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AhR/IL-22 pathway as new target for the treatment of post-infectious irritable bowel syndrome symptoms.
Alterations in brain/gut/microbiota axis are linked to Irritable Bowel Syndrome (IBS) physiopathology. Upon gastrointestinal infection, chronic abdominal pain and anxio-depressive comorbidities may persist despite pathogen clearance leading to Post-Infectious IBS (PI-IBS). This study assesses the influence of tryptophan metabolism, and particularly the microbiota-induced AhR expression, on intestinal homeostasis disturbance following gastroenteritis resolution, and evaluates the efficacy of IL-22 cytokine vectorization on PI-IBS symptoms. The Citrobacter rodentium infection model in C57BL6/J mice was used to mimic Enterobacteria gastroenteritis. Intestinal homeostasis was evaluated as low-grade inflammation, permeability, mucosa-associated microbiota composition, and colonic sensitivity. Cognitive performances and emotional state of animals were assessed using several tests. Tryptophan metabolism was analyzed by targeted metabolomics. AhR activity was evaluated using a luciferase reporter assay method. One Lactococcus lactis strain carrying an eukaryotic expression plasmid for murine IL-22 (L. lactisIL-22) was used to induce IL-22 production in mouse colonic mucosa. C. rodentium-infected mice exhibited persistent colonic hypersensitivity and cognitive impairments and anxiety-like behaviors after pathogen clearance. These post-infectious disorders were associated with low-grade inflammation, increased intestinal permeability, decrease of Lactobacillaceae abundance associated with the colonic layer, and increase of short-chain fatty acids (SCFAs). During post-infection period, the indole pathway and AhR activity were decreased due to a reduction of tryptophol production. Treatment with L. lactisIL-22 restored gut permeability and normalized colonic sensitivity, restored cognitive performances and decreased anxiety-like behaviors. Data from the video-tracking system suggested an upgrade of welfare for mice receiving the L.lactisIL-22 strain. Our findings revealed that AhR/IL-22 signaling pathway is altered in a preclinical PI-IBS model. IL-22 delivering alleviate PI-IBS symptoms as colonic hypersensitivity, cognitive impairments, and anxiety-like behaviors by acting on intestinal mucosa integrity. Thus, therapeutic strategies targeting this pathway could be developed to treat IBS patients suffering from chronic abdominal pain and associated well-being disorders.
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Anxiety, depression, chronic inflammation and aortic stiffness in Crohn's disease: the brain--gut--vascular axis.
BACKGROUND: Patients with Crohn's disease have an increased aortic stiffness, a known cardiovascular risk factor. Anxiety, a key factor of the brain--gut axis in patients with Crohn's disease, is implicated in the pathogenesis and progression of the disease, and is linked with aortic stiffening in other clinical settings. OBJECTIVES: Considering that depression is frequently linked to anxiety in Crohn's disease, we performed a mediation analysis to reveal the potential link between anxiety, depression and aortic stiffness in these patients. METHODS: Multicentre observational cross-sectional study of 86 consecutive patients with Crohn's disease and 86 matched control individuals. The connections between anxiety, depression, disease duration, aortic pulse wave velocity (aPWV), brachial and central SBP were tested using partial least squares structural equations modelling. RESULTS: In patients with Crohn's disease, anxiety (path coefficient: 0.220, P = 0.01) and disease duration (path coefficient: 0.270, P = 0.02) were associated with aPWV that in turn was associated with brachial SBP (path coefficient: 0.184, P = 0.03). These associations were even stronger in patients with active disease. The connection between anxiety and aPWV was in part mediated by central SBP (indirect effect: 0.090, P = 0.01; indirect-to-total effect ratio: 41%) as well as, in a pilot substudy, by sympathetic hyperactivity. Anxiety and depression were highly correlated in patients with Crohn's disease. Consequently, results were confirmed when anxiety was substituted by depression. CONCLUSION: The connections of anxiety, depression and chronic inflammation with aPWV and SBP could suggest the first evidence of a brain--gut--vascular axis and new potential targets for therapy in patients with Crohn's disease.
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Co-decoction of Lilii bulbus and Radix Rehmannia Recens and its key bioactive ingredient verbascoside inhibit neuroinflammation and intestinal permeability associated with chronic stress-induced depression via the gut microbiota-brain axis.
