Gut microbiome and major depressive disorder: insights from two-sample Mendelian randomization.

BACKGROUND: Existing evidence suggests that alterations in the gut microbiome are closely associated with major depressive disorder (MDD). We aimed to reveal the causal relationships between MDD and various microbial taxa in the gut. METHODS: We used the two-sample Mendelian randomization (TSMR) to explore the bidirectional causal effects between gut microbiota and MDD. The genome-wide association studies summary results of gut microbiota were obtained from two large consortia, the MibioGen consortium and the Dutch Microbiome Project, which we analyzed separately. RESULTS: Our TSMR analysis identified 10 gut bacterial taxa that were protective against MDD, including phylum Actinobacteria, order Clostridiales, and family Bifidobacteriaceae (OR: 0.96 ∼ 0.98). Ten taxa were associated with an increased risk of MDD, including phyla Firmicutes and Proteobacteria, class Actinobacteria, and genus Alistipes (OR: 1.01 ∼ 1.09). On the other hand, MDD may decrease the abundance of 12 taxa, including phyla Actinobacteria and Firmicutes, families Bifidobacteriaceae and Defluviitaleaceae (OR: 0.63 ∼ 0.88). MDD may increase the abundance of 8 taxa, including phylum Bacteroidetes, genera Parabacteroides, and Bacteroides (OR: 1.12 ∼ 1.43). CONCLUSIONS: Our study supports that there are mutual causal relationships between certain gut microbiota and the development of MDD suggesting that gut microbiota may be targeted in the treatment of MDD.

Gut microbiota and inflammatory factor characteristics in major depressive disorder patients with anorexia.

BACKGROUND: This study aimed to explore the gut microbiota and inflammatory factor characteristics in major depressive disorder (MDD) patients with anorexia and to analyze the correlation between gut microbiota and inflammatory factors, anorexia, and HAMD scores. METHODS: 46 MDD patients and 46 healthy controls (HC) were included in the study. The 46 MDD patients were divided into two groups according to whether they had anorexia:20 MDD without anorexia (MDA0 group) and 26 MDD with anorexia (MDA1 group). We used the Hamilton Depression Scale-24 (HAMD-24) to evaluate the depression status of all participants and 16 S ribosomal RNA (16 S rRNA)sequencing to evaluate the composition of the gut microbiota. Inflammatory factors in peripheral blood such as C-reactive protein (CRP) were detected using enzyme-linked immunosorbent assay (ELISA). Spearman's correlation analysis was used to evaluate the correlation between gut microbiota and inflammatory factors, HAMD scores, and anorexia. RESULTS: 1). CRP was significantly higher in the MDA0, MDA1, than HC. 2). An analysis of α-diversity shows: the Simpson and Pielou indices of the HC group are higher than the MDA1 group (P < 0.05). 3). The ß-diversity analysis shows differences in the composition of microbial communities between the MDA0, MDA1, and HC group. 4). A correlation analysis showed that Blautia positively correlated with anorexia, HAMD scores, and CRP level, whereas Faecalibacterium, Bacteroides, Roseburia, and Parabacteroides negatively correlated with anorexia, HAMD scores, and CRP level. 5). The receiver operating characteristic (ROC) curve was drawn using the differential bacterial genera between MDD patients with or without anorexia as biomarkers to identify whether MDD patients were accompanied with anorexia, and its area under curve (AUC) was 0.85. The ROC curve was drawn using the differential bacterial genera between MDD patients with anorexia and healthy controls as biomarkers to diagnose MDD patients with anorexia, with its AUC was 0.97. CONCLUSION: This study suggested that MDD patients with anorexia had a distinct gut microbiota compared to healthy individuals, with higher level of CRP. Blautia was more abundant in MDD patients with anorexia and positively correlated with CRP, HAMD scores, and anorexia. The gut microbiota might have influenced MDD and anorexia through the inflammatory factor CRP.

The Microbiome in Child and Adolescent Psychiatry.

Recent research has increasingly emphasized the function of the microbiome in human health. The gut microbiome is essential for digesting food and seems to play a vital role in mental health as well. This review briefly overviews the gut microbiome and its interplay with the central nervous system. We then summarize some of the latest findings on the possible role of the microbiome in psychiatric disorders in children and adolescents. In particular, we focus on autism spectrum disorder, attention-deficit/hyperactivity disorder, anorexia nervosa, bipolar disorder, and major depressive disorder. Although the role of microbiota in mental development and health still needs to be researched intensively, it has become increasingly apparent that the impact of microbiota must be considered to better understand psychiatric disorders.

