. A decrease in melatonin levels has significant consequences. It directly disrupts the biological clock of intestinal epithelial cells. Furthermore, it may indirectly alter the microbiota's survival environment by affecting the intestinal immune system and permeability. Ultimately, these changes lead to the dysregulation of microbiota rhythms (14). Therefore, gut jet lag is not an isolated phenomenon but a natural consequence of modern lifestyles acting on the Chrono-Microbiota-Motility axis. Once this desynchronized state forms, it translates upstream rhythm disruption into downstream intestinal motility disorders through the following three main pathways, ultimately manifesting as FC.

Similar to physiological "jet lag," we propose the concept of gut jet lag to describe intestinal motility disorders caused by desynchronization between the host's biological clock and gut microbiota rhythms. This constitutes the core pathophysiological mechanism of FC at the chronobiological level. In modern society, various common lifestyle factors, such as irregular routines (shift work, staying up late), transmeridian travel, irregular eating times, and high-fat/high-sugar diets, continuously disrupt the host's endogenous biological rhythms. These factors pose a continuous challenge to the Chrono-Microbiota-Motility axis and are major drivers of gut jet lag Existing research clearly indicates that shift work is closely associated with a higher incidence of functional bowel symptoms (including constipation), and its underlying mechanism points to circadian rhythm disruption altering the gut microbiome (15).

Irregular eating times and nocturnal eating behaviors are more common and insidious rhythm disruptors. Eating is the strongest signal for synchronizing the gut's biological clock, and the regularity of its timing is crucial. When eating times become random or conflict with the host's endogenous rhythms (such as the sleep–wake cycle), the intestine and microbiota lose reliable external time references and cannot anticipate when the next wave of nutrients will arrive. This "temporal uncertainty" weakens the effectiveness of "eating" as a synchronizing signal, leading to disordered or flattened rhythmic oscillations of the gut microbiota and potentially impairing the integrity of the intestinal barrier (5, 13). Studies have confirmed that irregular eating patterns are closely related to gut dysbiosis, disruption of SCFA synthesis rhythms, and metabolic disorders. Conversely, synchronizing eating times with endogenous circadian rhythms, such as adopting early time-restricted feeding (eTRF), can enhance microbiota diversity and function and improve metabolic health (16). Therefore, the widespread irregular eating habits in modern life, by disrupting the rhythmicity of the microbiota, directly lead to functional disorders of the Chrono-Microbiota-Motility axis, which is key for the gut jet lag theory to explain a broader FC population.

Furthermore, nocturnal artificial light exposure (ALAN) interferes with the entire system from upstream. ALAN directly weakens the signal strength of the central clock by inhibiting the secretion of melatonin, a key "darkness signal," thereby indirectly affecting its ability to regulate peripheral intestinal clocks (17). This internal biological clock desynchronization caused by light pollution is considered one of the core mechanisms leading to a high incidence of metabolic diseases in groups such as shift workers. Carefully regulating light exposure (e.g., avoiding blue light exposure at night) to adjust melatonin peaks is a potential intervention strategy for recalibrating the biological clock, improving sleep, and metabolic health (18).

In summary, gut jet lag is a complex pathological state resulting from the synergistic action of various modern lifestyle factors, including shift work, irregular eating, and nocturnal light exposure. These factors collectively cause the host and microbiota to transition from "synchronized dancers" to a "chaotic combination" with inconsistent steps, thereby systematically inducing intestinal motility disorders.

Gut jet lag translates upstream rhythm desynchronization into downstream intestinal motility disorders through three interconnected core mechanisms, ultimately leading to the occurrence of FC.

Identifying and quantifying gut jet lag is a prerequisite for precise intervention. Its assessment should combine subjective questionnaires and objective biomarkers to comprehensively capture the patient's lifestyle, rhythm status, and intestinal function. Subjective questionnaires, as a rapid and non-invasive cornerstone for screening gut jet lag risk, are clinically recommended to be used in combination with various validated standardized questionnaires for multi-dimensional assessment. In terms of sleep and rhythm assessment, the Pittsburgh Sleep Quality Index (PSQI) can comprehensively evaluate the patient's sleep quality, sleep onset latency, sleep duration, sleep efficiency, and daytime dysfunction over the past month. A total score > 5 usually indicates poor sleep quality, which is an important signal of gut jet lag (20); while the Morningness-Eveningness Questionnaire (MEQ) is used to assess an individual's "chronotype," i.e., their intrinsic biological rhythm preference. Studies show that evening types are more prone to irregular eating and sleep deprivation, thereby increasing the risk of gut jet lag (21). In terms of emotional state assessment, given the close bidirectional relationship between emotional disorders, gut microbiota, and circadian rhythms, using the Center for Epidemiologic Studies Depression Scale (CES-D) to screen for depressive symptoms helps identify psychological factors that may exacerbate gut jet lag (22). Dietary behavior assessment is also crucial. Tools like food frequency questionnaires (FFQ) or 24-h dietary recalls, combined with eating time records, can assess the patient's dietary structure. Importantly, these methods can also determine if the eating rhythm is disrupted by behaviors such as skipping breakfast or late-night eating. This is critical because irregular eating patterns are a core driver of gut microbiota rhythm dysregulation (23). Through the combination of these questionnaires, clinicians can systematically assess the presence of gut jet lag and its potential inducing factors from multiple dimensions such as sleep, emotion, diet, and individual rhythm preferences, providing a solid basis for subsequent individualized interventions.

To complement subjective findings and achieve a more accurate diagnosis of gut jet lag, objective biomarkers are essential. These markers span multiple biological levels, reflecting the complex nature of the Chrono-Microbiota-Motility axis. They can be broadly grouped into several key categories: (1) markers of the central clock, such as core rhythmic hormones; (2) indicators of the peripheral microbiota clock, including microbial metabolites; (3) physiological markers reflecting systemic rhythmicity, like autonomic nervous system activity; and (4) molecular markers related to gene expression, intestinal barrier integrity, and low-grade inflammation.provides a comprehensive, detailed summary of these potential biomarkers. Supplementary material S1

Based on the gut jet lag theory, the core of intervention strategies for FC is to resynchronize the biological rhythms of the host and gut microbiota through multi-dimensional, synergistic approaches, restoring the homeostasis of the Chrono-Microbiota-Motility axis. These interventions, namely "chronotherapy," primarily use non-pharmacological means to adjust lifestyle and environmental factors to reset the disordered biological clock. The main strategies include behavioral interventions, environmental interventions, and supplement interventions.