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Targeting the Microbiota-Gut-Brain Axis: Prebiotics Have Anxiolytic and Antidepressant-like Effects and Reverse the Impact of Chronic Stress in Mice.
BACKGROUND: The realization that the microbiota-gut-brain axis plays a critical role in health and disease, including neuropsychiatric disorders, is rapidly advancing. Nurturing a beneficial gut microbiome with prebiotics, such as fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS), is an appealing but underinvestigated microbiota manipulation. Here we tested whether chronic prebiotic treatment modifies behavior across domains relevant to anxiety, depression, cognition, stress response, and social behavior. METHODS: C57BL/6J male mice were administered FOS, GOS, or a combination of FOS+GOS for 3 weeks prior to testing. Plasma corticosterone, microbiota composition, and cecal short-chain fatty acids were measured. In addition, FOS+GOS- or water-treated mice were also exposed to chronic psychosocial stress, and behavior, immune, and microbiota parameters were assessed. RESULTS: Chronic prebiotic FOS+GOS treatment exhibited both antidepressant and anxiolytic effects. Moreover, the administration of GOS and the FOS+GOS combination reduced stress-induced corticosterone release. Prebiotics modified specific gene expression in the hippocampus and hypothalamus. Regarding short-chain fatty acid concentrations, prebiotic administration increased cecal acetate and propionate and reduced isobutyrate concentrations, changes that correlated significantly with the positive effects seen on behavior. Moreover, FOS+GOS reduced chronic stress-induced elevations in corticosterone and proinflammatory cytokine levels and depression-like and anxiety-like behavior in addition to normalizing the effects of stress on the microbiota. CONCLUSIONS: Taken together, these data strongly suggest a beneficial role of prebiotic treatment for stress-related behaviors. These findings strengthen the evidence base supporting therapeutic targeting of the gut microbiota for brain-gut axis disorders, opening new avenues in the field of nutritional neuropsychopharmacology.
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Landscapes of gut microbiome and metabolic signatures in vitiligo patients with co-morbid emotional distress.
BACKGROUND: Vitiligo is a depigmentation disorder frequently associated with emotional distress; however, the precise mechanisms underlying this co-morbidity remain unclear. OBJECTIVE: This study aims to investigate whether gut dysbiosis and gut metabolites contributes to emotional distress in patients with vitiligo. METHODS: Depression and anxiety were assessed using the Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7, respectively. Totally enrolled 28 vitiligo patients were diagnosed with depression or anxiety (VWD), 44 without such conditions (VTD), and 37 healthy controls (HC). Stool samples were analyzed using 16S rRNA gene sequencing and liquid chromatography triple quadrupole tandem mass spectrometry. RESULTS: The intestinal flora of VWD group changed significantly with reduced α-diversity. The β-diversity varied among groups. Megasphaera and Anaerostipes increased in the VWD group, whereas Bilophila etc. decreased. Linear Discriminant Analysis Effect Size revealed Lachnoclostridium as a representative flora in the VWD and Faecalibacterium as a representative flora in the VTD. Metabolites such as L-glutamic acid and indole were lower in the VWD group than in the HC, while oleamide, cuminaldehyde, and taurine were higher in the VWD with VTD group. Lachnoclostridium negatively correlated with indole and L-glutamic acid. This study identified notable variations in pathways involved in the biosynthesis of phenylalanine, tyrosine, and tryptophan bile secretion, GABAergic synapses, and taurine and hypotaurine metabolism between the VWD and HC groups. CONCLUSION: Specific fecal microbes and metabolites may contribute to the pathogenesis of VWD. These findings provide a novel perspective for addressing emotional distress in patients with vitiligo by targeting the gut-brain-skin axis.
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Chronic corticosterone exposure causes anxiety- and depression-related behaviors with altered gut microbial and brain metabolomic profiles in adult male C57BL/6J mice.
