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Multi-omic analyses of the development of obesity-related depression linked to the gut microbe Anaerotruncus colihominis and its metabolite glutamate.
Emerging evidence implicates gut microbiota in the pathogenesis of obesity-related depression (OD); however, the underlying molecular mechanisms remain inadequately explored. This study compared the microbial and transcriptional profiles between patients with OD and healthy individuals. The results revealed an enrichment of Anaerotruncus colihominis (A. colihominis) and glutamate metabolism-related genes in the OD group. Fecal microbiota transplantation (FMT) from patients with OD induced weight gain, compromised barrier function, and intensified depression-like behaviors in high-fat diet (HFD) mice. Microbial analysis in the mice feces corroborated the clinical findings. Single-cell RNA sequencing highlighted the pivotal role of the Efnb2-Ephb2 interaction in cell communication among colon epithelial and hippocampal neuron subtypes in OD mice. Notably, A. colihominis correlated with glutamate levels in the OD mice and patients. It produced glutamate through a glutamic acid metabolism-related DNA sequence, verified in an engineered Escherichia coli MG1655 strain. Both A. colihominis and glutamate reduced barrier proteins in colon epithelial cells and modulated cognitive proteins in neurons. Finally, A. colihominis treatment induced the Efnb2-Ephb2 interaction, exacerbating depression-like behaviors in germ-free HFD mice. Collectively, these findings reveal that A. colihominis and glutamate are potential intervention targets for OD treatment.
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Microbiota-derived tryptophol attenuates chronic stress-induced pain- and depression-like phenotypes in female mice via colonic aryl hydrocarbon receptor signaling through reduced neuroinflammation.
Chronic stress contributes to comorbid hyperalgesia and depression-like behaviors, but the microbial-metabolic mediators linking stress to these phenotypes remain unclear. Using a chronic restraint stress (CRS) model, we found that CRS induced hyperalgesia and depression-like behaviors together with gut microbial dysbiosis and remodeling of fecal tryptophan metabolites. Fecal microbiota transplantation from CRS donors to antibiotic-treated recipients reproduced these behavioral abnormalities, supporting a causal contribution of the gut microbiota. Targeted metabolomics identified reduced fecal tryptophol (IEt) in both female and male mice. Because IEt is a reported aryl hydrocarbon receptor (AHR) ligand, we evaluated it pharmacologically in vivo. Oral IEt alleviated CRS-induced behavioral abnormalities in females, but not males, under the dose and regimen tested, and this effect was abolished by the gastrointestinal-specific AHR antagonist GNF351. In females, IEt increased colonic AHR signaling-related proteins, improved barrier-associated markers, and reduced the degree of colonic and systemic inflammation. These changes were accompanied by preservation of blood-brain barrier tight-junction markers' expression and attenuation of neuroinflammatory and neuronal/synaptic alterations in the medial prefrontal cortex and ventral hippocampus. Together, these findings support a female-selective, gut AHR-associated mechanism linking chronic stress-induced pain- and depression-like phenotypes to coordinated enteric and neuroinflammation.
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A Narrative Review of Intestinal Microbiota's Impact on Migraine with Psychopathologies.
Migraine is a common and debilitating neurological disorder characterized by the recurrent attack of pulsating headaches typically localized on one side of the head associated with other disabling symptoms, such as nausea, increased sensitivity to light, sound and smell and mood changes. Various clinical factors, including the excessive use of migraine medication, inadequate acute treatment and stressful events, can contribute to the worsening of the condition, which may evolve to chronic migraine, that is, a headache present on >15 days/month for at least 3 months. Chronic migraine is frequently associated with various comorbidities, including anxiety and mood disorders, particularly depression, which complicate the prognosis, response to treatment and overall clinical outcomes. Emerging research indicates a connection between alterations in the composition of the gut microbiota and mental health conditions, particularly anxiety and depression, which are considered disorders of the gut-brain axis. This underscores the potential of modulating the gut microbiota as a new avenue for managing these conditions. In this context, it is interesting to investigate whether migraine, particularly in its chronic form, exhibits a dysbiosis profile similar to that observed in individuals with anxiety and depression. This could pave the way for interventions aimed at modulating the gut microbiota for treating difficult-to-manage migraines.
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Affective Immunology: The Crosstalk Between Microglia and Astrocytes Plays Key Role?
Emerging evidence demonstrates the critical role of the immune response in the mechanisms relating to mood disorders, such as major depression (MDD) and bipolar disorder (BD). This has cast a spotlight on a specialized branch committed to the research of dynamics of the fine interaction between emotion (or affection) and immune response, which has been termed as "affective immunology." Inflammatory cytokines and gut microbiota are actively involved in affective immunology. Furthermore, abnormalities of the astrocytes and microglia have been observed in mood disorders from both postmortem and molecular imaging studies; however, the underlying mechanisms remain elusive. Notably, the crosstalk between astrocyte and microglia acts as a mutual and pivotal intermediary factor modulating the immune response posed by inflammatory cytokines and gut microbiota. In this study, we propose the "altered astrocyte-microglia crosstalk (AAMC)" hypothesis which suggests that the astrocyte-microglia crosstalk regulates emotional alteration through mediating immune response, and thus, contributing to the development of mood disorders.
