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Altered gut bacterial-fungal interkingdom networks in children and adolescents with depression.
BACKGROUND: Most studies of the gut-brain axis have focused on bacteria; little is known about commensal fungi. Children and adolescents with depression were reported to have gut bacterial microbiota dysbiosis, but the role of the mycobiota has not been evaluated. METHODS: Faecal samples were obtained from 145 children and adolescents with depression and 110 age- and gender-matched healthy controls. We analysed the fungal microbiota, including in terms of their associations with the gut microbiota, and subjected the internal transcribed spacer 2 (ITS2) rRNA gene to mitochondrial sequencing. RESULTS: Our findings revealed unaltered fungal diversity, but altered taxonomic composition, of the faecal fungal microbiota in the children and adolescents with depression. Key fungi such as Saccharomyces and Apiotrichum were enriched in the depressed patients, while Aspergillus and Xeromyces showed significantly decreased abundance. Interestingly, the bacterial-fungal interkingdom network was markedly altered in the children and adolescents with depression, and mycobiome profiles were associated with different bacterial microbiomes. LIMITATION: The cross-sectional design precluded the establishment of a causal relationship between the gut mycobiota and the children and adolescents with depression. CONCLUSIONS: The gut mycobiome is altered in the children and adolescents with depression. Our findings suggest that fungi play an important role in the balance of the gut microbiota and may help identify novel therapeutic targets for depression.
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Bugs and Brains, the Gut and Mental Health Study: a mixed-methods study investigating microbiota composition and function in anxiety, depression and irritable bowel syndrome.
INTRODUCTION: Research has highlighted relationships between the micro-organisms that inhabit our gastrointestinal tract (oral and gut microbiota) with host mood and gastrointestinal functioning. Mental health disorders and functional gastrointestinal disorders co-occur at high rates, although the mechanisms underlying these associations remain unclear. The Bugs and Brains Study aims to investigate complex relationships between anxiety/depression and irritable bowel syndrome (IBS) in two ways. First, its primary component will compare the gut and oral microbiota in females with anxiety/depression and/or IBS relative to controls, and investigate underlying physiological, endocrine and immune factors, as well as associations with diet and psychosocial factors. In an ancillary component, the study will also investigate gastrointestinal and mental health symptoms in a larger sample, and explore relationships with diet, exercise, oral health, substance use, medical history, early life adversity and psychosocial factors. METHODS AND ANALYSIS: The Bugs and Brains Study aims to recruit 160 females to the primary component: (1) 40 controls; (2) 40 participants with a depressive/anxiety disorder, but no IBS; (3) 40 participants with IBS, but no depressive/anxiety disorder and (4) 40 participants with both depressive/anxiety disorder and IBS. Participation is completed within 1 month, and involves comprehensive questionnaires, anthropometrics, a diagnostic clinical interview, collection of two saliva samples, and stool, urine and hair samples. This study aims to use a systems biology approach to characterise oral and gut microbial composition and function using 16S rRNA gene sequencing and nuclear MR spectroscopy. As part of the ancillary component, it will collect questionnaire data from 1000 participants aged 18-40 years, capturing mental health, gastrointestinal health, oral health, diet and psychosocial factors. ETHICS AND DISSEMINATION: Approval was granted by the University of Melbourne Human Research Ethics Committee (#1749221). All participants voluntarily provided informed consent. Results will be published in peer-reviewed journals and presented at scientific conferences.
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Young versus aged microbiota transplants to germ-free mice: increased short-chain fatty acids and improved cognitive performance.
Aging is associated with cognitive decline and decreased concentrations of short-chain fatty acids (SCFAs) in the gut. SCFAs are significant in that they are protective to the gut and other organs. We tested the hypothesis that the aged gut microbiome alone is sufficient to decrease SCFAs in the host and produce cognitive decline. Fecal transplant gavages (FTGs) from aged (18-20 months) or young (2-3 months) male C57BL/6 mice into germ-free male C57BL/6 mice (N = 11 per group) were initiated at ~3 months of age. Fecal samples were collected and behavioral testing was performed over the study period. Bacterial community structures and relative abundances were measured in fecal samples by sequencing the bacterial 16S ribosomal RNA gene. Mice with aged and young microbiomes showed clear differences in bacterial β diversity at 30, 60, and 90 d (P = .001 for each) after FTGs. The fecal SCFAs, acetate, propionate, and butyrate (microbiome effect, P < .01 for each) were decreased in mice with an aged microbiome. Mice with an aged microbiome demonstrated depressive-like behavior, impaired short-term memory, and impaired spatial memory over the 3 months following the initial FTG as assessed by the tail suspension (P = .008), the novel object recognition (P < .001), and the Barnes Maze (P = .030) tests, respectively. We conclude that an aged microbiome alone is sufficient to decrease SCFAs in the host and to produce cognitive decline.
