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Ketogenic Diet Modulates Depressive-Like Behavior via Gut Bacterial Metabolism of Tyrosine.
Emerging evidence suggests the therapeutic potential of ketogenic diet (KD) for mood disorders such as depression, yet the underlying mechanisms are poorly understood. Here we report a gut microbe-to-brain signaling pathway through which KD protects against depressive-like behavior in mice. We show that KD feeding triggers a prompt and dynamic remodeling of the gut microbiome, the depletion of which abrogates the protective effect of KD against depressive-like behavior in stressed mice. Colonization with Roseburia intestinalis (R. intestinalis), which is enriched by 1-week KD, sustains the protective effect of KD against depressive-like behavior in mice. The protective effect of KD is linked to the reduction of a host-microbe co-metabolite p-Cresol sulfate (p-CS), the supplementation of which negates the protective effect of KD against depressive-like behavior. Mechanistically, p-CS enters the brain and activates lateral habenula (LHb) to counteract the protective effect of KD. Our findings uncover a gut microbiota-brain axis mechanism for KD consumption to protect against depressive-like behavior.
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Pre-mating nitenpyram exposure in male mice leads to depression-like behavior in offspring by affecting tryptophan metabolism in gut microbiota.
Several studies have confirmed that the health status of the paternal affects the health of the offspring, however, it remains unknown whether paternal exposure to pesticides affect the offspring health. Here, we used untargeted metabolomics and 16S rRNA sequencing technology, combined with tail suspension test and RT-qPCR to explore the effects of paternal exposure to nitenpyram on the neurotoxicity of offspring. Our results found that the paternal exposure to nitenpyram led to the offspring's depressive-like behaviors, accompanied by the reduction of tryptophan content and the disorder of microbial abundance in the gut of the offspring. Further, we determined the expression of tryptophan metabolism-related genes tryptophanase (tnaA) and tryptophan hydroxylase 1 (TpH1) in gut bacteria and colonic tissues. We found that tryptophan is metabolized to indoles rather than being absorbed into colonocytes, which coursed the reduce of tryptophan availability after nitenpyram exposure. In conclusion, our study deepens our understanding of the intergenerational toxic effects of pesticides.
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Circadian Rhythms and Sleep Disorders Associated to Major Depressive Disorder: Pathophysiology and Therapeutic Opportunities.
Major depressive disorder (MDD) is a complex mood disorder. While much progress has been made in understanding the pathophysiology of MDD, no single mechanism can explain all facets of this disorder. Several studies show that disturbances in biological rhythms can lead to the development of MDD. Indeed, insomnia or hypersomnia are symptoms included in the MDD diagnostic criteria. Clinical studies and meta-analyses showed a strong relationship between MDD and sleep disorders. Sleep disorder and MDD are associated with activation in the hypothalamicpituitary- adrenal (HPA) axis and inflammation. The increase in inflammatory response can activate the kynurenine pathway, decrease serotonin synthesis, and affect other factors involved in the pathophysiology of neuropsychiatric conditions. Moreover, sleep disorders and MDD can change the gut microbiota and alter the microbiota-gut-brain axis. Thus, this review discusses the relationship between MDD, circadian rhythms, and sleep disorders, describing the potential pathophysiological mechanism shared in these conditions. In addition, therapeutic opportunities based on antiinflammatory, antioxidant, HPA axis regulatory, and synapse-modulating actions are raised. For the article search, we used the PubMed database. Both sleep disorders and changes in biological rhythms have a bidirectional relationship with MDD. Although some pathophysiological mechanisms, including inflammation, changes in the gut microbiota, and decreased neuroplasticity, may be involved in the relationship between sleep, circadian rhythms, and MDD, other mechanisms are not yet well understood. Therapeutic opportunities based on anti-inflammatory, antioxidant, HPA regulatory axis, and synapse modulating actions appear to be promising targets in preventing MDD, circadian rhythm disturbances, and sleep disorders.
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Major Depressive Disorder and gut microbiota - Association not causation. A scoping review.