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Efavirenz-Altered Gut-Microbiota, Tph1, and Systemic 5-HT Levels: Could They Affect Depression Mechanisms in Mice?
The gut microbiota produces molecules that trigger responses at the local and distant levels. It affects the brain through several metabolic products, including serotonin (5-HT). Tryptophan hydroxylase type 1 (Tph1) is the rate-limiting enzyme during 5-HT biosynthesis in the gut. Efavirenz (EFV), an antiretroviral agent against HIV, is associated with depression disorders and Tryptophan hydroxylase type 2 (Tph2) deregulation in mice. The possible association between the depressive effects of EFV secondary to dysbiosis and the expression of Tph1 in the intestine is yet to be studied. Therefore, we aimed to elucidate the role of the gut microbiota in depression mechanisms. We reviewed the gut microbiota, their metabolites (short-chain fatty acids [SCFA]), Tph1 expression in the gut, and systemic 5-HT and tryptophan levels in CD1 mice after 36 days of oral EFV (10 mg/kg) treatment. The proportions of Bacteroidota and Bacillota_A_368345 decreased and increased, respectively, following EFV treatment. Additionally, the abundance of Lactobacillus spp. and Faecalbaculum decreased, whereas that of Dubosiella spp., Blautia_A_141780, and Anaerostipes increased. These bacteria contribute to SCFA production and may have counteracted the lack of protective effects provided by Lactobacillus. Tph1 expression was dysregulated in the gut, whereas serum 5-HT levels decreased following EFV treatment. Lactobacillus species promote 5-HT production in the gut, and the deregulation of Tph1 affects 5-HT synthesis. This disruption in the gut-brain axis decreased peripheral 5-HT levels. This affects the serotonergic system in the brain, which could contribute to depression.
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Gut microbiota depletion from early adolescence alters anxiety and depression-related behaviours in male mice with Alzheimer-like disease.
The gut-microbiota-brain axis plays an important role in stress-related disorders, and dysfunction of this complex bidirectional system is associated with Alzheimer's disease. This study aimed to assess the idea that whether gut microbiota depletion from early adolescence can alter anxiety- and depression-related behaviours in adult mice with or without Alzheimer-like disease. Male C57BL/6 mice were treated with an antibiotic cocktail from weaning to adulthood. Adult mice received an intracerebroventricular injection of amyloid-beta (Aβ)1-42, and were subjected to anxiety and depression tests. We measured, brain malondialdehyde and glutathione following anxiety tests, and assessed brain oxytocin and the hypothalamic-pituitary-adrenal (HPA) axis function by measuring adrenocorticotrophic hormone (ACTH) and corticosterone following depression tests. Healthy antibiotic-treated mice displayed significant decreases in anxiety-like behaviours, whereas they did not show any alterations in depression-like behaviours and HPA axis function. Antibiotic treatment from early adolescence prevented the development of anxiety- and depression-related behaviours, oxidative stress and HPA axis dysregulation in Alzheimer-induced mice. Antibiotic treatment increased oxytocin in the brain of healthy but not Alzheimer-induced mice. Taken together, these findings suggest that gut microbiota depletion following antibiotic treatment from early adolescence might profoundly affect anxiety- and depression-related behaviours, and HPA axis function in adult mice with Alzheimer-like disease.
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Microbiota alterations in proline metabolism impact depression.
The microbiota-gut-brain axis has emerged as a novel target in depression, a disorder with low treatment efficacy. However, the field is dominated by underpowered studies focusing on major depression not addressing microbiome functionality, compositional nature, or confounding factors. We applied a multi-omics approach combining pre-clinical models with three human cohorts including patients with mild depression. Microbial functions and metabolites converging onto glutamate/GABA metabolism, particularly proline, were linked to depression. High proline consumption was the dietary factor with the strongest impact on depression. Whole-brain dynamics revealed rich club network disruptions associated with depression and circulating proline. Proline supplementation in mice exacerbated depression along with microbial translocation. Human microbiota transplantation induced an emotionally impaired phenotype in mice and alterations in GABA-, proline-, and extracellular matrix-related prefrontal cortex genes. RNAi-mediated knockdown of proline and GABA transporters in Drosophila and mono-association with L. plantarum, a high GABA producer, conferred protection against depression-like states. Targeting the microbiome and dietary proline may open new windows for efficient depression treatment.
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Multiomics Study of Gut Bacteria and Host Metabolism in Irritable Bowel Syndrome and Depression Patients.
