Emerging Roles of Modern Lifestyle Factors in Microbiome Stability and Functionality

Abstract

Purpose of Review

It is now evident that the microorganisms living on and inside the human body modulate a myriad of host responses and activities. Particularly, the intestinal microbiota, which comprises diverse bacteria, fungi, archaea, viruses, and eukaryotic entities, forms a close relationship with the host. This relationship is essential for optimal biological function such as maintaining proper immune homeostasis, host metabolism, and prevention of pathogens colonization. The human gut microbiome is relatively stable after 3 years of age but is subjected to influences from diet, environment and lifestyle factors. This review covers recent findings on how lifestyle factors associated with modern society might affect the microbiome.

Recent Findings

Modern lifestyle factors including circadian rhythm disruption, sleep deprivation, exercise and stress impact the gut bacterial community (bacteriome) composition and function. The resultant gut bacteriome changes contribute to host metabolism dysregulation, inflammatory diseases and cancer development associated with these lifestyle factors.

Summary

Lifestyle factors influence the gut bacteriome to modulate host health and disease risks. Understanding the mechanistic roles of diverse host-associated microorganisms played in lifestyle factors-associated disease risks holds the promise for developing novel approaches to alleviate the detrimental effects.

Introduction

Alteration in the composition and metabolomic outputs of the intestinal bacteriome has the potential to modulate host health [1]. For example, in the case of cancer, the bacteriome has been studied for diagnostic, prognostic and therapeutic purposes, which have opened new horizons for cancer management [2]. Consequently, understanding the factors leading to a change in bacteriome composition and associated metabolic activities can potentially improve the management of various medical conditions. Several contributing factors can lead to changes in bacteriome, including inflammation, lifestyles, dietary habits, physical activity, and environmental conditions, all of which representing risk factors for numerous acute and chronic diseases. Here, we review the role of circadian clock, sleep patterns, exercise and stress on maintaining the intestinal bacteriome and, the consequences on the host when this interplay is disrupted.

Circadian Rhythm

Circadian rhythm (CR) refers to the natural physiological and behavioral oscillations synchronous with the 24-h light–dark cycle in a living organism. In humans, CR is controlled by the light-responsive central pacemaker neurons in the hypothalamic suprachiasmatic nucleus (central clocks), which drive the rhythmic expression activity of molecular clocks in peripheral tissues (peripheral clocks) [3]. In addition to photic cues, eating time and diet composition can entrain CR, particularly in peripheral tissues. Modern life-associated artificial light exposure, shift work and air-plane travel (jet lag) can cause CR disruption, which has been linked to increased risks for numerous diseases such as obesity, diabetes, inflammation and cancer [3]. Recent studies have revealed that the intestinal microbiota is a component and regulator of CR and can functionally contribute to CR disruption-related pathologies (Fig. 1).

Fig. 1.

The regulation of microbiota circadian oscillation and the impact on host metabolism, immunity and cancer development Recent studies have shown that the gut microbiota circadian oscillation can be modulated by photic cues, central and peripheral genetic clocks, eating time, diet pattern, shift work/jet lag, and gender. Microbiota circadian oscillation has been reported for gut luminal and tissue-attached microbiota loads and composition, relative abundance of specific bacterial taxa, microbiota metagenome, and microbial metabolites. Microbiota circadian oscillation plays a key role in regulating host metabolism and immunity. Disruption of the normal microbiota circadian oscillation may contribute to the pathogenesis of obesity, type 2 diabetes, colitis, rhythmic flares of inflammatory disease, and cancer development. The figure was generated in Biorender.com