One very promising hypothesis of Major Depressive Disorder (MDD) pathogenesis is the gut-brain axis (GBA) dysfunction, which can lead to subclinical inflammation, hypothalamic-pituitary (HPA) axis dysregulation, and altered neural, metabolic and endocrine pathways. One of the most important parts of GBA is gut microbiota, which was shown to regulate different functions in the central nervous system (CNS). The purpose of this scoping review was to present the current state of research on the relationship between MDD and gut microbiota and extract causal relationships. Further, we presented the relationship between the use of probiotics and antidepressants, and the microbiota changes. We evaluated the data from 27 studies aimed to investigate microbial fingerprints associated with depression phenotype. We abstracted data from 16 and 11 observational and clinical studies, respectively; the latter was divided into trials evaluating the effects of psychiatric treatment (n = 3) and probiotic intervention (n = 9) on the microbiome composition and function. In total, the data of 1187 individuals from observational studies were assessed. In clinical studies, there were 490 individuals analysed. In probiotic studies, 220 and 218 patients with MDD received the intervention and non-active study comparator, respectively. It was concluded that in MDD, the microbiota is altered. Although the mechanism of this relationship is unknown, we hypothesise that the taxonomic changes observed in patients with MDD are associated with bacterial proinflammatory activity, reduced Schort Chain Fatty Acids (SCFAs) production, impaired intestinal barrier integrity and neurotransmitter production, impaired carbohydrates, tryptophane and glutamate metabolic pathways. However, only in few publications this effect was confirmed by metagenomic, metabolomic analysis, or by assessment of immunological parameters or intestinal permeability markers. Future research requires standardisation process starting from patient selection, material collection, DNA sequencing, and bioinformatic analysis. We did not observe whether antidepressive medications influence on gut microbiota, but the use of psychobiotics in patients with MDD has great prospects; however, this procedure requires also standardisation and thorough mechanistic research. The microbiota should be treated as an environmental element, which considers the aetiopathogenesis of the disease and provides new possibilities for monitoring and treating patients with MDD.
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Analysis of a new anti-depression mechanism of Chaigui granules based on multi-omics integration: In-depth mining of intestinal microbiota-metabolite interaction network.
BACKGROUND: Depression is a common mental disorder that severely affects physical and psychological health of patients. Despite the proven clinical and experimental efficacy of Chaigui granules (CGG), a novel traditional Chinese medicine formulation for depression, its mechanism remains unclear owing to its multi-component nature. METHODS: To establish an optimal depression model, the gut microbiota of humanized and murine donors under healthy and depressed conditions was compared, and subsequent behavioral effects via fecal microbiota transplantation (FMT) in mice was assessed. Based on this, the mechanism of CCG in treating depression was characterized through combining 16S rRNA sequencing, LC-MS metabolomics and integration analysis. RESULTS: The gut microbiota was markedly disrupted in depressed patients and mice. Through FMT, microbiota from depressed donors successfully colonized recipient mice and induced depression-like behaviors. Comparative results demonstrated the superiority of the murine FMT-induced depression model in terms of stability and translational relevance. CGG produced significant improvements in behavioral phenotypes, metabolic profiles, and microbial composition in depressed mice. Specifically, the treatment regulated 17 key metabolites and 7 bacterial strains, primarily involved in 2 major metabolic pathways. Integrated correlation analysis revealed five bacterial strains and seven metabolites that were strongly associated with depression-like behaviors. CONCLUSION: Through integrated approaches, we hypothesize that Chaigui granules alleviate depressive-like behavior in murine FMT-induced depressed mice by modulating Aminoacyl-tRNA biosynthesis and Lysine degradation, inhibiting Bacteroides caccae, Clostridium cocleatum, and Muribaculum intestinale, while promoting Akkermansia muciniphila and Mucispirillum schaedleri, and regulating key metabolites including Glutaric acid, Threonine, Leucine, and Glutamic acid.
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Impacts of microbiota and its metabolites through gut-brain axis on pathophysiology of major depressive disorder.
