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Comprehensive analysis of the lysine acetylome and succinylome in the hippocampus of gut microbiota-dysbiosis mice.
INTRODUCTION: Major depressive disorder is caused by gene-environment interactions, and the host microbiome has been recognized as an important environmental factor. However, the underlying mechanisms of the host-microbiota interactions that lead to depression are complex and remain poorly understood. OBJECTIVES: The present study aimed to explore the possible mechanisms underlying gut microbiota dysbiosis-induced depressive-like behaviors. METHODS: We used high-performance liquid chromatography-tandem mass spectrometry to analyze alterations in the hippocampal lysine acetylome and succinylome in male mice that had received gut microbiota from fecal samples of either patients with major depressive disorder or healthy controls. This was followed by bioinformatic analyses. RESULTS: A total of 315 acetylation sites on 223 proteins and 624 succinylation sites on 494 proteins were differentially expressed in the gut microbiota-dysbiosis mice. The significantly acetylated proteins were primarily associated with carbon metabolism disruption and gene transcription suppression, while the synaptic vesicle cycle and protein translation were the most significantly altered functions for succinylated proteins. Additionally, our findings suggest that gut microbiota dysbiosis disturbs mitochondria-mediated biological processes and the MAPK signaling pathway through crosstalk between acetylation and succinylation on relevant proteins. CONCLUSIONS: This is the first study to demonstrate modifications in acetylation and succinylation in gut microbiota-dysbiosis mice. Our findings provide new avenues for exploring the pathogenesis of gut microbiota dysbiosis-related depression, and highlight potential targets for depression treatment.
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Bifidobacterium in the gut microbiota confer resilience to chronic social defeat stress in mice.
Accumulating evidence suggests that abnormalities in the composition of the gut microbiota may play a role in the pathogenesis of depression. Although approximately 30% mice are resilient to chronic social defeat stress (CSDS), the role of gut microbiota in this stress resilience is unknown. In this study, male C57BL/6 mice were exposed to a different CD1 aggressor mouse for 10 min on 10 consecutive days. A social interaction test was applied to distinguish between resilient and susceptible mice. Using 16S rRNA analysis, we examined the composition of gut microbiota in feces from control, resilient, and susceptible mice. The marked appearance of Bifidobacterium was detected in the resilient mice, whereas in the control and susceptible mice, Bifidobacterium were below the detection limit. Oral intake of Bifidobacterium significantly increased the number of resilient mice after CSDS compared with vehicle-treated mice. These findings suggest that Bifidobacterium may confer resilience to CSDS. Therefore, supplementation of Bifidobacterium may prevent the onset of depression from stress in humans. In addition, supplementation of Bifidobacterium may prevent or minimize relapse from remission induced by inflammation and/or stress in depressed patients.
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Alterations of gut microbiota composition in post-finasteride patients: a pilot study.
PURPOSE: Post-finasteride syndrome (PFS) has been reported in a subset of patients treated with finasteride (an inhibitor of the enzyme 5alpha-reductase) for androgenetic alopecia. These patients showed, despite the suspension of the treatment, a variety of persistent symptoms, like sexual dysfunction and cognitive and psychological disorders, including depression. A growing body of literature highlights the relevance of the gut microbiota-brain axis in human health and disease. For instance, alterations in gut microbiota composition have been reported in patients with major depressive disorder. Therefore, we have here analyzed the gut microbiota composition in PFS patients in comparison with a healthy cohort. METHODS: Fecal microbiota of 23 PFS patients was analyzed by 16S rRNA gene sequencing and compared with that reported in ten healthy male subjects. RESULTS: Sexual dysfunction, psychological and cognitive complaints, muscular problems, and physical alterations symptoms were reported in more than half of the PFS patients at the moment of sample collection. The quality sequence check revealed a low library depth for two fecal samples. Therefore, the gut microbiota analyses were conducted on 21 patients. The α-diversity was significantly lower in PFS group, showing a reduction of richness and diversity of gut microbiota structure. Moreover, when visualizing β-diversity, a clustering effect was found in the gut microbiota of a subset of PFS subjects, which was also characterized by a reduction in Faecalibacterium spp. and Ruminococcaceae UCG-005, while Alloprevotella and Odoribacter spp were increased compared to healthy control. CONCLUSION: Gut microbiota population is altered in PFS patients, suggesting that it might represent a diagnostic marker and a possible therapeutic target for this syndrome.
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Alterations of short-chain fatty acids in depression and effects of probiotics/prebiotics interventions on levels and clinical symptoms: a systematic review and meta-analysis.