Over a decade ago, it was first reported that the relative abundance of many bacterial taxa present in the feces exhibited diurnal fluctuations in mice (e.g., Clostridiales, Lactobacillales, Bacteroidales) and humans (e.g., Parabacteroides, Lachnospira, Bulleidia) [4]. Rhythmic changes have also been reported for microbiota composition in the small intestine [5], microbial loads [6, 7] and bacteria-epithelium attachment [5, 6, 8, 9] in mice. Metagenomic sequencing on mouse stools suggests that bacterial flagellar assembly, mucus degradation and bacterial motility functions are among the most significantly oscillating pathways observed during CR [6]. Microbiota CR is modulated by central and peripheral clocks, photic cues, feeding behavior, diet and gender. Mice with whole-animal deficiency in clock genes such as Period1/2 (Per1/2) [4–6], brain and muscle ARNT-like 1 (Bmal1) [7], and Clock [8] lacked feeding rhythms and showed loss or attenuation of rhythmic changes of microbiota composition. Time-restricted feeding (TRF) could restore microbiota CR in mice with genetic defects in central clocks [4, 6, 8], suggesting that irregular feeding behavior is the major driver of microbiota arrhythmicity in these animals. Defective genetic clocks in the intestinal epithelium [10–12], liver [13] and intestinal ILC3s [14] altered rhythmic oscillations of specific bacterial taxa. Since peripheral clock deficiency did not significantly change feeding behavior [10, 13], the effects on microbiota are likely driven by gut environment changes due to arrhythmic gene expression in peripheral tissues/cells. In line with the note that central clocks are entrained by photic cues, disrupting the normal light–dark cycle by inducing jet lag could change mouse feeding behavior to impair microbiota CR [4]. Interestingly, mice under constant dark exposure appeared to maintain microbiota CR [10], suggesting that the intrinsic clocks play a more dominant role in driving microbiota CR than photic cues. Diet is another important modulator of microbiota CR. High-fat diet (HFD) did not affect core clock gene oscillation [9] but dampened microbiota CR, characterized by a reduced number of oscillating OTUs and decreased amplitude of bacterial daily fluctuations [9, 15, 16], which could not be completely rescued by HFD TFR [15] or administration of the circadian hormone melatonin [17]. Lastly, gender-dependent changes of microbiota CR in response to clock deficiency [7, 13], jet lag and HFD [18] have been reported. This effect may be driven by the gender-specific diurnal rhythms of host gene expression and metabolism [19].

Microbiota plays an important role in the circadian control of the host metabolism, as microbiota depletion by antibiotics treatment or germ-free derivation significantly alters rhythmic gene expression in major metabolic organs such as the liver, gut, adipose tissues [6, 9, 13, 16, 19–23]. Microbiota-mediated programming of circadian transcriptome alters diurnal hepatic drug metabolism, as demonstrated in the case of acetaminophen detoxification [6]. Microbiota regulates circadian lipid absorption in intestinal epithelial cells (IECs) by repressing the circadian clock transcriptional repressor Rev-Erb alpha (RevErbα), which requires Toll-like receptors (TLR)- myeloid differentiation primary response 88 (MYD88) activation in dendritic cells (DCs) which then induce interleukin-22 (IL22) production by ILC3s and finally signal transducer and activator of transcription 3 (STAT3) activation in IECs [21]. Microbiota CR is associated with oscillations of microbial metabolites such as bile acids [10, 24, 25] and short-chain fatty acids (SCFAs) [16, 26]. Timed oral administration of SCFAs (acetate, butyrate, and propionate; in combination or individually) can change the expression rhythm of clock genes in mouse peripheral tissues including the liver, kidney and submandibular gland [26]. HFD reduced the levels and attenuated oscillations of SCFAs while exerting an opposite effect on H₂S levels [16]. SCFAs induced significant shifts in rhythmicity and enhancement of circadian clock gene amplitude in hepatic organoids, whereas the H₂S donor NaHS blunted liver clock rhythmicity [16]. The liver clock is a primary driver of rhythmic hepatic transcriptomes including glucose and fatty acid metabolic pathways [13]. Thus, HFD-induced disruption of oscillations of microbiota-derived metabolites may affect liver circadian control of host metabolism. SCFAs or sterile supernatants of SCFAs-producing bacteria dose-dependently induced phase shift expression of clock genes Per2 and Baml1 in mouse and human enteroids via histone deacetylase 3 (HDAC3), suggesting that SCFAs entrain IEC rhythmic gene expression [27]. HDAC3 activity drives a majority of microbiota-dependent rhythmic gene expression in IECs [23]. Microbiota induces HDAC3 expression via TLR-Myd88 signaling and is required for HDAC3 rhythmic recruitment to target gene promoters in IECs to regulate nutrient uptake [22]. For example, HDAC3 controls rhythmic expression of the lipid transporter CD36 in IECs to modulate lipid absorption [22]. CR disruption-associated microbiota promotes HFD-induced glucose intolerance and obesity, as demonstrated by the increased disease susceptibility in mice receiving fecal microbiota transplantation (FMT) from jet-lagged mice or humans [4]. Jet lag accelerated weight gain in HFD-fed Hdac3^flox/flox mice but had little effect on HFD-fed mice with IEC-specific Hdac3 deficiency (Hdac3^ΔIEC) [22], suggesting that impaired HDAC3 rhythmicity could be the major mechanism by which CR disruption promotes obesity and diabetes. Consistent with the critical impact of microbiota CR on mouse metabolism, a risk signature constructed by disease-associated arrhythmic microbial operational taxonomic units (OTUs) can be used to predict human type 2 diabetes [28].