Characteristics of gut microbiota and its correlation with hs-CRP and somatic symptoms in first-episode treatment-naive major depressive disorder.

OBJECTIVE: Most patients with major depressive disorder (MDD) have somatic symptoms, but little studies pay attention in the microbial-inflammatory mechanisms of these somatic symptoms. Our study aimed to investigate alterations in gut microbiota and its correlation with inflammatory marker levels and somatic symptoms in first-episode treatment-naive MDD. METHODS: Subjects contained 160 MDD patients and 101 healthy controls (HCs). MDD patients were divided into MDD with somatic symptoms group (MDDS) and MDD without somatic symptoms group (MDDN) based on Somatic Self-rating Scale (SSS). 16S ribosomal RNA sequencing were performed to analyze the composition of the fecal microbiota. The inflammatory factors were measured using enzyme linked immunosorbent assay (ELISA). Correlation among the altered gut microbiota, inflammatory factor and severity of clinical symptoms were analysized. RESULTS: Relative to HCs, MDD patients had higher levels of high-sensitivity C-reactive protein (hs-CRP) as well as disordered α-diversity and ß-diversity of gut microbiota. Linear discriminant effect size (LEfSe) analysis showed that MDD patients had higher proportions of Bifidobacterium, Blautia, Haemophilus and lower proportions of Bacteroides, Faecalibacterium, Roseburia, Dialister, Sutterella, Parabacteroides, Bordetella, and Phascolarctobacterium from the genus aspect. Furthermore, correlation analysis showed Bacteroides and Roseburia had negative correlations with the hs-CRP, HAMD-24, the total and factor scores of SSS in all participants. Further, compared with MDDN, the Pielous evenness was higher in MDDS. Random Forest (RF) analysis showed 20 most important genera discriminating MDD-S and MDDN, HCs. The ROC analysis showed that the AUC was 0.90 and 0.81 combining these genera respectively. CONCLUSION: Our study manifested MDD patients showed disordered gut microbiota and elevated hs-CRP levels, and altered gut microbiota was closely associated with hs-CRP, depressive symptoms, and somatic symptoms.

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.

A comprehensive analysis of the differential expression in the hippocampus of depression induced by gut microbiota compared to traditional stress.

Depression, which is a disease of heterogeneous etiology, is characterized by high disability and mortality rates. Gut microbiota are associated with the development of depression. To further explore any differences in the mechanisms of depression induced by gut microbiota and traditional stresses, as well as facilitate the development of microbiota-based interventions, a fecal microbiota transplantation (FMT) depression model was made. This was achieved by transplanting feces from major depressive disorder (MDD) patients into germ-free mice. Second, the mechanisms of the depression induced by gut microbiota were analyzed in comparison with those of the depression caused by different forms of stress. It turned out that mice exhibited depressive-like behavior after FMT. Then, PCR array analysis was performed on the hippocampus of the depressed mice to identify differentially expressed genes (DEGs). The KEGG analysis revealed that the pathways of depression induced by gut microbes are closely associated with immuno-inflammation. To determine the pathogenic pathways of physiological stress and psychological stress-induced depression, raw data was extracted from several databases and KEGG analysis was performed. The results from the analysis revealed that the mechanisms of depression induced by physiological and psychological stress are closely related to the regulation of neurotransmitters and energy metabolism. Interestingly, the immunoinflammatory response was distinct across different etiologies that induced depression. The findings showed that gut microbiota dysbiosis-induced depression was mainly associated with adaptive immunity, while physiological stress-induced depression was more linked to innate immunity. This study compared the pathogenesis of depression caused by gut microbiota dysbiosis, and physiological and psychological stress. We explored new intervention methods for depression and laid the foundation for precise treatment.

A further examination of growth factors, T helper 1 polarization, and the gut microbiome in major depression: Associations with reoccurrence of illness, cognitive functions, suicidal behaviors, and quality of life.