BACKGROUND: Short-chain fatty acids (SCFAs) are essential metabolites in the interaction between gut microbiota and the host. Recently, they have been implicated in the development of major depressive disorder (MDD). However, the alterations of SCFAs in the blood and feces of individuals with depression are still debated. Additionally, it is uncertain whether interventions targeting gut microbiota can reverse these changes. This research aims to investigate the variations of SCFAs in depression and assess the effects of probiotic and prebiotic interventions on SCFA levels and clinical symptoms. METHODS: This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We conducted a comprehensive search across databases including PubMed, Cochrane Library, Web of Science, Embase, PsycINFO, Wanfang Data, CNKI, VIP, and SinoMed. The search encompassed all published articles from their inception to March 13, 2026. RESULTS: This study synthesized evidence from 16 case-control studies and 6 randomized controlled trials (RCTs) through a systematic review and meta-analysis. The case-control analysis found significantly lower plasma levels of acetate (SMD = -0.51, 95% CI [-0.86, -0.15]), propionate (SMD = -0.65, 95% CI [-1.06, -0.25]), butyrate (SMD = -0.43, 95% CI [-0.72, -0.15]), and valerate(SMD = -1.09, 95% CI [-2.02, -0.17]) in individuals with depression compared to healthy controls. In fecal samples, no significant differences were found in the three main SCFAs, but fecal valerate was decreased and isobutyrate was increased. The RCT analysis showed that probiotic and prebiotic interventions, compared to placebo, significantly increased fecal levels of acetate (SMD = 0.58, 95% CI [0.07, 1.08]), propionate (SMD = 0.55, 95% CI [0.19, 0.91]), butyrate (SMD = 0.47, 95% CI [0.10, 0.85]) and isobutyrate(SMD = 0.64, 95% CI [0.41, 0.87]), and SCFA elevation was associated with improved depressive symptoms. CONCLUSION: MDD patients have significantly lower circulating levels of the main SCFAs (acetate, propionate, butyrate) and valerate, with distinct fecal changes (decreased valerate, increased isobutyrate). The results indicated that depression primarily associated with reduced circulating levels of SCFAs. However, intestinal microecological interventions partially regulated fecal SCFAs. This study offered preliminary evidence suggesting SCFAs as potential exploratory biomarkers for depression and their possible association with the gut microbiota-mood axis. Further validation through larger, standardized research is necessary. REGISTRY: PROSPERO, TRN: CRD420251251955.
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Microbiota matters: a cross-sectional study protocol for mapping gut microbiome diversity in Malaysian major depressive disorder cases.
INTRODUCTION: Mental health is now recognised as a major global concern affecting people from diverse backgrounds. There is growing evidence that the gut microbiota plays a crucial role by producing metabolites that significantly influence a person's mood and behaviour. Despite its importance, there is a significant gap in the profiling and understanding of the gut microbiota's influence on mental health among Malaysians. Therefore, this study aims to determine gut microbiome profiles among patients with major depressive disorders (MDD) of different treatment groups attending psychiatric clinics in the state hospitals and compare them to healthy individuals in the community of Klang Valley, Malaysia. METHODS AND ANALYSIS: This cross-sectional study will be carried out in Klang Valley, Malaysia. Eligibility of the patients will be assessed by the psychiatrists prior to recruitment of patients. Patients with MDD will be categorised into monotherapy and polypharmacy while healthy individuals will be used as a comparison group. Demographic data will be recorded. Stool samples will be subjected to DNA extraction and 16S rRNA gene-sequencing analysis to determine the microbial compositions of the gut microbiome. ETHICS AND DISSEMINATION: This study will be conducted following the procedure set by the National Medical Research Register Malaysia. The Medical Research Ethics Committee (MREC), Ministry of Health Malaysia, has ratified this study and granted ethical approval to conduct this study (NMRR ID-22-00893-JVW). All the participants will be given an information sheet and will sign a consent form to participate. Participants have the right to withdraw from the study at any time without an explanation. All information gathered will be used for research purposes only and treated as confidential. The results will be submitted to peer-reviewed journals for publication as well as presented at national and international conferences. Informing policy makers at all levels is a crucial aspect of the dissemination and will be done from local to international levels. TRIAL REGISTRATION NUMBER: This study was registered under National Medical Research Register Malaysia (NMRR ID-22-00893-JVW), a mandatory procedure of the Ministry of Health Malaysia before the start of a research.
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Unraveling microbial signatures in the comorbidity of autoimmune diseases and depression.
