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Interaction of the gut microbiota and brain functional connectivity in late-life depression.
BACKGROUND: Increasing evidence suggests an important role of the gut microbiome in the pathogenesis of mental disorders, including depression, along the microbiota-gut-brain axis. We sought to explore the interactions between gut microbe composition and neural circuits in late-life depression (LLD). METHODS: We performed fecal 16S ribosomal RNA (rRNA) sequencing and resting-state functional magnetic resonance imaging in a case-control cohort of older adults with LLD and healthy controls to characterize the association between gut microbiota and brain functional connectivity (FC). We used the Hamilton Depression Rating Scale (HAMD) to assess depressive symptoms. RESULTS: We included 32 adults with LLD and 16 healthy controls. At the genus level, the relative abundance of Enterobacter, Akkermansiaceae, Hemophilus, Burkholderia, and Rothia was significantly higher among patients with LDD than controls. Reduced FC within mood regulation circuits was mainly found in the frontal cortex (e.g., the right superior and inferior frontal gyrus, right lateral occipital cortex, left middle frontal gyrus, and left caudate) among patients with MDD. Group-characterized gut microbes among controls and patients showed opposite correlations with seed-based FC, which may account for the aberrant emotion regulation among patients with LDD. The abundance of Enterobacter (dominant genus among patients with LLD) was positively correlated with both HAMD scores (r = 0.49, p = 0.0004) and group-characterized FC (r = -0.37, p < 0.05), while Odoribacter (dominant genus among controls) was negatively correlated with both HAMD scores (r = -0.30, p = 0.04) and group-characterized FC. LIMITATIONS: The study's cross-sectional design and small sample size limit causal inferences; larger longitudinal studies are required for detailed subgroup analyses. CONCLUSION: We identified significant correlations between LDD-characterized gut microbes and brain FC, as well as depression severity, which may contribute to the pathophysiology of depression development among patients with LLD. Specific microbes were linked to altered brain connectivity, suggesting potential targets for treating LLD.
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Antidepressant treatment with fluoxetine during pregnancy and lactation modulates the gut microbiome and metabolome in a rat model relevant to depression.
Up to 10% of women use selective serotonin reuptake inhibitor (SSRI) antidepressants during pregnancy and postpartum. Recent evidence suggests that SSRIs are capable of altering the gut microbiota. However, the interaction between maternal depression and SSRI use on bacterial community composition and the availability of microbiota-derived metabolites during pregnancy and lactation is not clear. We studied this using a rat model relevant to depression, where adult females with a genetic vulnerability and stressed as pups show depressive-like behaviors. Throughout pregnancy and lactation, females received the SSRI fluoxetine or vehicle. High-resolution 16S ribosomal RNA marker gene sequencing and targeted metabolomic analysis were used to assess the fecal microbiome and metabolite availability, respectively. Not surprisingly, we found that pregnancy and lactation segregate in terms of fecal microbiome diversity and composition, accompanied by changes in metabolite availability. However, we also showed that fluoxetine treatment altered important features of this transition from pregnancy to lactation most clearly in previously stressed dams, with lower fecal amino acid concentrations. Amino acid concentrations, in turn, correlated negatively with the relative abundance of bacterial taxa such as Prevotella and Bacteroides. Our study demonstrates an important relationship between antidepressant use during the perinatal period and maternal fecal metabolite availability in a rat model relevant to depression, possibly through parallel changes in the gut microbiome. Since microbial metabolites contribute to homeostasis and development, insults to the maternal microbiome by SSRIs might have health consequences for mother and offspring.
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Mitochondria of intestinal epithelial cells in depression: Are they at a crossroads of gut-brain communication?
The role of gut dysbiosis in depression is well established. However, recent studies have shown that gut microbiota is regulated by intestinal epithelial cell (IEC) mitochondria, which has yet to receive much attention. This review summarizes the recent developments about the critical role of IEC mitochondria in actively maintaining gut microbiota, intestinal metabolism, and immune homeostasis. We propose that IEC mitochondrial dysfunction alters gut microbiota composition, participates in cell fate, mediates oxidative stress, activates the peripheral immune system, causes peripheral inflammation, and transmits peripheral signals through the vagus and enteric nervous systems. These pathological alterations lead to brain inflammation, disruption of the blood-brain barrier, activation of the hypothalamic-pituitary-adrenal axis, activation of microglia and astrocytes, induction of neuronal loss, and ultimately depression. Furthermore, we highlight the prospect of treating depression through the mitochondria of IECs. These new findings suggest that the mitochondria of IECs may be a newly found important factor in the pathogenesis of depression and represent a potential new strategy for treating depression.