Major depressive disorder (MDD) is characterized by a high rate of recurrence and disability, which seriously affects the quality of life of patients. That's why a deeper understanding of the mechanisms of MDD pathology is an urgent task, and some studies have found that intestinal symptoms accompany people with MDD. The microbiota-gut-brain axis is the bidirectional communication between the gut microbiota and the central nervous system, which was found to have a strong association with the pathogenesis of MDD. Previous studies have focused more on the communication between the gut and the brain through neuroendocrine, neuroimmune and autonomic pathways, and the role of gut microbes and their metabolites in depression is unclear. Metabolites of intestinal microorganisms (e.g., tryptophan, kynurenic acid, indole, and lipopolysaccharide) can participate in the pathogenesis of MDD through immune and inflammatory pathways or by altering the permeability of the gut and blood-brain barrier. In addition, intestinal microbes can communicate with intestinal neurons and glial cells to affect the integrity and function of intestinal nerves. However, the specific role of gut microbes and their metabolites in the pathogenesis of MDD is not well understood. Hence, the present review summarizes how gut microbes and their metabolites are directly or indirectly involved in the pathogenesis of MDD.
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The self-serving benefits of being a good host: A role for our micro-inhabitants in shaping opioids' function.
Opioids are highly efficacious in their ability to relieve pain, but they are liable for abuse, dependence, and addiction. Risk factors to develop opioid use disorders (OUD) include chronic stress, socio-environment, and preexisting major depressive disorders (MDD) and posttraumatic stress disorders (PTSD). Additionally, opioids reduce gut motility, induce loss of gut barrier function, and alter the composition of the trillions of microbes hosted in the gastrointestinal tract, known as the gut microbiota. The microbiota are significant contributors to the reciprocal communication between the central nervous system (CNS) and the gut, termed the gut-brain axis. They have strong influences on their host behaviors, including the ability to cope with stress, sociability, affect, mood, and anxiety. Thus, they are implicated in the etiology of MDD and PTSD. Here we review the latest studies demonstrating that intestinal flora can, directly and indirectly, by affecting sociability levels, responses to stress, and mental state, alter the responses to opioids. It suggests that microbiota can potentially be used to increase the resilience to develop analgesic tolerance and OUD.
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Investigation of the mechanism involved in high-fat diet-induced depressive behavior based on energy metabolism.
BACKGROUND: The specific mechanisms underlying high-fat diet (HFD) and depressive behaviors remain elusive. Meanwhile, the impact of calorie restriction (CR) on the development of depression has not been explored in-depth. Thus, we aimed to examine the pathways underlying how long-term HFD intake leads to depression, focusing on energy metabolism. METHODS: C57BL/6J mice were randomly divided into four groups-control (CK) group, CR group, HFD group, and chronic unpredictable mild stress (CUMS) group. Enzyme-linked immunosorbent assay, western blot, metabolomics and 16s rRNA gene sequencing analysis were undertaken to investigate the 5-hydroxytryptamine system, glucolipid metabolism, brain energy metabolism and gut microbiome. RESULTS: Mice with HFD- and CUMS-induced depressive-like symptoms exhibited a significant decrease in serotonergic activity in the hippocampus. The behaviors of CR mice did not differ significantly from CK mice. Fasting blood glucose levels, fatty acid contents, and reactive oxygen species (ROS) levels were all negatively affected in unrestricted HFD and CUMS mice, suggestive of energy metabolism disruption. Metabolomic analysis revealed that tricarboxylic acid cycle activity was inhibited in the HFD and CUMS groups but not in the CR group. Additionally, analysis of the gut microbiome revealed that [Ruminococcus] gnavus exhibited higher predictive potential for HFD-induced depression, while Allobaculum showed greater predictive potential for stress-induced depression. LIMITATIONS: Causal relationship between brain energy metabolism and gut microbiome unclear. CONCLUSION: An unrestricted HFD promotes dysbiosis of the gut microbiota, impairs energy metabolism in the brain, affects the serotonergic system, and ultimately induces depressive-like behaviors.
