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High-intensity interval training alleviates depressive-like behaviors and is associated with differences in gut microbiota composition and prefrontal LPS-associated inflammatory measures in CUMS rats.
BACKGROUND: Exercise is a safe and effective intervention for improving depressive symptoms, but the effects and related mechanisms of high-intensity interval training (HIIT) remain unclear. Growing evidence suggests that interactions among the gut microbiota, immune-inflammatory responses, and the central nervous system may contribute to the development and progression of depression. This study investigated whether a 4-week HIIT intervention attenuated depressive-like behaviors and explored related differences in gut microbiota composition and prefrontal cortical lipopolysaccharide (LPS)-associated inflammatory measures. METHODS: Forty male Sprague-Dawley rats were initially assigned to either the chronic unpredictable mild stress (CUMS) or control conditions. Following CUMS modeling and corresponding control procedures, rats were further allocated to four groups: CUMS_Sed, CUMS_Ex, Con_Sed, and Con_Ex. Exercise groups performed HIIT on motorized treadmills. Depressive-like behaviors were assessed using the sucrose preference test and the open field test, and body weight was monitored longitudinally as a secondary physiological outcome during CUMS exposure. Gut microbiota composition was profiled using 16S rRNA gene sequencing. LPS levels in the prefrontal cortex and ileum, and IL-1β levels in the prefrontal cortex, were measured using enzyme-linked immunosorbent assay, and prefrontal cortical Toll-like receptor 4 (TLR4) and Rela (NF-κB p65/RelA) mRNA expression levels were assessed by reverse transcription quantitative PCR. RESULTS: CUMS induced marked depressive-like behaviors, including reduced sucrose preference and altered open field test performance. HIIT partially attenuated these behavioral alterations. In exploratory microbiota analyses, HIIT-treated CUMS rats differed from sedentary CUMS rats in gut microbial diversity and taxonomic composition and also showed lower prefrontal cortical LPS and IL-1β levels and lower TLR4 and Rela mRNA expression. In contrast, IL-1β was higher in exercised control rats, and ileal LPS levels were lower overall in exercised rats. CONCLUSIONS: These findings suggest that HIIT-related improvements in depression-related phenotypes were accompanied by attenuation of LPS-associated inflammatory changes in the prefrontal cortex, while exploratory microbiota analyses identified differences in gut microbiota composition. HIIT may represent a promising exercise-based strategy for improving stress-related depressive-like phenotypes.
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The role of the intestinal microbiota in the pathogenesis of host depression and mechanism of TPs relieving depression.
Depression is a prevalent neuropsychiatric disease with a high recurrence rate, affecting over 350 million people worldwide. Intestinal flora disorders and gut-brain-axis (GBA) dysfunction may cause mental disorders. Alterations in the intestinal flora composition could increase the permeability of the gut barrier, activate systemic inflammation and immune responses, regulate the release and efficacy of monoamine neurotransmitters, alter the activity and function of the hypothalamic-pituitary-adrenal (HPA) axis, and modify the abundance of the brain-derived neurotrophic factor (BDNF); all of these showed a close correlation with the occurrence of depression. In addition, the disturbance of the intestinal flora is related to circadian rhythm disorders, which aggravate the symptoms of depression. Tea polyphenols (TPs) have been found to have antidepressant effects. Therefore, the close reciprocity between the intestinal flora and circadian rhythm provides a new opportunity for TPs to regulate depression relying on the intestinal flora. In this review, we discussed the relationship between intestinal flora dysbiosis and the pathogenesis of depression and the mechanism of TPs relieving depression via the GBA.
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Obesity-induced emotional alterations in mice are associated with impairments of tryptophan metabolism along the kynurenine and indole pathways.