BACKGROUND: Depression is a common comorbidity in autoimmune diseases (ADs), including inflammatory bowel disease (IBD), a well-characterized AD with prominent gut involvement and strong host-microbiome interactions. Yet, its underlying microbial associations remain insufficiently understood. This study aimed to explore the gut microbial composition and function in patients with ADs comorbid depression, including a subgroup with IBD comorbid depression, and to identify potential microbial and metabolic signatures associated with this comorbidity. METHODS: We analyzed two curated cohorts from the American Gut Project: an AD cohort (n = 344; AD with depression: n = 115, AD without depression: n = 120, healthy controls: n = 109), and an IBD subgroup (n = 75; IBD with depression: n = 25, IBD without depression: n = 30, healthy controls: n = 20). Gut microbial profiles were evaluated using 16S rRNA gene sequencing (V4 region). Microbial diversity was assessed via α- and β-diversity indices. Differential abundance analysis was conducted using Linear Discriminative Analysis Effect Size (LEfSe) and Linear Discriminant Analysis (LDA) methods. Functional predictions were performed based on Kyoto Encyclopedia of Genes and Genomes (KEGG) orthology inference. Microbial co-occurrence networks were also constructed to explore taxonomic interaction patterns. RESULTS: In the AD cohort, β-diversity was significantly reduced in patients with comorbid depression compared to those without, whereas α-diversity did not show statistically significant differences. A total of 40 microbial taxa were significantly different between patients with AD comorbid depression and AD without depression. In the IBD subgroup, 12 taxa were differentially abundant between patients with and without depression. Functional pathway predictions suggested disruptions in carbohydrate metabolism, energy metabolism, and glycan biosynthesis in patients with AD and comorbid depression compared to those without depression. Microbial network analysis revealed distinct co-occurrence structures in patients with comorbid depression. CONCLUSIONS: This exploratory study suggests that individuals with ADs or IBD and comorbid depression exhibit distinct gut microbiome compositions and functional potentials compared to non-depressed counterparts. These associations may offer insights into gut-brain interactions in autoimmunity and mental health. However, due to the cross-sectional design, mechanistic and clinical inferences remain speculative and require validation in future studies.
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The Gut Microbiota-Astrocyte Axis: New Insights into the Mechanisms of Comorbid Major Depressive Disorder in Type 2 Diabetes Mellitus.
Type 2 diabetes mellitus (T2DM) and major depressive disorder (MDD) are two prevalent chronic conditions that interact bidirectionally, with their high comorbidity posing a serious global health challenge. Recent studies highlight the gut-brain axis, particularly the gut microbiota-astrocyte axis, as a key mechanism underlying this comorbidity. The review reveals a common gut dysbiosis pattern in both T2DM and MDD, marked by reduced short-chain fatty acids (SCFAs)-producing bacteria and elevated lipopolysaccharide (LPS)-associated pro-inflammatory bacteria. Nevertheless, the two diseases present opposing astrocytic states: overactivation in T2DM and inhibition in MDD. In the progression from T2DM to secondary MDD, microbiota dysbiosis induces astrocyte hyperactivation in the hippocampus and hypothalamus, which in turn reduces glutamine synthetase (GS) and brain-derived neurotrophic factor (BDNF), exacerbates neuroinflammation, promotes insulin resistance (IR) and hypothalamic-pituitary-adrenal (HPA) axis overactivation, and disrupts the glutamate-glutamine (Glu-Gln) cycle, ultimately culminating in MDD. Conversely, as MDD progresses to secondary T2DM, microbiota dysbiosis suppresses astrocyte activation in the hippocampus and prefrontal cortex, which similarly aggravates neuroinflammation, promotes IR, and disrupts the Glu-Gln cycle, thereby contributing to T2DM. Together, these results advance our knowledge of the bidirectional interplay between T2DM and MDD, while simultaneously identifying potential nodes for therapeutic modulation.
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Gut Microbiota Signatures Are Associated With Psychopathological Profiles in Patients With Ulcerative Colitis: Results From an Italian Tertiary IBD Center.
BACKGROUND: Several patients with ulcerative colitis (UC) suffer from psychiatric disorders, such as major depressive disorder, anxiety, or bipolar disorder, and show specific personality traits. Despite this, there are few data about personality profiles' characterization in UC patients and about correlation of their psychopathological profile with their intestinal microbiota.The aim of our study is to analyze the psychopathological and personality profile of UC patients and correlate it with specific signatures of their gut microbiota. METHODS: This is a prospective interventional longitudinal cohort study. We enrolled consecutive patients affected by UC attending to the IBD Unit of Center for Digestive Disease of "A. Gemelli" IRCCS Hospital in Rome and a group of healthy subjects, matched for specific characteristics. Each patient was evaluated by a gastroenterologist and a psychiatrist. Moreover, all participants underwent psychological tests and a collection of stool samples. RESULTS: We recruited 39 UC patients and 37 healthy subjects. Most patients showed high level of alexithymia, anxiety symptoms, depressive symptoms, as well as neuroticism and hypochondria, with obsessive-compulsive features at the behavioral level, which significantly impaired their quality of life and abilities at work. Gut microbiota analysis in UC patients demonstrated an increase in actinobacteria, Proteobacteria and Saccharibacteria (TM7), with a reduction in verrucomicrobia, euryarchaeota and tenericutes. CONCLUSIONS: Our study confirmed the presence of high levels of psycho-emotional distress in UC patients, alongside alterations of the intestinal microbiota, and highlighted some families and genera of bacteria (Enterobacteriaceae, Streptococcus, Veillonella, Klebsiella, and Clostridiaceae) as potential markers of an altered gut-brain axis in these patients.