The circadian clock and microbiota coordinate to generate diurnal rhythms in the intestinal immune milieu. Many host immune components exhibit rhythmic expression in IECs, such as innate receptors TLRs and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) [20], antimicrobial proteins regenerating family member 3 gamma (REG3γ), lipocalin-2 (LCN-2) and S100 calcium-binding protein A8 (S100A8) [8], barrier proteins mucin 2 (MUC2) and claudin-8 (CLDN8) [9, 12], and Major histocompatibility complex class II (MHC-II) [5]. Gram-negative bacteria-derived lipopolysaccharide promotes rhythmic expression of TLRs and NOD2, which are critical for rhythmic activities of transcriptional factors activating protein-1 (AP-1) and nuclear factor Kappa B (NF-κB) in mouse IECs [20]. Lactobacillus OTUs oscillate in the small intestine and positively correlate with REG3γ expression rhythm [9]. A Lactobacillus rhamnosus GG type strain secrets unidentified small molecules to induce REG3γ expression in a MYD88-dependent manner, which could be a strategy for Lactobacillus to compete with REG3γ-sensitive bacteria like Peptostreptococcaceae to establish their diurnal oscillations [9]. REG3γ rhythmicity is also a driver of oscillating densities of bacteria attaching to the gut epithelium [8]. The functional impact of rhythmic epithelial attachment by bacteria has been demonstrated using Segmented filamentous bacteria (SFB) [5, 6, 8]. CR of bacteria-epithelium contact influences intestinal circadian transcriptome [6]. SFB epithelial attachment, controlled by central clocks, induces REG3γ expression via a myeloid cells-ILC3s-IECs signaling axis [8]. Rhythmic MHC-II expression in the small intestinal epithelium is critical for maintaining the circadian oscillations of intra-epithelium CD4 + T cells, interleukin-10 (IL10) expression and small intestinal permeability [5]. Gram-positive, vancomycin-sensitive bacteria are mainly responsible for inducing MHC-II expression in the small intestine, and specific bacterial inducers (e.g., Akkermansia, Lachnospiraceae and SFB) have been identified [5]. Microbiota, via the regulation of IECs-derived HDAC3 activity, is required for rhythmic tufts cell biogenesis, which modulates immune responses to helminth and noro-virus infections [29]. Microbiota can be a critical player in CR disruption-associated inflammatory diseases. The coordinated diet-microbiota-MHC-II CR regulates diurnal changes in small intestinal barrier function, and disrupting this interaction by inducing jet lag increases susceptibility to Crohn’s-like enteritis [5]. Microbiota tuning of REG3γ oscillations, which depends on host clocks and can be entrained by TRF or disrupted by HFD [9], modulates resistance to Salmonella Typhimurium infection [8]. Bmal defect in the colonic epithelium increased mouse susceptibility to acute dextran sodium sulfate (DSS)-induced colitis [11], and Bmal^ΔIEC;Il10^−/− mice developed heightened colitis compared to Il10^−/− mice [24]. TRF promoted microbiota rhythmicity and ameliorated colitis in Il10^−/− mice [24]. Microbiotas from Bmal^ΔIEC and wild-type mice induced distinct immune responses in recipient mice, as shown by differences in spleen weights, DCs in the small intestine, and recruitment of DCs and T cells in the colon [10]. These observations suggest that microbiota may affect colitis risks induced by CR disruption. Microbiota CR could contribute to the rhythmic flares of rheumatoid arthritis (RA) [30]. Inflammatory cytokines and immune cells exhibited diurnal oscillations, highest at early morning and declined during the daytime, in RA patients [30]. FMT showed that the morning microbiota from active RA patients induced stronger inflammation than the night microbiota in the collagen-induced arthritis mouse model [30]. Parabacteroides distasonis, which was influenced by feeding rhythm and showed high abundance during the low inflammation phase in RA patients and arthritis mice, could produce the anti-inflammatory metabolite glycitein from diet flavonoids via β-glucosidase activity [30]. This suggests that manipulating CR of the bacteria by timed eating of flavonoids-rich diet could be a way to alleviate rhythmic RA exacerbations.