Chronic inflammatory conditions, such as obesity, are frequently associated with a high prevalence of mood disorders and a reduced response to conventional antidepressants. Therefore, identifying the biological substrates underlying these comorbidities is crucial, as it could help uncover new therapeutic strategies to improve current treatments. Growing evidence implicates inflammation-driven dysregulation of tryptophan breakdown along the kynurenine pathway (KP) as a key contributor, although the specific roles of its various metabolites remain unclear. Additionally, the involvement of the gut-derived indole pathway (IP) of tryptophan metabolism is still poorly understood, despite increasing evidence linking gut microbiota metabolites to mood regulation. To address these questions, we assessed depressive-like and anxiety-like behaviors in C57BL/6J mice chronically exposed to high-fat diet (HFD), a reliable preclinical model of inflammatory depression. We also measured plasma and brain (hippocampus, frontal cortex, striatum) levels of a broad panel of KP and IP metabolites. HFD increased emotional behaviors and altered plasma and brain levels of tryptophan metabolites. Notably, it promoted a systemic neurotoxic-neuroprotective KP imbalance favoring neurotoxicity. It also drastically reduced indole production, with significant repercussions on brain indole-3 sulfate levels. Importantly, these metabolomic changes correlated with the severity of emotional alterations, with distinct metabolite-behavior relationships depending on the specific neuropsychiatric symptom dimensions assessed. In conclusion, this study offers valuable novel insights into the role of KP- and IP-derived tryptophan metabolites as key mediators between obesity and depression, and thus potential new promising therapeutic targets to improve neuropsychiatric comorbidities of obesity.
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Selective Gut Microbiota Remodeling Induced by a Traditional Mexican Diet and Exercise Program Improves Metabolic Health and Intestinal Permeability in Adults with Obesity and Affective Symptoms.
Background: Obesity and mental disorders are associated with gut microbiota dysbiosis and gut-brain axis dysfunction. This secondary analysis evaluated the effects of a 12-week weight loss program (WLP) based on a hypocaloric traditional Mexican diet (TMD) and moderate-intensity exercise on gut microbiota, body composition (BC), and metabolic parameters in Mexican adults with obesity with and without depression and anxiety symptoms. Methods: A total of 106 adults with obesity were classified based on the presence or absence of depressive and anxiety symptoms into an obesity control group without symptoms (OCG), improved symptoms (OIS), and persistent symptoms (OPS). Stool samples were analyzed by sequencing the V3-V4 region of the 16S rRNA gene. Longitudinal changes in serum biochemistry, BC, intestinal permeability markers, and gut microbiota were analyzed using linear mixed-effects models. Differential taxa were identified using linear discriminant analysis effect size (LEfSe), and associations between bacterial genera, biochemical variables, and dietary components were explored using MaAsLin 2. Results: The WLP significantly improved metabolic, inflammatory, intestinal permeability, and BC markers, as well as depressive and anxiety symptoms, although participants remained in WHO grade I obesity. These improvements were accompanied by selective, group-dependent modulation of bacterial genera rather than broad microbiota restructuring. LEfSe identified 22 taxonomic biomarkers: 16 in OPS, 5 in OIS, and 1 in OCG. Conclusions: The culturally adapted WLP, which combined a hypocaloric TMD with exercise, promoted improvements in metabolism and BC in all participants, along with group-specific gut microbiota remodeling that may be associated with differential changes in depressive and anxiety symptoms in the context of persistent obesity.
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Supplementation with Lactobacillus kefiranofaciens ZW3 from Tibetan Kefir improves depression-like behavior in stressed mice by modulating the gut microbiota.
Increasing evidence indicates that probiotics can effectively improve depression-like behavior. However, the underlying mechanism is still unclear. In this study, the antidepressant effect of Lactobacillus kefiranofaciens CGMCC2809 (ZW3) isolated from Tibetan Kefir grains was investigated using a mouse model of chronic unpredictable mild stress (CUMS). ZW3 improved depression-like behavior and independent exploration ability in the CUMS group. Moreover, ZW3 regulated biochemical disorders in the hypothalamic-pituitary-adrenal axis, immune system and tryptophan metabolism caused by stress. Furthermore, ZW3 could modulate the composition of the gut microbiota, and alleviate constipation by improving the fecal water content in stressed mice. We found that the probiotic strain was present in the whole intestine, even 7 days after its administration was stopped. These results suggest that L. kefiranofaciens ZW3 might improve depression by regulating the gut microbiota as a probiotic food.
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Association of maternal gut microbiota with prenatal depression and the potential mediation effect by plasma tryptophan.