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Mapping the reciprocal interactions between antidepressants and the gut microbiome: novel targets for the personalisation and optimization of drug response.
Although accumulating evidence suggests a role of the gut microbiome in the response to antidepressant medications, its mechanistic basis is largely unknown. We performed a comprehensive analysis and presented an up-to-date atlas of the relationship between antidepressants and gut microbiome. The main findings were: 1. Treatment with antidepressants increases the abundance of anti-inflammatory species (e.g., Bifidobacterium) and decreases that of pro-inflammatory species (e.g., Escherichia_coli); 2. The nature of microbiome at baseline and of its changes following the start of treatment can be used to predict the efficacy of individual antidepressants. 3. Two sets of bacterial taxa (termed "Microhancers" and "Microlencers") are candidate pre-treatment targets for optimizing the therapeutic response. Two mechanisms that appear to underlie the modulation of the antidepressant treatment response are biotransformation and bioaccumulation, and these appear to be mediated by specific bacterial strains. These findings could support the personalisation of treatment by informing the selection of the best antidepressant for each individual. In addition, they suggest that the therapeutic response to antidepressants may be optimised by manipulating the gut microbiome prior to treatment.
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The characteristics of anhedonia in depression: a review from a clinically oriented perspective.
Anhedonia, as one of the core symptoms of major depressive disorder (MDD), has been regarded as a potential endophenotype of the disease. Multiple studies have evaluated the potential mechanisms of anhedonia in MDD, and found that MDD patients with anhedonia showed different functions in clinical features. In this review, we focus on the clinical research to explore the differences between MDD patients with and without anhedonia in the clinical manifestations and biological alterations, and elaborate the treatments and prognosis of anhedonia. It is demonstrated that anhedonia is associated with adverse outcomes including more severe depressive episode and suicidality, and poor prognosis in patients with MDD. At the biological level, MDD patients with anhedonia seem to present higher levels of inflammatory factors, abnormal metabolic function and hypermetabolism of BDNF. In brain imaging studies, there are some structural and/ or functional changes in multiple brain regions of subcortical and cortical areas, as well as the limbic system in MDD patients with anhedonia. Meanwhile, preliminary research findings have also indicated that there are associations between intestinal flora imbalance and anhedonia. Moreover, evidence indicated the benefit of some selective serotonin reuptake inhibitors seemed limited on anhedonia, and other treatments including psychotherapy, physical therapy and probiotic interventions has remained to be explored but has interesting potential. Therefore, increased awareness of the anhedonic symptoms and the unique clinical features would benefit improved early diagnosis and therapeutic effects in MDD.
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The Microbiota-Gut-Brain Axis in Depression: The Potential Pathophysiological Mechanisms and Microbiota Combined Antidepression Effect.
Depression is a kind of worldwide mental illness with the highest morbidity and disability rate, which is often accompanied by gastrointestinal symptoms. Experiments have demonstrated that the disorder of the intestinal microbial system structure plays a crucial role in depression. The gut-brain axis manifests a potential linkage between the digestion system and the central nervous system (CNS). Nowadays, it has become an emerging trend to treat diseases by targeting intestinal microorganisms (e.g., probiotics) and combining the gut-brain axis mechanism. Combined with the research, we found that the incidence of depression is closely linked to the gut microbiota. Moreover, the transformation of the gut microbiota system structure is considered to have both positive and negative regulatory effects on the development of depression. This article reviewed the mechanism of bidirectional interaction in the gut-brain axis and existing symptom-relieving measures and antidepression treatments related to the gut microbiome.
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A Microbial Relationship Between Irritable Bowel Syndrome and Depressive Symptoms.
Irritable bowel syndrome (IBS) is associated with depressive symptoms, but this relationship is poorly understood. Emerging research suggests that gut microbes are associated with symptoms in persons with IBS. The purpose of this integrative review is to describe the state of the science of the microbial relationship between IBS and depressive symptoms. PubMed, CINAHL, PsychINFO, and Web of Science were searched using "irritable bowel syndrome," "microbiome," "depression," and related terms. Included articles were published in peer reviewed journals in English from 2009 to 2018. Studies on inflammatory bowel conditions, extra-intestinal microbiomes, or animal models were excluded. Fourteen quantitative studies met inclusion criteria, were critically appraised, and were analyzed using the Whittemore and Knafl method. Analysis revealed a consistently lower microbial biodiversity and lower proportions of Bifidobacterium and Lactobacillus in persons with IBS and co-occurring depressive symptoms. Inclusion of participants with moderate or greater depressive symptoms scores distinguished the studies which reported microbe differences in depressive symptoms. The results of this integrative review underscore the need for studies with larger samples and inclusion of a larger range of depressive symptoms guided by an overarching conceptual framework, such as the biopsychosocial ecology framework. This effort needs to be combined with longitudinal designs in order to identify related microbial markers.