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Linking the Triad of Telomere Length, Inflammation, and Gut Dysbiosis in the Manifestation of Depression.
Telomere length is an indispensable marker for cellular and biological aging, and it also represents an individual's physical and mental health status. Telomere shortening has been observed in chronic inflammatory conditions, which in turn accelerates aging and risk for psychiatric disorders, including depression. Considering the influence of inflammation and telomere shortening on the gut-brain axis, herein we describe a plausible interplay between telomere attrition, inflammation, and gut dysbiosis in the neurobiology of depression. Telomere shortening and hyperinflammation are well reported in depression. A negative impact of augmented inflammation has been noted on the intestinal permeability and microbial consortia and their byproducts in depressive patients. Moreover, gut dysbiosis provokes host-immune responses. As the gut microbiome is gaining importance in the manifestation and management of depression, herein we discuss whether telomere attrition is connected with the perturbation of commensal microflora. We also describe a pathological connection of cortisol with hyperinflammation, telomere shortening, and gut dysbiosis occurring in depression. This review summarizes how the triad of telomere attrition, inflammation, and gut dysbiosis is interconnected and modulates the risk for depression by regulating the systemic cortisol levels.
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Depression linked to the microbiome.
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Gut microbiota, immune cells, and postpartum depression: A mediation Mendelian randomization study.
BACKGROUND: Recent studies suggest links between the gut microbiome, immune cells, and postpartum depression (PPD), but causal relationships are unclear. This study employed the Mendelian randomization (MR) to explore the causal relationship and mediating effect among the three factors. METHODS: Summary data from genome-wide association studies were analyzed using MR techniques, including inverse variance weighted, weighted median, MR-Egger, simple mode, and weighted mode. Mediation analysis was conducted to assess the roles of immune cells and gut microbiota in PPD. Sensitivity tests were performed to verify the stability of the findings. RESULTS: The analysis results showed that there were 26 positive correlations (risk factors) (OR > 1, p < 0.05) and 19 negative correlations (protective factors) (OR < 1, p < 0.05) between immune cell traits and PPD. In addition, there were 13 positive correlations (OR > 1, p < 0.05) and 20 negative correlations (OR < 1, p < 0.05) between gut microbiota and PPD. Additionally, 6 relationships were identified with the gut microbiota serving as mediators, among them, "GCA-900066755" increased the risk of PPD via "CD45RA- CD4+ T cell %T cell" (9.4 %). With immune cells acting as mediators, "CD4+ CD8dim T cell Absolute Count" was found to reduce the risk of "Holdemania sp900120005" on PPD (25.8 %). Sensitivity tests corroborated the reliability of the findings. CONCLUSION: This MR study indicates a causal relationship among immune cells, gut microbiota, and PPD. It clarifies the mediating roles of immune cells and gut microbiota in PPD, offering new insights into the underlying mechanisms for PPD.
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The Gut Microbiota Is Altered in Antidepressant-Free Depressed Patients and Is Associated With Depression Severity.
Interest in the microbiota-gut-brain axis is increasing, but data on the associations between the microbiota and major depressive disorder (MDD), particularly in relation to symptomatology and treatment response, remain scarce and inconsistent. This study aims at characterizing the gut microbiota of antidepressant-free MDD patients with a Major Depressive Episode (MDE) in comparison to healthy controls (HCs) and to investigate whether microbiota composition is associated with depression severity. Twenty-five adults with a current MDE, who had been antidepressant-free for at least 1 month, were evaluated for both depression severity and fecal microbiota composition using 16S rRNA sequencing. Their microbiota profiles were compared with those of twenty-eight HCs. Psychiatric assessments were conducted at baseline using the Hamilton Depression Rating Scale (HDRS) and the Clinical Global Impression (CGI) scale. Compared to HCs, MDE patients showed no significant differences in microbial alpha diversity. However, alterations in the relative abundance of several taxa, including Lachnospiraceae and Bifidobacteriaceae, along with an increase in Bifidobacterium, were detected. Beta-diversity analyses (PCoA plot) identified two distinct compositional clusters. Significant alterations were found in 7 out of 25 families and 20 out of 61 genera, with a notable decrease of the Lachnospiraceae NK4A136 genus in MDE patients, which was associated with worse symptom severity. These findings reveal distinct alterations in the gut microbiota of antidepressant-free MDE patients compared to HCs, particularly in key phyla and families. They suggest that the gut microbiota may represent a novel target for the management and treatment of MDD.
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Mood Disorders: The Gut Bacteriome and Beyond.