Chronic exposure to glucocorticoids in response to long-term stress is thought to be a risk factor for major depression. Depression is associated with disturbances in the gut microbiota composition and peripheral and central energy metabolism. However, the relationship between chronic glucocorticoid exposure, the gut microbiota, and brain metabolism remains largely unknown. In this study, we first investigated the effects of chronic corticosterone exposure on various domains of behavior in adult male C57BL/6J mice treated with the glucocorticoid corticosterone to evaluate them as an animal model of depression. We then examined the gut microbial composition and brain and plasma metabolome in corticosterone-treated mice. Chronic corticosterone treatment resulted in reduced locomotor activity, increased anxiety-like and depression-related behaviors, decreased rotarod latency, reduced acoustic startle response, decreased social behavior, working memory deficits, impaired contextual fear memory, and enhanced cued fear memory. Chronic corticosterone treatment also altered the composition of gut microbiota, which has been reported to be associated with depression, such as increased abundance of Bifidobacterium, Turicibacter, and Corynebacterium and decreased abundance of Barnesiella. Metabolomic data revealed that long-term exposure to corticosterone led to a decrease in brain neurotransmitter metabolites, such as serotonin, 5-hydroxyindoleacetic acid, acetylcholine, and gamma-aminobutyric acid, as well as changes in betaine and methionine metabolism, as indicated by decreased levels of adenosine, dimethylglycine, choline, and methionine in the brain. These results indicate that mice treated with corticosterone have good face and construct validity as an animal model for studying anxiety and depression with altered gut microbial composition and brain metabolism, offering new insights into the neurobiological basis of depression arising from gut-brain axis dysfunction caused by prolonged exposure to excessive glucocorticoids.
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Prenatal depression-associated gut microbiota induces depressive-like behaviors and hippocampal neuroinflammation in germ-free mice.
Numerous studies have described the role of the microbiome-gut-brain axis in depression. However, the molecular mechanisms underlying the involvement of gut microbiota in the development of prenatal depression are limited. In this study, fecal microbiota from women with prenatal depression was transplanted into germ-free mice to investigate the potential causal relationships between the gut microbiota and depressive phenotypes. Shotgun metagenomic sequencing and untargeted metabolomics approaches were used to investigate the characteristics of gut microbiota and microbial metabolites. The levels of neuroinflammation in the brain were detected using immunofluorescence and real-time quantitative PCR. We found significant changes in gut microbiota composition and metabolites in mice with fecal microbiota transplantation (FMT) from women with prenatal depression, including decreased Ligilactobacillus, increased Akkermansia, and abnormal glycerophospholipid metabolism. Besides, significant increase in plasma lipopolysaccharide (LPS) levels and significant proliferation of microglia in the hippocampus were observed in mice receiving FMT from women with prenatal depression, accompanied by a significant increase in the expression of nuclear factor-κB (NF-κB) p65, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) mRNA. The gut microbiota and its metabolites were strongly associated with depressive-like behaviors, plasma LPS and neuroinflammation. Our study collectively demonstrates that dysbiosis of the gut microbiota may play a causal relationship in the development of prenatal depression. This process potentially involves the activation of neuroinflammation through the LPS-NF-κB signaling pathway.
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Changes in Gut Microbiome Associated With Co-Occurring Symptoms Development During Chemo-Radiation for Rectal Cancer: A Proof of Concept Study.
PURPOSE: To examine a) whether there are significant differences in the severity of symptoms of fatigue, sleep disturbance, or depression between patients with rectal cancer who develop co-occurring symptoms and those with no symptoms before and at the end of chemotherapy and radiation therapy (CRT); b) differences in gut microbial diversity between those with co-occurring symptoms and those with no symptoms; and c) whether before-treatment diversity measurements and taxa abundances can predict co-occurrence of symptoms. METHODS: Stool samples and symptom ratings were collected from 31 patients with rectal cancer prior to and at the end of (24-28 treatments) CRT. Descriptive statistics were computed and the Mann-Whitney U test was performed for symptoms. Gut microbiome data were analyzed using R's vegan package software. RESULTS: Participants with co-occurring symptoms reported greater severity of fatigue at the end of CRT than those with no symptoms. Bacteroides and Blautia2 abundances differed between participants with co-occurring symptoms and those with no symptoms. Our random forest classification (unsupervised learning algorithm) predicted participants who developed co-occurring symptoms with 74% accuracy, using specific phylum, family, and genera abundances as predictors. CONCLUSION: Our preliminary results point to an association between the gut microbiota and co-occurring symptoms in rectal cancer patients and serves as a first step in potential identification of a microbiota-based classifier.