Microbiota may contribute to the pro-tumorigenic effect of CR disruption. Genetic clock defects or jet lag accelerated intestinal tumorigenesis in mice with Apc mutations [12, 31, 32] and promoted colorectal cancer (CRC) lung metastasis [25]. Cancer development in the presence of CR disruption was associated with distinct microbiota profiles and functions compared to carcinogenesis with normal CR [12, 25]. Microbiota from jet-lagged mice or mice with defective clocks aggravated CRC lung metastasis (MC38 tail vein injection mouse model) in recipient control mice, whereas microbiota from control mice alleviated metastasis in jet-lagged mice [25]. Mechanistically, CR disruption-associated dysbiosis resulted in higher intestinal taurocholic acid, which could promote the accumulation of myeloid-derived suppressor cells, thereby suppressing anti-tumor responses [25].

Aside from shift work and jet lag, a common cause of CR disruption associated with modern society is sleep deprivation (SD), whose effects on microbiota composition and function are discussed in the following section.

Sleep Deprivation and Exercise

Like CR, sleep plays a crucial role in maintaining physiological homeostasis, and its disruption can have profound effects on host health. Data from over 400,000 participants in a large prospective cohort revealed that individuals with healthy sleep patterns (7–8 h of sleep, minimal insomnia symptoms, and no frequent daytime sleepiness) had a 17% lower risk of developing CRC. Among participants adhering to all components of a healthy lifestyle—including regular physical activity (≥ 150 min/week), a balanced diet (rich in fruits, vegetables, and whole grains), moderate alcohol intake (< 14 drinks/week for men, < 7 for women), and no smoking—the risk reduction reached 22% [33]. Importantly, those who combined healthy sleep with these lifestyle habits experienced a 31% overall reduction in CRC risk. The study also found that sleep disorders, such as insomnia or irregular sleep patterns, were associated with a 12% higher CRC risk, independent of other lifestyle factors. SD is characterized by insufficient or poor-quality sleep and is driven by factors similar to those affecting CR. For example, individuals with shorter sleep durations had significantly lower levels of human defensin 5 (HD5), an antimicrobial peptide secreted by Paneth cells in the small intestine [34]. HD5 plays a key role in maintaining intestinal barrier integrity by targeting pathogenic bacteria and regulating gut microbiota composition. Its reduction can impair the gut’s antimicrobial defenses, leading to increased intestinal permeability and microbiota dysbiosis [34]. Additionally, chronic sleep deprivation disrupts immune function, for example through elevation of pro-inflammatory cytokines like interleukin-6 (IL-6) [35]while reducing anti-inflammatory cytokines such as IL-10, leading to a heightened inflammatory state [36]. Moreover, sleep-deprived individuals experience a marked reduction in natural killer (NK) cell activity, impairing the body’s ability to combat infections and tumor cells. These changes have also been associated with anxiety-like behaviors. For instance, recent reports have found that mice subjected to 72 h SD exhibited increased anxiety-like behaviors, as measured by standard behavioral tests such as open-field tests and confirming the detrimental changes to the intestinal microbiota composition as measured by a decrease in abundance of beneficial bacteria like SCFAs producers that generate butyrate, essential for maintaining gut epithelium integrity [34, 37]. Additionally, another regimen of acute SD (6-h sleep deprivation) combined with gentle handling of mice to keep them “awake”, led to noticeable anxiety-like behaviors in open-field tests and depressive-like behaviors in forced swim tests. SD also disrupted key circadian clock genes in the hypothalamus, with Bmal1 and Clock levels decreasing and Per1 and Per2 increasing, throwing off normal circadian rhythms [35].

