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Psychobiotics: Evolution of Novel Antidepressants.
The gut-brain axis is a bidirectional communication system which allows the central nervous system and gastrointestinal tract to interact with and respond to each other rapidly and effectively. It is becoming increasingly clear that major players in this complex system are gut bacteria. The mechanisms of signal transmission from bacteria to the brain are complex and not fully elucidated, but include neural, endocrine, immune, and metabolic pathways. It was initially demonstrated in a rodent model of depression that the gut microbiota was altered. This observation has been replicated in patients with major depression who show decreased microbial diversity. Furthermore, when rodents receive a microbiota transplant from a depressed patient their behaviour alters, as does their tryptophan metabolism and immune status. Several studies of psychobiotics (bacteria with a potential mental health benefit) have been conducted in healthy populations and in patients with depression. While some psychobiotics have shown efficacy in treating depression, other bacteria have yielded negative findings. Larger-scale, well-designed studies are required. EU-funded guidelines recommend that patients with depression or vulnerability to depression should be encouraged to enhance a plant-based diet with a high content of grains/fibres, fermented foods, and fish. A significant impact of such a diet is likely mediated through the gut microbiota.
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Is anxiety and depression transmissible? Depressed mother rats transmit anxiety- and depression-like phenotypes to cohabited rat pups through gut microbiota assimilation.
OBJECTIVE: This study is to investigate the role of gut microbiota transmission in the development of anxiety/depression in offspring exposed to maternal depression. METHOD: Offspring rats were cohabitated with their depressed mother or father rats (which exposed to chronic unpredictable mild stress (CUMS)) for 2, 4, and 6 months, the anxiety- and depression-like behaviors, and interaction/caring activities between mother/father and their pups were detected. The gut microbiota composition and its relationship with behaviors were analyzed. Fecal microbiota transplantation (FMT) was performed to establish the gut microbiota of depressed/normal mother rats in the offspring rats to further confirm the role of "depressive gut microbiota" transmission in mediating the anxiety/depression in the pups. RESULTS: Anxiety and depression phenotypes can be transmitted from depressed mother rats to their cohabited offspring. Frequent interactions and gut microbiota assimilation were observed between rat mothers and their pups. Remodeling of the gut microbiota in pups by FMT could induce or attenuate anxiety- and depression-like phenotypes depending on the origin of the fecal microbiota. By comparison, the pups cohabiting with depressed father rats exhibited milder anxiety and depression. CONCLUSIONS: These data together support that depressed mothers can transmit anxiety/depression to their pups through gut microbiota assimilation, which is related to frequent interactions. Our study reinforces the significance of mental health of mothers in preventing the occurrence of childhood anxiety and depression, and pointing out the possibility of remodeling intestinal microbiota as an effective therapeutic approach for treating anxiety/depression in children.
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Gut Microbiome Diversity and Abundance Correlate with Gray Matter Volume (GMV) in Older Adults with Depression.
Growing evidence supports the concept that bidirectional brain-gut microbiome interactions play an important mechanistic role in aging, as well as in various neuropsychiatric conditions including depression. Gray matter volume (GMV) deficits in limbic regions are widely observed in geriatric depression (GD). We therefore aimed to explore correlations between gut microbial measures and GMV within these regions in GD. Sixteen older adults (>60 years) with GD (37.5% female; mean age, 70.6 (SD = 5.7) years) were included in the study and underwent high-resolution T1-weighted structural MRI scanning and stool sample collection. GMV was extracted from bilateral regions of interest (ROI: hippocampus, amygdala, nucleus accumbens) and a control region (pericalcarine). Fecal microbiota composition and diversity were assessed by 16S ribosomal RNA gene sequencing. There were significant positive associations between alpha diversity measures and GMV in both hippocampus and nucleus accumbens. Additionally, significant positive associations were present between hippocampal GMV and the abundance of genera Family_XIII_AD3011_group, unclassified Ruminococcaceae, and Oscillibacter, as well as between amygdala GMV and the genera Lachnospiraceae_NK4A136_group and Oscillibacter. Gut microbiome may reflect brain health in geriatric depression. Future studies with larger samples and the experimental manipulation of gut microbiome may clarify the relationship between microbiome measures and neuroplasticity.
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F. prausnitzii potentially modulates the association between citrus intake and depression.
BACKGROUND: The gut microbiome modulates the effects of diet on host health, but it remains unclear which specific foods and microbial features interact to influence risk of depression. To understand this interplay, we leveraged decades of dietary and depression data from a longitudinal cohort of women (n = 32,427), along with fecal metagenomics and plasma metabolomics from a substudy (n = 207) nested in this cohort, as well as an independent validation cohort of men (n = 307). RESULTS: We report that citrus intake and its components are prospectively associated with a lower risk of depression and altered abundance of 15 gut microbial species, including enriched Faecalibacterium prausnitzii. In turn, we found a lower abundance of F. prausnitzii and its metabolic pathway, S-adenosyl-L-methionine (SAM) cycle I in participants with depression. To explore causality, we found that lower SAM production by F. prausnitzii may decrease intestinal monoamine oxidase A gene expression implicated in serotonin and dopamine synthesis. CONCLUSIONS: These data underscore the role of diet in the prevention of depression and offer a plausible explanation for how the intestinal microbiome modulates the influence of citrus on mental health. Video Abstract.