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Lactobacillus fermentum ATCC 9338 ameliorates immune dysregulation via indoleamine 2, 3-dioxygenase through modulating gut microbial diversity of chronic unpredictable mild stressed mouse.
Gut microbiota (GM) plays a significant role in the pathophysiology of neuropsychiatric diseases like depression. A complex two-way system between gut and brain termed as gut-brain axis (GBA) dependent on intestinal GM and central nervous system (CNS). Alterations in the GM can affect behavior and brain neurochemistry including tryptophan metabolism through immune mediated pathways. Researchers focused to understand immune challenges involving kynurenine action via indoleamine-2,3-dioxygenase (IDO) induces depressive like "sickness behavior". This study examined the role of Lactobacillus fermentum (LF) and 1-methyl-D-tryptophan (1-MT) on IDO regulation, proinflammatory cytokine responses, and gut microbial diversity in chronic unpredictable mild stress (CUMS) depression model. LF (oral administration, 1 × 108 CFU/day/mouse for 28 days) and 1-MT (intraperitoneal, 15 mg/KgBW/day for 21 days) supplementation decreases the expression of cytokines and IDO in cortex, hippocampus, and medulla. Likewise, the mRNA and protein level of cytokines and IDO were modulated after LF and 1-MT administration. Additionally, 16 S rRNA gene sequencing showed that Lactobacillus fermentum restored gut microbial β-diversity and increased overall community richness, indicating a shift toward a balanced microbiome. These results suggest that LF alleviates stress-induced neuroinflammatory and immune changes by modulating IDO activity in the tryptophan pathway. The findings highlight the therapeutic potential of LF as a microbiota-based intervention for regulating neuroinflammation and mood disorders such as depression.
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Targeted β-Glucan-Veiled Oral Apremilast Nanotherapy Modulates Key Dysbiosis-Associated Gut Microbiota and Alleviates Ulcerative Colitis-Associated Anxiety, Depression, and Neuropsychiatric Behaviors.
Oral nanomedicines that modulate gut microbiota and gut-brain interactions are crucial for effectively treating inflammatory bowel disease (IBD) and associated psychiatric disorders, such as anxiety and depression. However, the underlying causes of psychiatric disorders in patients with IBD remain unclear, and effective treatment strategies have yet to be established. Herein, we developed oral gastroprotective βG@Apr-WPG NMs (β-glucan armored apremilast encapsulating tryptophan-poly(lactic-co-glycolic acid)-glutathione nanomicelles). This system effectively treats IBD and associated anxiety/depression by modulating the microbiota-gut-brain axis. βG@Apr-WPG NMs demonstrated gastroprotection enhances retention, and enables sustained release within the inflamed colon, enhances drug solubility, and inflammation-responsive apremilast release significantly improving oral therapeutic efficacy. Oral βG@Apr-WPG NMs administration outperformed free apremilast by restoring gut barrier integrity, reducing histopathological damage, and modulating microbial dysbiosis. Systemic inflammation and neuroinflammation were markedly suppressed. Notably, the βG@Apr-WPG NMs ameliorated anxiety- and depression-like symptoms, as well as cognitive deficits in colitis-induced mice, highlighting its therapeutic impact beyond the gut. Addressing reduced efficacy of conventional therapies, this multifunctional βG@Apr-WPG NMs platform offers safe, simple, and highly efficient therapeutic strategy integrating targets intestinal inflammation, microbiota-gut-brain axis modulation, in the pathogenesis of IBD with comorbid neuropsychiatric disorders with confirmed safety.
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The Impact of Nutrition and Intestinal Microbiome on Elderly Depression-A Systematic Review.