Disruptions to the microbiota due to SD also impairs key processes such as metabolism and cognitive health. For instance, mice subjected to chronic SD over 4 weeks exhibited a significant loss of microbial diversity, with a reduction in beneficial bacteria such as Lactobacillus and Bifidobacterium [34, 37, 38], and an increase in the bacteria family Lachnospiraceae, which is associated with inflammation. This change in microbiota composition was also confirmed in a short-term SD regimen [39]. Chronic SD correlated to metabolic and inflammatory changes, including elevated fasting blood glucose levels and signs of reduced insulin sensitivity compared to controls [38]. The relationship between sleep pattern and energy metabolism was also examined in healthy adults. Subjects who exhibited poor sleep quality had a 5% reduction in resting metabolic rate (RMR) compared to those with good sleep quality. Additionally, individuals with shorter sleep durations had a 3% increase in respiratory quotient (RQ), indicating a shift towards greater carbohydrate utilization over fat oxidation [40]. These findings suggest that compromised sleep quality and reduced sleep duration can adversely affect energy metabolism, potentially leading to decreased energy expenditure and altered substrate utilization. This highlights the importance of adequate sleep in maintaining optimal metabolic health and preventing metabolic disorders. In addition, chronic insomnia has been linked to cardiometabolic diseases (CMD) through alterations in the gut microbiota-bile acid axis. For example, a longitudinal cohort study of 1,809 participants found that individuals with chronic insomnia had reduced levels of the gut bacteria Ruminococcaceae UCG-002 and UCG-003, which are essential for converting primary bile acids into secondary bile acids and associated with improved glucose and lipid metabolism. This reduction was associated with decreased levels of isolithocholic acid (ILCA), a bile acid with anti-inflammatory properties, and increased levels of murocholic acid and norcholic acid, which are linked to inflammation and metabolic dysfunction. These bile acids mediated the changes in gut microbiota composition and an increased risk of CMD, findings that were validated in an independent cohort of 6,122 participants [41].

Although the negative effects of SD-induced dysbiosis are at the core of these sequelae, the microbiota can also be targeted to correct the effects of SD. For example, regular tea consumption is associated with increased levels of Ruminococcaceae UCG-002 and decreased levels of norcholic acid, suggesting a protective effect against the adverse impacts of chronic insomnia on cardiometabolic health [41]. These results highlight the gut microbiota-bile acid axis as a potential target for interventions aimed at mitigating the negative health effects associated with chronic insomnia. Similarly, gut-derived metabolites like butyrate and ergothioneine, exhibit neuroprotective and anti-inflammatory properties. For example, administration of butyrate led to a 50% increase in non-rapid eye movement (NREM) sleep during the light phase compared to control mice. Additionally, sleep depth was significantly enhanced, reflecting improved sleep quality during NREM sleep [42]. Similarly, these improvements were accompanied by a decrease in corticosterone levels, indicating a reduced stress response and a potential role for ergothioneine in mitigating the physiological impacts of stress-induced sleep disturbances by modulating the hypothalamic–pituitary–adrenal (HPA) axis [43].

Similarly, exercise promoted favorable changes in gut microbiota composition, including an increased abundance of beneficial bacterial genera such as Akkermansia, which is linked to improved gut barrier function and reduced inflammation [44]. Human studies corroborate these findings, for example participants in a structured endurance exercise program experienced improvements in cardiorespiratory fitness and metabolic health markers. Significant changes in gut microbiota composition were also observed, including enrichment of beneficial bacterial genera like Bacteroides and Faecalibacterium, which are associated with anti-inflammatory effects and enhanced gut barrier integrity. Fecal SCFA concentrations also increased, correlating with reductions in circulating markers of inflammation [45]. Interestingly, exercise motivation itself may be microbiota-dependent. Certain gut bacteria, like Veillonella, metabolize lactate into propionate, which has been shown to enhance endurance and support reward pathways in the brain [46]. Mice with a disrupted gut microbiome exhibited reduced voluntary running distance compared to control mice. The study pinpointed specific gut bacteria that produce fatty acid amides (FAAs). Specifically, the bacterium Eubacterium rectale was highlighted for its role in producing FAAs, including oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), which activate endo-cannabinoid receptors in the gut. This activation enhances dopamine signaling in the brain’s reward pathways during exercise, thereby increasing motivation for physical activity. Introducing FAA-producing bacteria into mice with disrupted microbiomes restored their exercise capacity and dopamine levels [46]. Furthermore, the efficacy of exercise in preventing metabolic disorders such as diabetes may be influenced by the gut microbiome. A study found that in men with prediabetes, exercise-induced alterations in the gut microbiota correlated closely with improvements in glucose homeostasis and insulin sensitivity [47]. The microbiome of responders exhibited an enhanced capacity for biosynthesis of SCFAs and catabolism of branched-chain amino acids, whereas those of non-responders were characterized by increased production of metabolically detrimental compounds such as phenolic derivatives (indole and p-cresol) and sulfate from aromatic and sulfur-containing amino acids (SAAs), respectively, which can damage the gut barrier and increase intestinal inflammation. FMT from responders, but not non-responders, mimicked the effects of exercise on alleviation of insulin resistance in obese mice. These findings suggest that targeting the gut microbiota could maximize the benefits of exercise for diabetes prevention. Additionally, targeting the gut-brain axis through the administration of sleep-inducing compounds, such as melatonin, has shown promise in alleviating cognitive deficits caused by sleep deprivation. Melatonin influences gut microbiota and its metabolites, restoring balance and improving cognitive function in sleep-deprived mice [48]. Overall, SD can lead to detrimental changes in gut microbiota composition, contributing to systemic inflammation and metabolic dysfunction. Conversely, regular exercise promotes beneficial shifts in the gut microbiome, enhancing metabolic health and potentially mitigating the adverse effects of sleep deprivation (Fig. 2).