OBJECTIVES: Prenatal depression is one of the most common psychological disorders during pregnancy, with an incidence of approximately 19.7% in China, and the incidence is showing a significant upward trend. Prenatal depression seriously endangers maternal and infant health, may lead to self-injury and suicide, and has lasting effects on the health of offspring. Studies have shown that gut microbiota imbalance and disruption of the gut-brain axis can affect brain function and behavior and play an important role in the occurrence and development of depression. Significant changes occur in the gut microbiota of pregnant women during pregnancy, which may influence inflammation and metabolism. Gut microbiota play a key role in tryptophan metabolism; however, the mechanisms by which maternal gut microbiota regulate tryptophan metabolism to affect brain function and mood remain unclear. This study aims to clarify the role of plasma tryptophan in the relationship between gut microbiota and prenatal depression in pregnant women based on the gut-brain axis mechanism. METHODS: A total of 73 pregnant women were included in the study. The Edinburgh Postnatal Depression Scale (EPDS) was used for assessment. According to the cutoff score (10 points), participants were divided into a prenatal depression group (pregnant women with prenatal depression) and a control group (pregnant women without prenatal depression). Demographic information, fecal samples, and plasma samples were collected. Gut microbiota sequencing was performed using 16S ribosomal RNA (rRNA) sequencing. Amino acid detection in plasma and feces was conducted using ultrahigh performance liquid chromatography-electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS). Data were analyzed using SPSS 26.0 and R software, and mediation model analysis was performed using SPSS PROCESS. RESULTS: There were no statistically significant differences in α-diversity or β-diversity of gut microbiota between the 2 groups (all P>0.05). Compared with the control group, plasma tryptophan levels were significantly higher in the prenatal depression group (t=-2.964, P<0.05). The abundances of Candidatus_Soleaferrea (β=-19.945, OR<0.001, 95% CI <0.001 to 0.002, P=0.004) and Enterococcus (β=-9.074, OR<0.001, 95% CI <0.001 to 0.183, P=0.016) were negatively correlated with prenatal depression, whereas the abundance of Lachnospiraceae_NC2004_group was positively correlated with prenatal depression (β=5.870, OR=354.354, 95% CI 1.248 to 100 619.527, P=0.042). Plasma tryptophan levels played a mediating role between Enterococcus abundance and prenatal depression. CONCLUSIONS: Depressive symptoms during pregnancy are associated with the composition of gut microbiota during pregnancy. Tryptophan, as a precursor of serotonin, may play a mediating role in this process, providing new insights for improving prenatal depression through interventions targeting gut microbiota or tryptophan metabolism.
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Antidepressant properties of voluntary exercise mediated by gut microbiota.
Although regular exercise has been reported to prevent depression, it has not been clarified whether the gut microbiota is involved in the factors that prevent depression through exercise. We investigated the effects of voluntary exercise on the gut microbiota and the prevention of depression-like behaviors using mice. C57BL/6 J male mice were subjected to 10 weeks of sedentary control or wheel running, then they were subjected to social defeat stress (SDS). Exercise attenuated that sucrose drinking was decreased by SDS treatment. Exercise increased the expression of Bdnf and decreased expression of Zo-1 and Claudin5 in the brain. Fecal Turicibacter, Allobaculum, and Clostridium sensu stricto, and propionate in the cecum were decreased by the exercise. Voluntary exercise-induced antidepressant properties might be partially caused by suppression of serotonin uptake into gut microbiota and increase the permeability of the blood-brain barrier via reduced propionate production.
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Irritable Bowel Syndrome, Depression, and Neurodegeneration: A Bidirectional Communication from Gut to Brain.