Growth factors, T helper (Th)1 polarization, and the microbiome are involved in the pathophysiology of major depression (MDD). It remains unclear whether the combination of these three pathways could enhance the accuracy of predicting the features of MDD, including recurrence of illness (ROI), suicidal behaviors and the phenome. We measured serum stem cell factor (SCF), stem cell growth factor (SCGF), stromal cell-derived factor-1 (SDF-1), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), macrophage-colony stimulating factor (M-CSF) and vascular endothelial growth factor (VEGF), the ratio of serum Th1/Th2 cytokines (zTh1-zTh2), and the abundances of gut microbiome taxa by analyzing stool samples using 16S rDNA sequencing from 32 MDD patients and 37 healthy controls. The results show that serum SCF is significantly lower and VEGF increased in MDD. Adverse childhood experiences (ACE) and ROI are significantly associated with lowered SCF and increasing VEGF. Lifetime and current suicidal behaviors are strongly predicted (63.5%) by an increased VEGF/SCF ratio, Th1 polarization, a gut microbiome enterotype indicating gut dysbiosis, and lowered abundance of Dorea and Faecalobacterium. Around 80.5% of the variance in the phenome's severity is explained by ROI, ACEs, and lowered Parabacteroides distasonis and Clostridium IV abundances. A large part of the variance in health-related quality of life (54.1%) is explained by the VEGF/SCF ratio, Th1 polarization, ACE, and male sex. In conclusion, key features of MDD are largely predicted by the cumulative effects of ACE, Th1 polarization, aberrations in growth factors and the gut microbiome with increased pathobionts but lowered beneficial symbionts.

Just a gut feeling: Faecal microbiota transplant for treatment of depression - A mini-review.

BACKGROUND: The microbiota-gut-brain axis (MGBA) allows bidirectional crosstalk between the brain and gut microbiota (GM) and is believed to contribute to regulating mood/cognition/behaviour/metabolism/health and homeostasis. Manipulation of GM through faecal microbiota transplant (FMT) is a new, exciting and promising treatment for major depressive disorder (MDD). AIMS: This mini-review examines current research into GM and FMT as a therapy for depression. METHODS: Original research articles published in Medline/Cochrane Library/PubMed/EMBASE/PsycINFO databases/National Institute of Health website Clinicaltrials.gov/controlled-trials.com were searched. Full articles included in reference lists were evaluated. We summarise current data on GM and depression and discuss communication through the MGBA and the interaction of antidepressants and GM through this. We review compositions of dysbiosis in depressed cohorts, focusing on future directions in the treatment of MDD. RESULTS: Studies have demonstrated significant gut dysbiosis in depressed patients compared to healthy cohorts, with overgrowth of pro-inflammatory microbiota, reduction in anti-inflammatory species and reduced overall stability and taxonomic richness. FMT allows the introduction of healthy microbiota into the gastrointestinal tract, facilitating the restoration of eubiosis. CONCLUSION: The GM plays an integral role in human health and disease through its communication with the rest of the body via the MGBA. FMT may provide a means to transfer the healthy phenotype into the recipient and this concept in humans is attracting enormous attention as a prospective treatment for psychopathologies, such as MDD, in the future. It may be possible to manipulate the GM in a number of ways, but further research is needed to determine the exact likelihood and profiles involved in the development and amelioration of MDD in humans, as well as the long-term effects and potential risks of this procedure.

Relationships between the gut microbiome and brain functional alterations in first-episode, drug-naïve patients with major depressive disorder.

OBJECTIVE: Increasing evidence has shown that the microbiota-gut-brain axis (MGB) is involved in the mechanism of major depressive disorder (MDD). However, the relationship between the gut microbiome and brain function in MDD patients has not been determined. Here, we intend to identify specific changes in the gut microbiome and brain function in first-episode, drug-naïve MDD patients and then explore the associations between the two omics to elucidate how the MGB axis plays a role in MDD development. METHODS: We recruited 38 first-episode, drug-naïve MDD patients and 37 healthy controls (HC). The composition of the fecal microbiome and neural spontaneous activity alterations were examined using 16S rRNA gene amplicon sequencing analysis and regional homogeneity (ReHo). Spearman correlation analyses were conducted to assess the associations between the gut microbiome and brain function. RESULTS: Compared with HC, MDD patients exhibited distinct alterations in the gut microbiota and elevated ReHo in the frontal regions. In the MDD group, a positive relationship was noted between the relative abundance of Blautia and the HAMD-17 and HAMA scores, as well as between the relative abundance of Oxalobacteraceae and the HAMD-17 score. The relative abundances of Porphyromonadaceae and Parabacteroides were negatively correlated with the ReHo values of frontal regions. LIMITATIONS: Our study utilized a cross-sectional design, and the number of subjects was relatively small. CONCLUSION: We found that some specific gut microbiomes were associated with frontal function, and others were associated with clinical symptoms in MDD patients, which may support the role of the MGB axis underlying MDD.

Research Progress on Mechanisms of Modulating Gut Microbiota to Improve Symptoms of Major Depressive Disorder.