The aim of this review is to systematically review the evidence whether proper nutrition has a positive impact on the prevention or decline of depressive symptoms among elderly people. In addition, possible connections between nutrition, microbiome, and serotonin molecules and its tryptophan precursor are discussed. The methodology follows the PRISMA guidelines, including the PRISMA flow chart. The authors systematically reviewed peer-review, English-written articles published in Web of Science and PubMed between 2013 and 2018. The findings of six original articles, detected on the set inclusion and exclusion criteria, indicate that there is an association between nutrition and depressive symptoms in the target group, i.e., that proper nutrition has a positive impact on the prevention or reduction of depressive symptoms among elderly people. The findings also reveal that there is a considerable correlation between the intakes of vitamin B and a decrease in the prevalence of depressive symptoms. Furthermore, sufficient nutrient intake of tryptophan appears to be an important factor in terms of nutrition and serotonin levels in the body. The authors consider it important to explore associations between the overall dietary intake and depression since diets are not consumed as individual nutrients. Returning to preventive approaches seems to be a rational way to promote the mental health of seniors. Future studies thus need to include interdisciplinary collaboration: from a good diagnosis of the disease by a psychiatrist, through an analysis of the need for nutrient metabolism by a biochemist to the development of a nutritional plan by a nutritional therapist. The limitations of this review consist in a relatively small number of the studies on this topic, including just few randomized controlled trials, which are a guarantee of efficacy and objectivity in comparison with cross-sectional studies.
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Microbiota-immune crosstalk underlying cancer-induced depression in patients with breast cancer.
BACKGROUND: Cancer-induced depression (CID) is frequent in breast cancer (BC), yet its biological basis is poorly understood. We examined CID-related gut microbiota changes and their associations with immune and mood alterations. METHODS: A total of 49 female BC patients were enrolled, of whom 17 developed CID during treatment. Prior to the onset of depressive symptoms at baseline, gut microbiota composition, diversity, and functional potential were analyzed, while serum cytokines and changes in depressive symptoms (ΔBDI) before and after intervention were measured, and their interrelationships were explored. RESULTS: CID patients showed increased baseline immune activation, with higher IFN-α, IL-12p70, and IFN-γ levels. They also exhibited significantly reduced gut microbial α-diversity. In addition, six differential genera were identified, including Lawsonella, Holdemania, Lachnospiraceae UCG010, Actinomyces, Negativibacillus and Scardovia, which showed significant differences between the CID and BC groups. Functional analysis indicated reduced glycosphingolipid biosynthesis and increased N-glycan biosynthesis, with these pathway changes corresponding to specific differential genera such as Actinomyces and Lachnospiraceae UCG010. Notably, at baseline, Lawsonella abundance was positively correlated with both IFN-α levels and ΔBDI, and mediation analysis revealed a statistically significant association between Lawsonella and ΔBDI through IFN-α, with the estimated indirect effect (ACME = 0.128, p < 0.05) accounting for approximately 19.3% of the total association. CONCLUSION: CID patients showed marked gut microbiota dysbiosis and functional pathway alterations at baseline. The Lawsonella-IFN-α-mood axis may be associated with subsequent mood changes, providing a theoretical basis for exploring CID mechanisms and early identification.
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Gut microbiota of patients with post-stroke depression in Chinese population: a systematic review and meta-analysis.
BACKGROUND: Evidence of changes in the composition and function of the gut microbiota (GM) in post-stroke depression (PSD) patients is gradually accumulating. This study aimed to systematically evaluate the relationship between PSD and GM. METHODS: We searched in PubMed, Web of Science, Embase, Cochrane databases, Wangfang, VIP, CBM, and CNKI from the establishment of the database to April 17, 2024, and systematic review and meta-analysis were performed to investigate the differences of GM between patients with PSD spectrum and healthy controls (HC) or stroke spectrum. RESULT: There were 14 studies consisting a total of 1,556 individuals included in the meta-analysis. The pooled results showed that PSD spectrum demonstrated significantly increased α diversity as indexed by Chao1 index, ACE indexes, Shannon index, and Simpson index as compared to HC. Additionally, stroke spectrum significantly increased α diversity as indexed by Simpson index compared to PSD. Furthermore, the pooled estimation of relative abundance showed that Bacteroidota, Fusobacteriota, and Pseudomonadota in PSD patients were significantly higher than those in the HC group, while the abundance of Bacillota was higher in the HC group. Moreover, significant differences in GM were observed between PSD patients and HC at the family and genus levels. CONCLUSION: This study found that the α diversity of PSD patients was higher than that of HC. Moreover, there were also differences in the distribution of GM at the phylum, family, and genus levels, respectively. At the same time, the level of Lachnospira in PSD patients was lower than that in the stroke group. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024582708.