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Associations between gut microbiota and Alzheimer's disease, major depressive disorder, and schizophrenia.
BACKGROUND: Growing evidence has shown that alterations in the gut microbiota composition were associated with a variety of neuropsychiatric conditions. However, whether such associations reflect causality remains unknown. We aimed to reveal the causal relationships among gut microbiota, metabolites, and neuropsychiatric disorders including Alzheimer's disease (AD), major depressive disorder (MDD), and schizophrenia (SCZ). METHODS: A two-sample bi-directional Mendelian randomization analysis was performed by using genetic variants from genome-wide association studies as instrumental variables for gut microbiota, metabolites, AD, MDD, and SCZ, respectively. RESULTS: We found suggestive associations of host-genetic-driven increase in Blautia (OR, 0.88; 95%CI, 0.79-0.99; P = 0.028) and elevated γ-aminobutyric acid (GABA) (0.96; 0.92-1.00; P = 0.034), a downstream product of Blautia-dependent arginine metabolism, with a lower risk of AD. Genetically increased Enterobacteriaceae family and Enterobacteriales order were potentially associated with a higher risk of SCZ (1.09; 1.00-1.18; P = 0.048), while Gammaproteobacteria class (0.90; 0.83-0.98; P = 0.011) was related to a lower risk for SCZ. Gut production of serotonin was potentially associated with an increased risk of SCZ (1.07; 1.00-1.15; P = 0.047). Furthermore, genetically increased Bacilli class was related to a higher risk of MDD (1.07; 1.02-1.12; P = 0.010). In the other direction, neuropsychiatric disorders altered gut microbiota composition. CONCLUSIONS: These data for the first time provide evidence of potential causal links between gut microbiome and AD, MDD, and SCZ. GABA and serotonin may play an important role in gut microbiota-host crosstalk in AD and SCZ, respectively. Further investigations in understanding the underlying mechanisms of associations between gut microbiota and AD, MDD, and SCZ are required.
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Shouhui Tongbian capsule is associated with antidepressant-like effects and gut-brain axis-related biological improvements in mouse models of depression.
BACKGROUND: Major depressive disorder (MDD) is a global health challenge with complex etiology. The gut-brain axis, particularly neuroinflammation and synaptic dysfunction, has emerged as a critical therapeutic target. Shouhui Tongbian Capsule (SHTB), a clinically used Chinese patent medicine for constipation, has shown potential in modulating gut microbiota and alleviating comorbid mood symptoms, yet its systemic antidepressant mechanisms remain unexplored. PURPOSE: This study aimed to evaluate the antidepressant-like effects of SHTB in mouse models and characterize accompanying gut- and brain-related biological changes. STUDY DESIGN AND METHODS: Network pharmacology was used to assess whether reported SHTB constituents were relevant to depression-related gene networks. Subsequent in vivo validation was conducted in lipopolysaccharide (LPS)-induced and chronic unpredictable mild stress (CUMS) mouse models of depression. Behavioral phenotypes, neuroinflammation, hippocampal neuronal and synaptic integrity, intestinal barrier function, and mRNA expression of selected predicted targets were evaluated. RESULTS: Exploratory network analysis indicated potential associations between reported SHTB constituents and depression-related gene networks, providing a preliminary rationale for animal experiments. In vivo, SHTB administration was associated with significant improvements in depressive- and anxiety-like behaviors in both LPS and CUMS-induced mouse models of depression. These behavioral effects were accompanied by attenuation of neuroinflammatory responses, preservation of hippocampal neuronal and synaptic features, maintenance of intestinal barrier integrity, and altered hippocampal expression of several neurotransmitter-related genes. CONCLUSION: SHTB showed significant antidepressant-like effects accompanied by gut-brain axis-related biological improvements. This study provides a novel, multi-evidence rationale for repurposing SHTB as a promising multi-target therapeutic agent for MDD, mediated via the gut-brain axis.