Fig. 2.

The effect of sleep and exercise on gut microbiota: implications for host metabolism, immunity, and inflammation Studies have demonstrated that exercise and sleep deprivation exert opposing effects on gut microbiota composition and host physiology. On the one hand, exercise increases gut microbial diversity, enhances SCFA production, and improves bile acid metabolism leading to better glucose and lipid metabolism, reduced inflammation, and a lower risk of CRC. In contrast, SD has been shown to reduce beneficial gut bacteria, impair SCFA and bile acid production, and weaken gut barrier integrity through decreased mucin and HD5 secretion. These disruptions are associated with increased inflammation, insulin resistance, metabolic dysfunction, and immune impairment. The figure was generated in Biorender.com

This highlights the potential for clinically relevant, integrative strategies that promote healthy sleep patterns and regular exercise to restore microbial balance and enhance metabolic and cognitive health. By targeting key pathways, such as those involving SCFA production and circadian rhythm regulation, these lifestyle-based interventions can mitigate SD-related health risks while optimizing overall well-being.

Stress

The role of gut microbiota in stress conditions has become an increasingly prominent area of research. Different forms of acute or chronic stressors in humans contribute to health ailments in modern lifestyles. Stress response affects the complex interconnected hypothalamic–pituitary–adrenal (HPA) axis, which further interacts with the central nervous system (CNS) and other organs to respond effectively to stressors. Any perturbation in this axis marks the disruption of the host response leading to uncontrolled stress [49]. Increasing evidence suggests that stress impacts gastrointestinal (GI) tract movements, visceral irritability, modified permeability of the intestinal barrier, and increased bacterial counts [50]. As discussed above, CR disruption is one such example of acute stress [51]. To understand the interplay between gut microbiome and CR genes, microbiome was depleted in a study using either germ-free mice or by administering antibiotics [51]. The authors observed arrhythmic expression of Bmal1 and Clock genes from germ-free mice and arrhythmic expression of the cryptochrome-2 (Cry2) gene from antibiotic-treated mice. These genes are critical for maintaining CR. The gut microbiome disruption also led to alterations to metabolome, HPA axis rhythmicity, and impaired corticosterone release. Furthermore, the study also identified that Lactobacillus reuteri, a probiotic commensal, is a circadian-sensitive strain that can modulate corticosterone levels in specific time-of-day events by influencing the HPA axis. These findings suggest that gut microbiota plays a defining role in maintaining CR and the associated metabolic health [51]. In another study [52], when acute restrained stress was applied by placing the mice in 50 ml conical tubes for 15 min, it altered gut permeability and tryptophan metabolism. They observed that the gut microbiome of these mice exhibited diurnal rhythmicity in tryptophan metabolism. Gut microbial depletion, either by antibiotics or using germ-free mice, drastically alters the diurnal rhythmicity of the gut lumen and host tryptophan metabolism. This study also found that the rhythmicity of the host-derived colonic tryptophan enzymes indoleamine 2,3-dioxygenase 1 (Ido1) and tryptophan hydroxylase 1 (Tph1) depends on the presence of a microbiota. Overall, these studies highlight the integral role of the gut microbiome in stress regulation and circadian rhythm.