BACKGROUND: Gut microbiota plays a critical role in the pathogenesis of depression and are a therapeutic target via maintaining the homeostasis of the host through the gut microbiota-brain axis (GMBA). A co-decoction of Lilii bulbus and Radix Rehmannia Recens (LBRD), in which verbascoside is the key active ingredient, improves brain and gastrointestinal function in patients with depression. However, in depression treatment using verbascoside or LBRD, mechanisms underlying the bidirectional communication between the intestine and brain via the GMBA are still unclear. PURPOSE: This study aimed to examine the role of verbascoside in alleviating depression via gut-brain bidirectional communication and to study the possible pathways involved in the GMBA. METHODS: Key molecules and compounds involved in antidepressant action were identified using HPLC and transcriptomic analyses. The antidepressant effects of LBRD and verbascoside were observed in chronic stress induced depression model by behavioural test, neuronal morphology, and synaptic dendrite ultrastructure, and their neuroprotective function was measured in corticosterone (CORT)-stimulated nerve cell injury model. The causal link between the gut microbiota and the LBRD and verbascoside antidepressant efficacy was evaluate via gut microbiota composition analysis and faecal microbiota transplantation (FMT). RESULTS: LBRD and Verbascoside administration ameliorated depression-like behaviours and synaptic damage by reversing gut microbiota disturbance and inhibiting inflammatory responses as the result of impaired intestinal permeability or blood-brain barrier leakiness. Furthermore, verbascoside exerted neuroprotective effects against CORT-induced cytotoxicity in an in vitro depression model. FMT therapy indicated that verbascoside treatment attenuated gut inflammation and central nervous system inflammatory responses, as well as eliminated neurotransmitter and brain-gut peptide deficiencies in the prefrontal cortex by modulating the composition of gut microbiota. Lactobacillus, Parabacteroides, Bifidobacterium, and Ruminococcus might play key roles in the antidepressant effects of LBRD via the GMBA. CONCLUSION: The current study elucidates the multi-component, multi-target, and multi-pathway therapeutic effects of LBRD on depression by remodeling GMBA homeostasis and further verifies the causality between gut microbiota and the antidepressant effects of verbascoside and LBRD.
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Combined Effects of Early Life Stress and Prolonged Exposure to Western Diet on Emotional Responses and Gut Microbiota.
BACKGROUND: Exposure to early life stress (ELS) and maternal consumption of a high-fat and high-sugar diet can have detrimental effects on adult emotional responses. The microbiota and gut-brain axis have been proposed as playing a mediating role in the regulation of stress and emotion. METHOD: Young male rats were exposed to maternal separation (MS) together with maternal and postnatal consumption of a HFS diet (45%kcal saturated fat, 17%kcal sucrose). Anxiety-like behaviour was evaluated using an elevated zero-maze, and depression-like behaviour using the forced-swim and sucrose preference tests. Microbiota composition and derived metabolites were also analysed in faecal samples using a gas chromatograph and mass spectrometry. RESULTS: Combined exposure to MS and lifelong consumption of a HFS diet partially reversed the abnormal anxiety-like and depression-like behaviours in early adulthood caused by each adverse factor alone. Diet composition had a greater negative impact than ELS exposure on the gut microbiota, and both environmental factors interacted with microbiota composition partially counteracting their negative effects. CONCLUSIONS: The effects of exposure to early life stress and a HFS diet independently are partially reversed after the combination of both factors. These results suggest that ELS and diet interact to modulate adult stress response and gut microbiota.
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Exploring the Association of dietary index for gut microbiota with Parkinson's disease and depression: Insights from NHANES.
BACKGROUND: Depression and Parkinson's disease (PD) are important public health issues strongly associated with diet and gut microbiota. The aim of this study was to investigate the association of the dietary index for gut microbiota (DI-GM) with Parkinson's disease and depression. METHODS: This cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) database (2007-2020), with a total of 26,473 participants aged 18-80 years, weighted to represent 256 million US adults. Dietary recall data were used to calculate the DI-GM. Weighted logistic regression was used to analyze the relationship between the DI-GM and depression and PD, and to explore the potential mediating role of the DI-GM in depression and PD. Subgroup analyses and restricted cubic spline (RCS) analyses were also performed. RESULTS: The weighted prevalence of PD combined with depression was approximately 22.99 %. We found a possible inverted U-shaped relationship between DI-GM and depression. Higher DI-GM scores were associated with a lower risk of PD (OR = 0.84, 95 % CI (0.75,0.94)). Mediation modelling indicated no significant role for DI-GM in the relationship between depression and PD. The RCS showed a non-linear association between DI-GM and PD. CONCLUSIONS: A dose-dependent nonlinear association was identified between the DI-GM and PD. Preliminary evidence suggests a potential inverted U-shaped DI-GM-depression relationship requiring validation. This suggests that focusing on DI-GM may be helpful in studying PD and depression.