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Hyperforin-induced gut microbiota metabolite carbocysteine protects against depressive-like behaviors in mice by modulating the colonic mucus barrier.
OBJECTIVE: Depression affects millions, and current treatments have limitations, necessitating new approaches. Earlier research confirms Hyperforin's ability to reduce anhedonic behaviors in mice and modulate gut microbiota. This study aims to identify specific metabolic changes induced by Hyperforin that could illuminate its impact on gut microbiome metabolism, possibly uncovering novel metabolites for developing antidepressant therapies. METHODS: Following the chronic stress model, untargeted metabolomic analysis of fecal samples was conducted to identify metabolic changes induced by Hyperforin. Bioinformatics tools analyzed the origins of differentially expressed metabolites and their correlation with Akkermansia muciniphila and Muribaculum intestinale. The significant metabolite Carbocysteine was further investigated for its antidepressant effects using behavioral assays in a mouse model of depression. Additionally, the response of the colonic mucus barrier was evaluated using Periodic Acid-Schiff (PAS) staining, scanning electron microscopy (SEM), and enzyme-linked immunosorbent assays (ELISA). RESULTS: Hyperforin significantly altered fecal metabolite profiles in stressed mice, with a notable shift in 239 metabolites mainly associated with co-metabolism pathways and microbiota-specific processes. Among these, Carbocysteine emerged as a key metabolite linked to beneficial bacteria Akkermansia muciniphila and Muribaculum intestinale, with its levels significantly elevated following Hyperforin treatment. Behavioral assessments indicated that Carbocysteine supplementation ameliorated depressive-like behaviors in the chronic restraint stress mouse model. It also enhanced colonic mucus production and integrity. CONCLUSION: Our research highlights Hyperforin's role in modulating gut microbiota metabolism and identifies Carbocysteine as a potential antidepressant. These findings advance our understanding of the gut-brain axis (GBA) in depression and pave the way for developing new therapeutics.
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Research Progress on the Mechanism of Bile Acids and Their Receptors in Depression.
Depression, a highly prevalent mental disorder worldwide, arises from multifaceted interactions involving neurotransmitter imbalances, inflammatory responses, and gut-brain axis dysregulation. Emerging evidence highlights the pivotal role of bile acids (BAs) and their receptors, including farnesoid X receptor (FXR), Takeda G protein-coupled receptor 5 (TGR5), and liver X receptors (LXRs) in depression pathogenesis through modulation of neuroinflammation, gut microbiota homeostasis, and neural plasticity. Clinical investigations demonstrated altered BA profiles in depressed patients, characterized by decreased primary BAs (e.g., chenodeoxycholic acid (CDCA)) and elevated secondary BAs (e.g., lithocholic acid (LCA)), correlating with symptom severity. Preclinical studies revealed that BAs ameliorate depressive-like behaviors via dual mechanisms: direct CNS receptor activation and indirect gut-brain signaling, regulating neuroinflammation, oxidative stress, and BDNF/CREB pathways. However, clinical translation faces challenges including species-specific BA metabolism, receptor signaling complexity, and pharmacological barriers (e.g., limited blood-brain barrier permeability). While FXR/TGR5 agonists exhibit neuroprotective and anti-inflammatory potential, their adverse effects (pruritus, dyslipidemia) require thorough safety evaluation. Future research should integrate multiomics approaches and interdisciplinary strategies to develop personalized BA-targeted therapies, advancing novel treatment paradigms for depression.
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Effect of encapsulated spice oleoresins on chronic unpredictable mild stress-induced depression and gut microbiome modulation in mice model.
Depression affects millions globally, prompting the search for novel treatments. Natural compounds like spice oleoresins show promise due to their bioactive constituents. This study explores the use of Hydroxypropyl-beta-cyclodextrin (HPBCD) for nano-encapsulation to enhance the efficacy of pepper, turmeric, and chilli oleoresins in alleviating depression in a mice model. Chronic unpredictable mild stress (CUMS) was induced for 28 days, followed by administering nano-encapsulated oleoresins (25 mg/kg). Behavioural analyses revealed improved activity, while neurochemical studies showed increased serotonin and dopamine levels with reduced monoamine oxidase (MAO) activity. Western blot highlighted changes in BDNF, supported by histopathological evidence of neuroprotection. Biochemical assays indicated reduced oxidative stress, acetylcholinesterase activity, and enhanced catalase and superoxide dismutase levels. 16S rRNA sequencing revealed improved gut microbiota, with increased beneficial bacteria. Notably, nano-encapsulated chilli oleoresin exhibited the highest efficacy. These findings support the multi-targeted potential of nano-encapsulated spice oleoresins as complementary treatments for depression, addressing neurobiological and gut-related factors.