BACKGROUND AND AIMS: Irritable bowel syndrome (IBS) and depression have high tendencies of comorbidity. In particular, diarrhea-predominant IBS (IBS-D) and depression exhibit similar fecal microbiota signatures, yet little is known about their pathogenic mechanism. Here, we propose that the differences in structure and composition of IBS-D and depression gut microbiota give rise to different downstream functions, which lead to distinct clinical phenotypes via host metabolism and further influence the interaction of brain-gut axis. METHODS: We performed multiomics study, including fecal metagenome-wide sequencing and serum metabolomics profiling in 65 individuals with IBS-D (n=22), depression (n=15), comorbid patients (n=13), and healthy controls (n=15). We analyzed functional genes contributed by the primary genus and evaluated their correlations with clinical indices and host metabolites. RESULTS: Metagenomic analysis revealed 26 clusters of orthologous groups of protein (COG) categories consisting of a total of 4,631 functional genes. Trehalose and maltose hydrolase (COG1554) and fucose permease (COG0738) were the most relevant and enriched functional genes in the IBS-D patients; urease accessory proteins UreE (COG2371) was that in the depression patients. Context based genome annotation suggest that an alteration of Escherichia coli and Enterobacter cloacae in IBS-D and depression respectively may be responsible for the enrichment described above. Correlation with host metabolites, such as maltotriose and isomaltose in carbohydrate metabolism and anandamide in neuroactive metabolism, drew further connections between these findings. CONCLUSIONS: These changes led us to propose a connection between genomic signatures and clinical differences observed in IBS-D and depression. Our findings provide further insights into the involvement of gut microbiota in diseases related to brain-gut disorder.
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IL-6 expression-suppressing Lactobacillus reuteri strains alleviate gut microbiota-induced anxiety and depression in mice.
Fecal microbiota transplantation from patients with depression/inflammatory bowel disease (PDI) causes depression with gut inflammation in mice. Here, we investigated the effects of six Lactobacillus reuteri strains on brain-derived neurotropic factor (BDNF), serotonin, and interleukin (IL)-6 expression in neuronal or macrophage cells and PDI fecal microbiota-cultured microbiota (PcM)-induced depression in mice. Of these strains, L6 most potently increased BDNF and serotonin levels in corticosterone-stimulated SH-SY5Y and PC12 cells, followed by L3. L6 most potently decreased IL-6 expression in lipopolysaccharide (LPS)-stimulated macrophages. When L1 (weakest in vitro), L3, and L6 were orally administered in mice with PcM-induced depression, L6 most potently suppressed depression-like behaviors and hippocampal TNF-α and IL-6 expression and increased hippocampal serotonin, BDNF, 5HT7, GABAARα1, and GABABR1b expression, followed by L3 and L1. L6 also suppressed TNF-α and IL-6 expression in the colon. BDNF or serotonin levels in corticosterone-stimulated neuronal cells were negatively correlated with depression-related biomarkers in PcM-transplanted mice, while IL-6 levels in LPS-stimulated macrophage were positively correlated. These findings suggest that IL-6 expression-suppressing and BDNF/serotonin expression-inducing LBPs in vitro, particularly L6, may alleviate gut microbiota-involved depression with colitis in vivo.
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Transplantation of fecal microbiota from patients with inflammatory bowel disease and depression alters immune response and behavior in recipient mice.
Gut dysbiosis is closely associated with the occurrence of inflammatory bowel disease (IBD) and psychiatric disorder. Here, to understand the difference of gut microbiota composition and physiological effect between IBD patients with (IBD/D+) or without depression (IBD/D-), we analyzed the fecal microbiota composition of patients with IBD with (/D+) or without depression (/D-) and healthy volunteers (HVs) and examined the effects of these fecal microbiota transplantations (FMTs) on the occurrence of systemic inflammation and anxiety/depression in mice. FMTs from patients with IBD/D+ or IBD/D- caused IBD-like colitis in the transplanted mice: they increased the myeloperoxidase activity, IL-1β and IL-6 expression, and NF-κB+/CD11c+ cell population in the colon. Transplantation of the IBD/D+ patient feces (IBD/D+-F) caused IBD-like colitis more strongly than that of IBD/D--F. FMTs from patients with IBD/D+ also caused anxiety-/depression-like behaviors, increased the NF-κB+/Iba1+ and lipopolysaccharide (LPS)+/Iba1+ cell populations, and decreased the BDNF+/NeuN+ cell population in the hippocampus. They increased LPS levels in the blood. FMTs from patients with IBD/D- caused anxiety-like, but not depression-like, behaviors. α-/β-diversities and composition of gut microbiota in IBD-F were different from those of HV feces (HV-F). The Enterobacteriaceae and Enterococcaceae populations and LPS levels were higher in the IBD-F than in the HV-F. The Enterococcaceae population was higher in IBD/D+-F vs. IBD/D--F. However, the transplantation of HV-F into mice previously transplanted with IBD/D+-F significantly reduced depression-like behaviors, NF-κB+/Iba1+ and LPS+/Iba1+ cell populations in the hippocampus, LPS levels in the feces and blood, and IL-1β expression in the colon. These findings suggest that the outbreak of depression/anxiety may be dependent on the systemic inflammation with a leaky gut through the gut dysbiosis-attributable overproduction of bacterial LPS and suppression of tight junction protein expression in patients with IBD.