Patients with irritable bowel syndrome (IBS) are increasingly presenting with a wide range of neuropsychiatric symptoms, such as deterioration in gastroenteric physiology, including visceral hypersensitivity, altered intestinal membrane permeability, and gastrointestinal motor dysfunction. Functional imaging of IBS patients has revealed several abnormalities in various brain regions, such as significant activation of amygdala, thinning of insular and anterior cingulate cortex, and increase in hypothalamic gray matter, which results in poor psychiatric and cognitive outcomes. Interrelations between the enteric and central events in IBS-related gastrointestinal, neurological, and psychiatric pathologies have compelled researchers to study the gut-brain axis-a bidirectional communication that maintains the homeostasis of the gastrointestinal and central nervous system with gut microbiota as the protagonist. Thus, it can be disrupted by any alteration owing to the gut dysbiosis or loss of diversity in microbial composition. Available evidence indicates that the use of probiotics as a part of a balanced diet is effective in the management of IBS and IBS-associated neurodegenerative and psychiatric comorbidities. In this review, we delineate the pathogenesis and complications of IBS from gastrointestinal and neuropsychiatric standpoints while also discussing the neurodegenerative events in enteric and central nervous systems of IBS patients and the therapeutic potential of gut microbiota-based therapy established on clinical and preclinical data.
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Directed evolution of hydroxylase XcP4H for enhanced 5-HTP production in engineered probiotics to treat depression.
Depression exhibits a complex and multifaceted pathophysiology, accompanied by high rates of relapse and disability with current medication treatments. 5-Hydroxytryptophan (5-HTP) is a promising candidate for depression therapy, but its poor pharmacokinetics hinders its clinical application. To address this limitation, we introduced the hydroxylase XcP4H into Escherichia coli Nissle 1917 (EcN) to biosynthesize 5-HTP in vivo. To create a high-yielding EcN strain for 5-HTP production, we engineered XcP4H through enzyme-directed evolution using a novel genetic code expansion-based high-throughput screening method. The most effective XcP4H variant achieved a 22-fold increase in 5-HTP production, and molecular dynamic simulations elucidated the underlying mechanisms. After pathway engineering and gene editing, we further improved the 5-HTP yield in EcN. When the most robust strain, EcN@5-HTP, was employed as a live therapeutic, it alleviated depressive-like behaviors in mice by increasing 5-HT levels in both the gut and brain, repairing neurological abnormalities, inhibiting inflammation, elevating SCFAs concentrations, and modulating gut microbiota dysbiosis. By integrating synthetic biology with enzyme-directed evolution, we successfully addressed the pharmacokinetic limitations of 5-HTP through a live therapeutic approach. This proof-of-concept design clearly demonstrates that combining synthetic biology with probiotics has the potential to significantly revolutionize our strategies for disease detection, prevention, and treatment.
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Ketogenic diet is less effective in ameliorating depression and anxiety in obesity than Mediterranean diet: A pilot study for exploring the GUT-brain axis.
Obesity is associated with depressive symptoms due to biological and psychological factors. Dietary interventions, including the Ketogenic (Keto) and Mediterranean (Med) diets, impact weight loss and mental health differently. While the Keto diet promotes rapid weight loss by increasing ketone body levels, its effects on mental health, particularly in individuals with obesity, remain unclear. This exploratory pilot study explores the impact of both diets on depression and impulsiveness, focusing on the gut-brain axis. Sixty-four participants (Body Mass Index 30-45 kg/m2, ages 18-65) were randomly assigned to follow one of the two diets for three months. Due to attrition, 37 participants (Med n = 23; Keto n = 14) completed the study. Depression and impulsivity scores were evaluated before and after the intervention. Stool samples were collected for microbiota analysis, and faecal transplants were performed in healthy mice. Brain and serum metabolites in recipient mice were analysed using High-Resolution Magic Angle Spinning (HR-MAS) and Proton Nuclear Magnetic Resonance (1H NMR) spectroscopy. The Med diet showed greater improvement in depression scores compared to the Keto diet, while the latter was associated with reductions in impulsivity (urgency subscale). However, faecal transplants from the Keto group induced anxiety-like behaviours in recipient mice, which correlated with significant microbiota and metabolite changes. The Keto group exhibited increased levels of taurine, alanine, and betaine in the brain, and threonine levels were correlated with behavioural changes. These findings suggest that the Med diet offers more consistent short-term benefits related to depressive symptoms, while the Keto diet modulated impulsivity. The animal model findings highlighted the role of diet-induced microbiota changes and metabolite alterations in the gut-brain axis. Long-term studies in a larger population are needed to tailor dietary interventions, essential for optimizing mental and physical health in obesity.