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Inferior social hierarchy is vulnerable to anxiety-like behavior in chronic pain mice: Potential role of gut microbiota and metabolites.
Social dominance is a universal phenomenon among grouped animals that profoundly affects survival, health, and reproductive success by determining access to resources, and exerting a powerful influence on subsequent behavior. However, the understanding of pain and anxiety comorbidities in dominant or subordinate animals suffering from chronic pain is not well-defined. Here, we provide evidence that subordinate mice are more susceptible to pain-induced anxiety compared to dominant mice. We propose that the gut microbiota may play a mediating role in this mechanism. Our findings demonstrate that transplantation of fecal microbiota from subordinate mice with chronic inflammatory pain, but not dominant mice, into antibiotics-treated pseudo-germ-free mice significantly amplifies anxiety-like phenotypes, highlighting the critical involvement of gut microbiota in this behavioral response. Using chronic inflammatory pain model, we carried out 16S rRNA sequencing and untargeted metabolomic analyses to explore the relationship between microbiota and metabolites in a stable social hierarchy of mice. Interestingly, anxiety-like behaviors were directly associated with some microbial genera and metabolites, especially bile acid metabolism. Overall, we have demonstrated a close relationship between social status and anxiety susceptibility, highlighting the contributions of gut microbiota and the associated metabolites in the high-anxiety state of subordinate mice with chronic inflammatory pain.
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Exploring Causal Links Between Gut Microbiota and Geriatric Syndromes: A Two-Sample Mendelian Randomization Analysis.
Background: Both observational studies and clinical trials have demonstrated a link between the gut microbiota and the geriatric syndrome. Nevertheless, the exact nature of this relationship, particularly concerning causality, remains elusive. Mendelian randomization (MR) is a method of inference based on genetic variation to assess the causal relationship between an exposure and an outcome. In this study, we conducted a two-sample Mendelian randomization (TSMR) study to fully reveal the potential genetic causal effects of gut microbiota on geriatric syndromes. Methods: This study used data from genome wide association studies (GWAS) to investigate causal relationships between the gut microbiota and geriatric syndromes, including frailty, Parkinson's disease (PD), delirium, insomnia, and depression. The primary causal relationships were evaluated using the inverse-variance weighted method, MR Egger, simple mode, weighted mode and weighted median. To assess the robustness of the results, horizontal pleiotropy was examined through MR-Egger intercept and MR-presso methods. Heterogeneity was assessed using Cochran's Q test, and sensitivity was evaluated via the leave-one-out method. Results: We identified 41 probable causal relationships between gut microbiota and five geriatric syndrome-associated illnesses using the inverse-variance weighted method. Frailty showed five positive and two negative causal relationships, while PD revealed three positive and four negative causal connections. Delirium showed three positive and two negative causal relationships. Similarly, insomnia demonstrated nine positive and two negative causal connections, while depression presented nine positive and two negative causal relationships. Conclusions: Using the TSMR method and data from the public GWAS database and, we observed associations between specific microbiota groups and geriatric syndromes. These findings suggest a potential role of gut microbiota in the development of geriatric syndromes, providing valuable insights for further research into the causal relationship between gut microbiota and these syndromes.
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Maternal separation during lactation affects recognition memory, emotional behaviors, hippocampus and gut microbiota composition in C57BL6J adolescent female mice.