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The ethanolic extract of peanut shell attenuates the depressive-like behaviors of mice through modulation of inflammation and gut microbiota.
Peanut shell is an agricultural byproduct being wasted on a large scale, which is in urgent need to be recycled. To fully utilize its pharmacological ingredients, e.g. luteolin, eriodyctiol, and 5,7-dihydroxychromone, we evaluated the curative effect of ethanol extract deriving from peanut shell (PSE) in treating chronic unpredictable mild stress (CUMS)-induced depressive mice. The chronic stress lasted for 10 weeks, and PSE at 100-900 mg/kg/day was gavaged to mice in the last 2 weeks of modeling. The depressive behaviors were assessed by analyses of sucrose preference, tail suspension, and forced swimming. The brain injury was demonstrated by Hematoxylin and Eosin (H&E), Nissl body, and TdT-mediated dUTP nick end labeling (TUNEL) stainings in the mouse hippocampus. Biochemical indicators were analyzed, including levels of neurotrophic factors, neurotransmitters, stress hormones, and inflammatory mediators. The feces were collected for the 16S rDNA sequencing of gut microbiome. Administration of PSE improved the sucrose water consumption of depressive mice, while it decreased the immobile time in tail suspension and forced swimming tests. Meanwhile, the anti-depressive effect of PSE was supported by ameliorated histochemical staining, increased levels of neurotrophic factors and neurotransmitters, as well as down-regulated stress hormones. Furthermore, the treatment of PSE was able to mitigate the levels of inflammatory cytokines in brain, serum, and small intestine. Besides, the tight junction proteins, e.g., occludin and ZO-1, of gut showed elevated expressions, which coincided with the elevated abundance and diversity of gut microbiota upon PSE treatment. This study validated the therapeutic efficacy of PSE in fighting against depression, as well as its modulatory action on inflammation and gut microbiota, which promoted the recycling of this agricultural waste to be health supplements of added value.
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Effect of probiotic interventions on depressive symptoms: A narrative review evaluating systematic reviews.
Depression is one of the most prevalent mental illnesses and is often associated with various other medical disorders. Since the 1980s, the primary pharmacological treatment has been antidepressants, but due to the recent discovery of the association between the gut microbiome and mental health, probiotics have been proposed as an adjunctive or alternate treatment. In this narrative review, we aim to provide a holistic perspective by synthesizing and evaluating existing evidence, discussing key biological mechanisms, exploring the history of probiotic use, and appreciating the influence of modern diet on mental health. Five online databases were searched for relevant studies up to December 2017. Systematic reviews that included randomized controlled trials assessing the efficacy of probiotics in the treatment of depressive symptoms were included. Seven systematic reviews met the inclusion criteria. Three of these reviews conducted meta-analyses, out of which, two concluded that probiotics improved depressive symptoms in the sample population. Out of the four reviews that conducted qualitative analysis, three reviews concluded that probiotics have the potential to be used as a treatment. Due to the differences in clinical trials, a definitive effect of probiotics on depressive symptoms cannot be concluded. Nonetheless, probiotics seem to potentially produce a significant therapeutic effect for subjects with pre-existing depressive symptoms. Further studies are warranted for definitive conclusions.
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Regulation of colonic neuropeptide Y expression by the gut microbiome in patients with ulcerative colitis and its association with anxiety- and depression-like behavior in mice.
Patients with inflammatory bowel disease (IBD), including ulcerative colitis (UC), show an increased incidence of anxiety and depression; however, the association between UC-associated psychiatric disorders and the gut microbiota is unclear. This study aimed to examine whether gut microbiota from patients with UC can alter colonic gene expression, leading to anxiety- and depression-like behavior in mice receiving fecal microbiota transplantation (FMT). RNA sequencing transcriptome analyses revealed a difference in colonic gene expression between mice receiving FMT from patients with UC (UC-FMT mice) and those receiving FMT from healthy controls (HC-FMT mice). Gene ontology analysis revealed the downregulation of neuropeptide signaling pathways, including neuropeptide Y (NPY) expression, in the colons of UC-FMT mice. The protein levels of NPY also decreased in the colon and plasma of UC-FMT mice compared to those in HC-FMT mice. The oral administration of Enterococcus mundtii (EM), a bacterium isolated from the feces of patients with UC, reduced NPY expression in the colons of mice and induced intestinal inflammation, anxiety, and depression-like behavior. Reduced NPY protein levels were also observed in the plasma and hippocampus of EM-treated mice. Intraperitoneal administration of NPY significantly alleviated anxiety- and depressive-like behaviors induced by EM in mice. Capsular polysaccharide in EM was associated with EM-induced NPY downregulation in the colon. Analysis of Gene Expression Omnibus datasets showed markedly reduced NPY expression in the inflamed colons of patients with UC compared with that in the colons of healthy controls. In summary, EM-induced reduction in the colonic expression of NPY may be associated with a decrease in hippocampal NPY and anxiety- and depression-like behavior in mice.