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Continuous Alterations in the Gut Microbial Landscape Associated With Suicidal Ideation in First-Episode Drug-naïve Major Depressive Disorder.
BACKGROUND: Major depressive disorder (MDD) has been closely associated with gut microbiota dysbiosis; however, the role of the gut microbiota in the progression from depression to suicidal ideation (SI) remains unclear. METHODS: We enrolled a well-characterized clinical cohort of first-episode, drug-naïve MDD patients, explicitly classified into those without SI (MDDNSI) and those with SI (MDDSI), and matched with healthy controls (HC) on demographic variables. A severity-ordered HC-MDDNSI-MDDSI framework was established to capture progressive microbial and functional shifts, and correlation analyses were used to evaluate their relationships with clinical symptoms and cognitive function. RESULTS: We identified a group of taxa showing clear severity-related trends, with the potential pathogenic species Bacteroides stercoris and Bacteroides eggerthii increasing across the clinical spectrum, while seven species, including Faecalibacillus intestinalis and Dialister massiliensis, showed a steady decrease. Functional annotation indicated that several major metabolic pathways, such as the bacterial secretion system, weakened progressively with disease severity and formed stable microbe-pathway modules together with pathways involved in energy metabolism and signal transduction. These differential taxa and pathways showed strong associations with clinical features, with Bacteroides stercoris positively correlated with SI, whereas Bifidobacterium pseudocatenulatum displayed a negative association. In addition, mediation analysis further showed that Bacteroides stercoris indirectly influenced SI through the bacterial secretion system pathway, suggesting a meaningful mediating role in SI. CONCLUSION: These results revealed progressive alterations in gut microbial composition and metabolic function associated with SI, indicating that gut dysbiosis serves as a potential biological marker for suicide risk in MDD.
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Behavioral phenotype, intestinal microbiome, and brain neuronal activity of male serotonin transporter knockout mice.
The serotonin transporter (5-HTT) plays a critical role in the regulation of serotonin neurotransmission. Mice genetically deficient in 5-HTT expression have been used to study the physiological functions of 5-HTT in the brain and have been proposed as a potential animal model for neuropsychiatric and neurodevelopmental disorders. Recent studies have provided evidence for a link between the gut-brain axis and mood disorders. However, the effects of 5-HTT deficiency on gut microbiota, brain function, and behavior remain to be fully characterized. Here we investigated the effects of 5-HTT deficiency on different types of behavior, the gut microbiome, and brain c-Fos expression as a marker of neuronal activation in response to the forced swim test for assessing depression-related behavior in male 5-HTT knockout mice. Behavioral analysis using a battery of 16 different tests showed that 5-HTT-/- mice exhibited markedly reduced locomotor activity, decreased pain sensitivity, reduced motor function, increased anxiety-like and depression-related behavior, altered social behavior in novel and familiar environments, normal working memory, enhanced spatial reference memory, and impaired fear memory compared to 5-HTT+/+ mice. 5-HTT+/- mice showed slightly reduced locomotor activity and impaired social behavior compared to 5-HTT+/+ mice. Analysis of 16S rRNA gene amplicons showed that 5-HTT-/- mice had altered gut microbiota abundances, such as a decrease in Allobaculum, Bifidobacterium, Clostridium sensu stricto, and Turicibacter, compared to 5-HTT+/+ mice. This study also showed that after exposure to the forced swim test, the number of c-Fos-positive cells was higher in the paraventricular thalamus and lateral hypothalamus and was lower in the prefrontal cortical regions, nucleus accumbens shell, dorsolateral septal nucleus, hippocampal regions, and ventromedial hypothalamus in 5-HTT-/- mice than in 5-HTT+/+ mice. These phenotypes of 5-HTT-/- mice partially recapitulate clinical observations in humans with major depressive disorder. The present findings indicate that 5-HTT-deficient mice serve as a good and valid animal model to study anxiety and depression with altered gut microbial composition and abnormal neuronal activity in the brain, highlighting the importance of 5-HTT in brain function and the mechanisms underlying the regulation of anxiety and depression.