BACKGROUND: Maternal separation (MS) in rodents is a paradigm of early life events that affects neurological development in depression. Adolescence is a time of dramatic increases in psychological vulnerability, and being female is a depression risk factor. However, data on whether different MS scenarios affect behavioral deficits and the potential mechanisms in adolescent female mice are limited. METHODS: C57BL/6 J female pups were exposed to different MS (no MS, NMS; MS for 15 min/day, MS15; or 180 min/day, MS180) from postnatal day (PND)1 to PND21 and subjected for behavioral tests during adolescence. Behavioural tests, specifically the open field test (OFT), novel object recognition test (NOR) test and tail suspension test (TST), were performed. The expression of proinflammatory cytokines, hippocampal neurogenesis, neuroinflammation, and gut microbiota were also assessed. RESULTS: The results showed that MS180 induced emotional behavioral deficits and object recognition memory impairment; however, MS15 promoted object recognition memory in adolescent females. MS180 decreased hippocampal neurogenesis of adolescent females, induced an increase in microgliosis, and increased certain inflammatory factors in the hippocampus, including TNF-α, IL-1β, and IL-6. Furthermore, different MS altered gut microbiota diversity, and alpha diversity in the Shannon index was negatively correlated with the peripheral inflammatory factors TNF-α, IL-1β, and IL-6. Species difference analysis showed that the gut microbiota composition of the phyla Desulfobacterota and Proteobacteria was affected by the MS. LIMITATIONS: The sex differences in adolescent animal and causality of hippocampal neurogenesis and gut microbiota under different MS need to be further analyzed in depression. CONCLUSION: This study indicates different MS affect recognition memory and emotional behaviors in adolescent females, and gut microbiota-neuroinflammation and hippocampal neurogenesis may be a potential site of early neurodevelopmental impairment in depression.
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Natural products for depression: Preclinical insights into microbiota-gut-brain axis modulation and pharmacological potential.
The microbiota-gut-brain axis (MGBA) is progressively associated with the pathophysiology of depression. This analysis consolidates existing preclinical findings on MGBA mechanisms associated with depression and assesses natural-product therapies through three key metabolite-related pathways: bile acid-responsive signaling via the farnesoid X receptor, G protein-coupled bile acid receptor 1, vitamin D receptor, and pregnane X receptor; metabolites from the kynurenine pathway and their connection to N-methyl-D-aspartate receptor signaling; and microbial indole-aryl hydrocarbon receptor signaling. Bile acid-responsive receptors and signaling pathways are examined as a system connecting microbiota-altered bile acid profiles to receptor-specific impacts on bile acid equilibrium, epithelial barrier integrity, immune modulation, metabolic signaling, and subsequent neuroplasticity-related reactions. These metabolite-associated domains converge with extensive MGBA mechanisms, encompassing short-chain fatty acid signaling, vagal interactions, serotonergic modulation, gamma-aminobutyric acid signaling, hypothalamic-pituitary-adrenal axis function, and barrier-immune pathways. In this analytical framework, natural products from marine and terrestrial sources are evaluated across several mechanistic domains and evidence levels, with direct host-target interactions, microbiota-related alterations, and experimentally validated microbiota-dependent pathways examined independently. This method facilitates a more nuanced evaluation of diverse preclinical results by elucidating the extent of mechanistic backing and translational significance across various fields. Due to the mostly preclinical characteristics of the evidence foundation, clinical application will necessitate authenticated biomarkers, standardized natural product formulations, pharmacokinetic and pharmacodynamic assessments, and regulated human studies.
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L-theanine alleviates reserpine-induced depression in rats via modulation of the gut-brain axis.
L-theanine, a natural amino acid in tea, exhibits potential neuroprotective effects. However, its impact on depression via the microbiota-gut-brain axis remains unclear. Here, L-theanine alleviated reserpine-induced depression-like behaviors in rats, improving anhedonia, despair, and cognitive deficits, while reducing serum IL-1β, IL-6, and TNF-α, restoring hippocampal BDNF, and mitigating neuronal damage. Multi-tissue non-targeted metabolomics (serum, brain, colon, feces) revealed that L-theanine reversed phospholipid and bile acid disturbances and restored key neuroprotective metabolites. Targeted metabolomics validated the non-targeted findings by confirming that L-theanine alleviated bile acid dysregulation and restored SCFA profiles. Additionally, L-theanine modulated gut microbiota composition, increasing beneficial genera such as Alloprevotella and Prevotellaceae_UCG-001, while reducing potentially harmful taxa. Correlation analyses indicated that these microbiota changes were linked to bile acid and SCFA profiles, suggesting gut-brain axis involvement. Overall, L-theanine exerts antidepressant effects by modulating neuroinflammation, neuroplasticity, and metabolism, highlighting its potential as a functional food for depression.