A tight regulation exists between psychological state, gut microbiome, and immunity [53]. A recent study [54] underscored the importance of the Brunners gland (BG) in the duodenum for its role in coupling stress neural circuits to bacterial homeostasis. In this study, the authors profiled a polysynaptic circuit and identified that the central amygdala stimulates the BG via the vagus nerve. Upon BG stimulation, mucin is secreted, which acts as a substrate for Lactobacilli proliferation. The authors examined the effect of chronic stress on mice, which involved exposing the mice repeatedly to restraints on acrylic plastic boards for six hours for six consecutive days. Their findings revealed an inhibition in central amygdala activity that represses the BG function of mucin secretion. Less mucin secretion subsequently leads to reduced proliferation of Lactobacilli, altering host immunity by increasing pro-inflammatory and pro-apoptotic cytokines. Several studies have also reported that utilizing different forms of chronic stress, such as chronic social defeat, chronic mild stress, and chronic restraint stress, reduced the relative abundance of Lactobacillus in [54] the gut [55–57]. Another study [58] utilized a ten-day chronic social defeat model in which an aggressor mouse subjected the test mouse to repeated episodes of social defeat. Post-stress exposure, the mice were subjected to immune profiling and examined for a social interaction. The authors identified that chronic stress reduced Lactobacillus johnsonii (L. johnsonii), another probiotic commonly found in a healthy GI tract. L. johnsonii plays a critical role in maintaining immunity by interacting with the leukocytes to combat infections and mitigate inflammation [59]. Due to chronic stress-mediated suppression of L. johnsonii, there was marked reduction Treg cell population that are known to suppress the inflammatory γδ17T cells [60]. This led to the expansion and differentiation of colonic γδ17T that migrated and accumulated in the brain. The inflammatory signaling mediated by γδ17T cells affects neuronal signaling and synaptic plasticity in the regions of the brain associated with mood, ultimately leading to social avoidance behaviors in mice. In contrast, another study [61], showcases the role of enriched Lactobacillus murinus-derived Idole-3-acetate (IAA) metabolite on intestinal epithelial disturbance upon chronic stress. Microbially derived IAA metabolite impairs mitochondrial respiration and secretory lineage commitment of intestinal stem cells. Supplementation of α-ketoglutarate restores IAA levels and improves epithelial cell function by increasing villi length and crypt height [61]. All these studies suggest that stress has varying effects on the host depending on different Lactobacillus species. Interactions between gut microbiota and stress mechanisms are also being explored in the context of different disease models. Gut microbial dysbiosis has been recognized as a key player in sickle cell disease [62]. This disease is characterized by vaso-occlusive episodes (VOE) which are complications associated with severe pain due to obstruction of blood vessels as a result of sickle-shaped red blood cells [63]. In a humanized sickle cell disease model, upon exerting chronic psychological stress, HPA gets activated, leading to increased glucocorticoid secretion that augments gut permeability [64]. Increased gut permeability subsequently leads to the activation of T_H17 cells caused by SFB which contributes to VOE. Interestingly, in another chronic stress model study [65], the authors identified that stress induced by recurrently restraining the mice for 2 h, also led to gut leakage and microbiota exposure, and subsequent expansion of T_H17 cells. However, in this model, T_H17 proliferation led to the production of the protective cytokine IL-22. This cytokine then enters the brain septum to suppress neuron activation, reducing stress-related anxiety. It is worth emphasizing that while IL-22 shows potential benefits for animals, its production depends on interleukin 1 Beta (IL-1β) and T_H17 cells, both of which have been associated with exacerbating stress-related disorders [66–68]. These studies suggest that there are innate protective mechanisms in place to counter stress; but in conditions of uncontrolled chronic stress, it leads to the disruption of cellular homeostasis, contributing to chronic inflammation.