Knowledge of the microbiome-gut-brain axis has revolutionized the field of psychiatry. It is now well recognized that the gut bacteriome is associated with, and likely influences, the pathogenesis of mental disorders, including major depressive disorder and bipolar disorder. However, while substantial advances in the field of microbiome science have been made, we have likely only scratched the surface in our understanding of how these ecosystems might contribute to mental disorder pathophysiology. Beyond the gut bacteriome, research into lesser explored components of the gut microbiome, including the gut virome, mycobiome, archaeome, and parasitome, is increasingly suggesting relevance in psychiatry. The contribution of microbiomes beyond the gut, including the oral, lung, and small intestinal microbiomes, to human health and pathology should not be overlooked. Increasing both our awareness and understanding of these less traversed fields of research are critical to improving the therapeutic benefits of treatments targeting the gut microbiome, including fecal microbiome transplantation, postbiotics and biogenics, and dietary intervention. Interdisciplinary collaborations integrating systems biology approaches are required to fully elucidate how these different microbial components and distinct microbial niches interact with each other and their human hosts. Excitingly, we may be at the start of the next microbiome revolution and thus one step closer to informing the field of precision psychiatry to improve outcomes for those living with mental illness.
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Dynamic alterations of depressive-like behaviors, gut microbiome, and fecal metabolome in social defeat stress mice.
Gut microbiome is implicated in the onset and progression of major depressive disorder (MDD), but the dynamic alterations of depressive symptoms, gut microbiome, and fecal metabolome across different stages of stress exposure remain unclear. Here, we modified the chronic social defeat stress (CSDS) model to evaluate mice subjected to social defeat stress for 1, 4, 7, and 10 days. Behavioral tests, 16S rRNA, metagenomics, and fecal metabolomics were conducted to investigate the impact of stress exposure on behaviors, gut microbiota and fecal metabolites. We observed that depressive-like behaviors, such as anhedonia and social avoidance, worsened significantly as stress exposure increased. The microbial composition, function, and fecal metabolites exhibited distinct separations across the different social defeat stress groups. Mediation analysis identified key bacteria, such as Lachnospiraceae_UCG-001 and Bacteroidetes, and fecal metabolites like valeric acid and N-acetylaspartate. In our clinical depression cohort, we confirmed that fecal valeric acid levels, were significantly lower in depressive-like mice and MDD patients, correlating closely with stress exposure and anhedonia in mice. Further analysis of serum and brain metabolites in mice revealed sustained changes of N-acetylaspartate abundance in fecal, serum, and cortical samples following increasing stress exposure. Together, this study elucidated the characteristics of depressive-like behaviors, gut microbiome, and fecal metabolome across various social defeat stress exposure, and identified key bacteria and fecal metabolites potentially involved in modulating social defeat stress response and depressive-like behaviors, providing new insights into the pathogenesis and intervention of depression.
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Lignans Alleviate Depression by Modulating the Gut-Brain Axis: Effect and Mechanism Based on Multi-Omics Analyses.
Major depressive disorder (MDD) is a highly disabling psychiatric illness characterized by persistent low mood and psychomotor retardation, often leading to cognitive impairment or even suicidality. As the pathogenesis remains poorly understood, the currently available treatment regimens are mostly symptomatic therapies with little satisfactory curative effect. The emerging paradigm of gut-brain axis has highlighted gut dysbiosis as a key etiological factor to elicit neuro-inflammation and jeopardize the central nervous system homeostasis. In this study, we evaluated the ameliorating effects of flaxseed lignans on the gut microbiome to regain the gut micro-environmental functionality and alleviate MDD. The lignans significantly mitigated the severity of disease and markedly altered the gut microbiota structure in the participants. In the MDD mouse model, the lignans reversed the experimental depression-like behaviors, repaired neural and gut damage and restored barrier integrity. Of great significance, the lignans elevated the levels of 5-hydroxytryptamine (5-HT), brain-derived neurotrophic factor (BDNF) and γ-aminobutyric acid (GABA), and markedly attenuated microglial and systemic inflammation. Mechanistically, the lignans inhibited the IL-17/AP-1/NF-κB axis through direct interaction with the Fos protein. In the BV-2 cells, the lignan enterolactone reduced levels of nitric oxide and pro-inflammatory cytokines, further validating the anti-inflammatory mechanism of the lignans. Together, these findings demonstrate that lignans exert potent antidepressant effects by modulating the gut-brain axis and resolving neuro-inflammation, providing useful information for the development of novel therapeutic strategies for MDD prevention and treatment.