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Maternal Fiber Intake and Perinatal Depression and Anxiety.
(1) Background: Dietary fiber can significantly alter gut microbiota composition. The role of the gut microbiome in the Gut-Brain Axis and modulation of neuropsychiatric disease is increasingly recognized. The role of antenatal diet, particularly fiber intake, in mitigating maternal mental health disorders remains unexplored. The objective of this review is to investigate the association between maternal fiber intake and perinatal depression and anxiety (PDA). (2) Methods: A literature review of PubMed and Google Scholar was conducted using appropriate keyword/MeSH terms for pregnancy, diet, fiber, and mental health. Observational and clinical trials published between 2015 and 2021 were included and data pertaining to dietary patterns (DP), food intake, mental health, and demographic data were extracted. The top three fiber-containing food groups (FG) per study were identified using a sum rank scoring system of fiber per 100 g and fiber per serving size. The consumption of these top three fiber FGs was then ranked for each dietary pattern/group. Mental health outcomes for each study were simplified into three categories of improved, no change, and worsened. The relationship between top three fiber FGs consumed within each DP and mental health outcomes was analyzed using Spearman's correlation. (3) Results: Thirteen of fifty-two studies met the inclusion criteria. Ten (76.9%) studies assessed DPs (seven examined depression only, two examined depression and anxiety, and one examined anxiety only). Seven (53.9%) studies reported at least one significant positive relationship between mental health outcomes and DPs while three reported at least one negative outcome. Three (23.1%) studies compared intake of different food groups between depressed and non-depressed groups. In studies of DPs, the average consumption ranking of the top three fiber FGs bore a significant inverse association with mental health outcomes [r = -0.419 (95%CI: -0.672--0.078)] p = 0.015. In studies comparing the intake of different FGs between depressed and non-depressed groups, the consumption of top-ranking fiber foods was higher in the non-depressed groups, but significantly higher in four of the ten high fiber FGs. (4) Conclusions: This study reframes findings from previously published studies of maternal diet and mental health outcomes to focus on fiber intake specifically, using a fiber ranking system. A significant correlation between lower intake of fiber and poorer mental health outcomes warrants further investigation in future studies.
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Mechanistic Insights into the Link between Gut Dysbiosis and Major Depression: An Extensive Review.
Depression is a highly common mental disorder, which is often multifactorial with sex, genetic, environmental, and/or psychological causes. Recent advancements in biomedical research have demonstrated a clear correlation between gut dysbiosis (GD) or gut microbial dysbiosis and the development of anxiety or depressive behaviors. The gut microbiome communicates with the brain through the neural, immune, and metabolic pathways, either directly (via vagal nerves) or indirectly (via gut- and microbial-derived metabolites as well as gut hormones and endocrine peptides, including peptide YY, pancreatic polypeptide, neuropeptide Y, cholecystokinin, corticotropin-releasing factor, glucagon-like peptide, oxytocin, and ghrelin). Maintaining healthy gut microbiota (GM) is now being recognized as important for brain health through the use of probiotics, prebiotics, synbiotics, fecal microbial transplantation (FMT), etc. A few approaches exert antidepressant effects via restoring GM and hypothalamus-pituitary-adrenal (HPA) axis functions. In this review, we have summarized the etiopathogenic link between gut dysbiosis and depression with preclinical and clinical evidence. In addition, we have collated information on the recent therapies and supplements, such as probiotics, prebiotics, short-chain fatty acids, and vitamin B12, omega-3 fatty acids, etc., which target the gut-brain axis (GBA) for the effective management of depressive behavior and anxiety.
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The Gut Microbiome Modulates the Changes in Liver Metabolism and in Inflammatory Processes in the Brain of Chronic Unpredictable Mild Stress Rats.
Generally, depression is the result of complex gene-environment interactions. Recent studies have showed that the gut microbiota can affect brain function through the microbiota-gut-brain axis. However, the underlying mechanism of the microbiota and potential influence of depression remain elusive. We aimed to determine how gut microbiome contributes to the process of depression and further influences the host. Chronic unpredictable mild stress (CUMS) is used to establish a depression model. Fecal microbiota transplant (FMT) is applied to illustrate that depression can be transmitted via microbiota, and metabolism of liver analysis is applied to demonstrate further influence to the liver. We also analyzed the astrocyte activation in the brain by immunofluorescence (IF). Here, we show that the structure of the gut microbiome changes markedly after rats undergo CUMS. Notably, we found that the ratio of Lactobacillus to Clostridium can be a vital index for the development of depression. Depression-like behavior can be duplicated through FMT. Moreover, increased zonulin and fatty acid binding protein-2 indicates that gut barrier integrity is broken after FMT. Subsequently, metabolomics shows that liver metabolic disorder occurs and leads to liver coagulative necrosis. In addition, increased inflammatory cytokine expression and higher astrocyte activation indicate an inflammatory process in the brain. These findings suggest that dysbiosis gut microbiome contributes to development of depression and further causes liver metabolic disorders in a way that may be relevant to the Lactobacillus to Clostridium ratio.