Another crucial factor that modulates the gut microbiome is diet that affects stability, functionality, and diversity of the microbiome [69]. In an investigation of the interplay between diet and stress [70], mice were subjected to chronic restraint stress that were either fed a chow diet, isocaloric purified diet, or purified diet supplemented with raffinose. They observed that dietary raffinose maintains Lactobacillus reuteri growth, which metabolizes raffinose to fructose and promotes intestinal stem cell maintenance by glycolysis during stress, suggesting the role of diet in alleviating gut-related disorders. Bacterial-derived metabolites also play a key role in shaping the gut microbiome. In a different study [71], chronic stress affects the level of microbial-derived ammonia directly impacting host behavior. Chronic stress alters urease-producing microbiota, resulting in lower systemic ammonia levels. Lower ammonia levels reduce glutamine availability in the brain, which is essential for the brain cortisol function. Reduced glutamine in the astrocytes increases stress vulnerability and contributes to depressive-like behavior in mice. Oral gavage of Streptococcus thermophilus, a urease-producing strain, reverses depressive-like behavior in mice. Additionally, restoring ammonia or supplementing mice with glutamine also alleviates the depressive effects. These studies suggest that diet or bacterial-derived metabolites play a key role in stress resilience and management, underscoring the importance of a healthy diet. It is worth noting that not only these environmental stress factors, but also genetic pre-disposition plays a vital role in the dynamic regulation of stress and gut microbiome. In this context, another study [72] investigated the role of G protein-coupled receptor 35 (Gpr35), a critical regulator for host-microbe interaction [73, 74], in modulating behaviors through gut microbiota. Genetic ablation of Gpr35 in mice led to an increased abundance of Parabacteroides distasonis (P. distasonis) compared to the control mice. Increased P. distasonis reduces indole-3-carboxaldehyde (IAId) and increases indole-3-lactate (ILA) balance. Supplementation of IAId was shown to reverse the depressive symptoms in Gpr35-ablated mice. Furthermore, in another human study, lower IAId correlated with depressive symptoms in a clinical study in France [75]. These results underscore the critical role of a healthy gut microbiome in the complex interaction of stress, diet, and host genetic pre-disposition to maintain a homeostasis (Fig. 3).

Fig. 3.

Gut microbiota dynamics under stress and its implications for intestinal and neurological health Chronic stress alters the gut microbiome, disrupting intestinal stem cell renewal, reducing mucus secretion, and increasing pro-inflammatory cytokines. Stress impacts key bacteria, including L. reuteri, L. murinus, and L. johnsonii, while microbial metabolites like indole-3-acetic acid and ammonia influence gut and brain functions. The microbiome regulates stress responses through circadian rhythms, immune signaling, and metabolic pathways. Dietary strategies, like raffinose supplementation, help sustain beneficial microbes like L. reuteri, countering stress-related disruptions. The figure was generated in Biorender.com

Conclusions

Lifestyle factors associated with modern society, specifically CR disruption, SD, exercise and stress, can modulate microbiota composition and function to influence host health and diseases. It is clear that host CR disruption also perturbs CR of the microbiota, contributing to dysregulation of host metabolism, immune responses and carcinogenesis. While a few studies have linked specific bacterial taxa or metabolites to disease risks associated with CR disruption, the molecular mechanisms remain largely elusive. Current knowledge of the impact of CR disruption on microbiota is limited to bacteria, leaving out other important microorganisms such as fungi, virus and archaea in the gut. In addition, the relationship between the microbiome present at sites other than the intestine (oral, skin, etc.), lifestyles and physiological outcomes is still unclear. A general limitation of lifestyle research is the focus on rodent studies with limited human cohort investigation. This is important as a relatively large human cohort (> 4,000 subjects) study indicated that poly-pharmacy and not diet, daily lifestyle or diseases was the major driver of microbiome changes (phylogenic and gene pathways) [76]. There are over 651 clinical trials (clinicaltrials.gov) investigating the relations between microbiome and physiological outcomes during CR, SD, stress and exercise, and the outcomes of these studies could provide important insights into the role of microorganisms in these responses. A broader and deeper understanding of the roles of diverse microorganisms and associated metabolic outputs in mediating lifestyle adverse effects could lead to the development of microbial signatures aimed at identifying at-risk subjects. Similarly, interventions targeting the microbiota of at-risk subjects, in the form of live bacteriotherapy or post-biotics, may become possible once a mechanistic understanding is established regarding how bacteria modulate these pathological conditions.

Data Availability

No datasets were generated or analysed during the current study.