Major depressive disorder (MDD) is a clinical condition that significantly impacts patients' physical and mental well-being, quality of life, and social functioning. The pathogenesis of MDD remains unclear, but accumulating evidence suggests a close relationship between gut microbiota and the occurrence and progression of MDD. Gut microbiota refers to the microbial community in the human intestine, which engages in bidirectional communication with the host via the "gut-brain axis" and plays a pivotal role in influencing the host's metabolism, immune system, endocrine system, and nervous system. Modulating gut microbiota entails restoring the balance and function of the intestinal flora through methods such as probiotic intake, fecal transplantation, and dietary intervention. Such modulation has been shown to effectively alleviate depressive symptoms in the host. This review synthesizes recent advancements in research on gut microbiota modulation for ameliorating depressive symptoms and can serve as a foundation for further exploration of the gut microbiota's role in MDD and its potential therapeutic benefits.

Gut proinflammatory bacteria is associated with abnormal functional connectivity of hippocampus in unmedicated patients with major depressive disorder.

Accumulating evidence has revealed the gut bacteria dysbiosis and brain hippocampal functional and structural alterations in major depressive disorder (MDD). However, the potential relationship between the gut microbiota and hippocampal function alterations in patients with MDD is still very limited. Data of resting-state functional magnetic resonance imaging were acquired from 44 unmedicated MDD patients and 42 demographically matched healthy controls (HCs). Severn pairs of hippocampus subregions (the bilateral cornu ammonis [CA1-CA3], dentate gyrus (DG), entorhinal cortex, hippocampal-amygdaloid transition area, and subiculum) were selected as the seeds in the functional connectivity (FC) analysis. Additionally, fecal samples of participants were collected and 16S rDNA amplicon sequencing was used to identify the altered relative abundance of gut microbiota. Then, association analysis was conducted to investigate the potential relationships between the abnormal hippocampal subregions FC and microbiome features. Also, the altered hippocampal subregion FC values and gut microbiota levels were used as features separately or together in the support vector machine models distinguishing the MDD patients and HCs. Compared with HCs, patients with MDD exhibited increased FC between the left hippocampus (CA2, CA3 and DG) and right hippocampus (CA2 and CA3), and decreased FC between the right hippocampal CA3 and bilateral posterior cingulate cortex. In addition, we found that the level of proinflammatory bacteria (i.e., Enterobacteriaceae) was significantly increased, whereas the level of short-chain fatty acids producing-bacteria (i.e., Prevotellaceae, Agathobacter and Clostridium) were significantly decreased in MDD patients. Furthermore, FC values of the left hippocampal CA3- right hippocampus (CA2 and CA3) was positively correlated with the relative abundance of Enterobacteriaceae in patients with MDD. Moreover, altered hippocampal FC patterns and gut microbiota level were considered in combination, the best discrimination was obtained (AUC = 0.92). These findings may provide insights into the potential role of gut microbiota in the underlying neuropathology of MDD patients.

Core antibiotic resistance genes mediate gut microbiota to intervene in the treatment of major depressive disorder.

INTRODUCTION: The relationship between depression and gut microbiota remains unclear, but an important role of gut microbiota has been verified. The relationship between gut microbiota and antibiotic resistance genes (ARGs) may be a potential new explanatory pathway. METHODS: We collected samples from 63 depressed patients and 30 healthy controls for metagenomic sequencing. The two groups' microbiota characteristics, functional characteristics, and ARG differences were analyzed. RESULTS: We obtained 30 differential KEGG orthologs (KOs) and their producers in 5 genera and 7 species by HUMAnN3. We found 6 KOs from Weissella_cibaria and Lactobacillus_plantaru are potentially coring functional mechanism of gut microbiota. Different metabolites including sphingolipids, pyrans, prenol lipids, and isoflavonoids also showed significance between MDD and HC. We detected 48 significantly different ARGs: 5 ARGs up-regulated and 43 ARGs down-regulated in MDD compared to HC. Based on Cox model results, Three ARGs significantly affected drug efficacy (ARG29, ARG105, and ARG111). Eggerthella, Weissella, and Lactobacillus were correlated with different core ARGs, which indicated different mechanisms in affecting MDD. LIMITATIONS: The present study needs to be replicated in different ethnic groups. At the same time, a larger Chinese cohort study and detailed experimental verification are also the key to further discussion. CONCLUSION: Our findings suggest that ARGs play a role in the interplay between major depressive disorder and gut microbiota. The role of ARGs should be taken into account when understanding the relationship between depression and gut microbiota.