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Psychobiotics: are we on the cusp of a breakthrough?
BioTechniques' Senior Editor, Abigail Sawyer, explores current research on the human gut-brain axis and whether scientists are on the cusp of a breakthrough treatment for depression.
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Isovaleric acid in stool correlates with human depression.
OBJECTIVE: Human depression is a major burden, both on the individuals who suffer from the disease and on society at large. Traditionally, depression has been linked to psychological and biological causes, but there has been increasing interest in the gut-brain axis. In this regard, we have recently shown that specific bacteria are correlated with human depression, and we hypothesize that volatile fatty acids (VFAs) are mediators. METHODS: Here, we analyzed the direct correlation between VFAs, depression and cortisol in a cohort consisting of 34 depressed patients and 17 controls. RESULTS: We found statistically significant correlations between depression and the VFA isovaleric acid, as well as between isovaleric acid and cortisol. Furthermore, bacteria that previously have been identified as being correlated with depression were also correlated with isovaleric acid. Isovaleric acid showed a bimodal distribution in which the depressed patients were overrepresented in the high level group (P < 0.00005, binominal test). DISCUSSION: It has recently been shown that gut-derived VFAs can cross the blood-brain barrier, where isovaleric acid interferes with synaptic neurotransmitter release. The multiple correlation patterns, in addition to a potential mechanistic model, point towards a potential causal relationship between depression and isovaleric acid.
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Mood by microbe: towards clinical translation.
There is a growing realization that the gut-brain axis plays a key role in maintaining brain health and the stress response. Recently, the gut microbiota has emerged as a master regulator of this axis. Thus, opportunities to exploit the microbiome to treat stress-related psychiatric disorders are materializing. Clinical validation of such strategies is now warranted.
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Chronic Stress-Induced Depression and Anxiety Priming Modulated by Gut-Brain-Axis Immunity.
Chronic stress manifests as depressive- and anxiety-like behavior while recurrent stress elicits disproportionate behavioral impairments linked to stress-induced immunological priming. The gut-brain-microbiota-axis is a promising therapeutic target for stress-induced behavioral impairments as it simultaneously modulates peripheral and brain immunological landscapes. In this study, a combination of probiotics and prebiotics, known as a synbiotic, promoted behavioral resilience to chronic and recurrent stress by normalizing gut microbiota populations and promoting regulatory T cell (Treg) expansion through modulation of ileal innate lymphoid cell (ILC)3 activity, an impact reflecting behavioral responses better than limbic brain region neuroinflammation. Supporting this conclusion, a multivariate machine learning model correlatively predicted a cross-tissue immunological signature of stress-induced behavioral impairment where the ileal Treg/T helper17 cell ratio associated to hippocampal chemotactic chemokine and prefrontal cortex IL-1β production in the context of stress-induced behavioral deficits. In conclusion, stress-induced behavioral impairments depend on the gut-brain-microbiota-axis and through ileal immune regulation, synbiotics attenuate the associated depressive- and anxiety-like behavior.
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Genetic prediction of blood metabolites mediating the relationship between gut microbiota and postpartum depression: A mendelian randomization study.
BACKGROUND: Observational studies have suggested an association between gut microbiota(GM) and postpartum depression (PPD). However, the causal relationship remains unclear, and the role of blood metabolites in this association remains elusive. METHODS: This study firstly elucidated the causal relationship among 196 GM taxa, 224 blood metabolites, and PPD from a genetic perspective, employing two-sample Mendelian randomization (MR). Subsequently, a two-step mediation MR approach was employed to explore the role of blood metabolites as potential mediators. To validate the relevant findings, we further selected other data (GM and blood metabolites) from the IEU Open GWAS and GWAS Catalog for analysis. Our primary analysis utilized the inverse variance weighted method. To enhance the robustness of our results, we also applied MR-Egger method, weighted median method, Cochran's Q test, MR-Egger regression, and MR-PRESSO. RESULTS: MR analysis results revealed a nominal association (p < 0.05) between 13 GM taxa, 6 blood metabolites, and PPD. After multiple-testing correction (PFDR < 0.1), Bifidobacteriales (PFDR = 0.034), Bifidobacteriaceae (PFDR = 0.055) and Guanosine (PFDR = 0.081) showed significant causal relationships with PPD. In our validation results, the higher level of Alphaproteobacteria (OR: 1.057, 95% CI: 1.024-1.091; p = 0.0006) retained a causal relationship with a higher risk of PPD. Finally, mediation analysis revealed that the impact of Odoribacter on PPD was mediated indirectly through Hyodeoxycholate, with a mediation proportion of 16.8%. CONCLUSION: Our findings elucidated the underlying mechanisms between the GM, blood metabolites, and PPD. These findings contribute to the prevention and diagnosis of PPD, offering novel insights into microbiome-based therapies and metabolite-targeted interventions for the treatment of PPD.
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Banhasasim-tang Attenuates Corticosterone-Induced Behavioral Despair-like Responses and Is Associated with Gut Microbiota and Serum Metabolomic Changes in Mice.
Banhasasim-tang (BHSST) is a classical East Asian herbal formula traditionally used for gastrointestinal disorders, but its effects on stress-related depressive-like behavior and the associated microbiome-metabolome signatures remain unclear. This study evaluated the antidepressant-like effects of BHSST in a corticosterone (CORT)-induced mouse model and investigated fecal microbiota and serum metabolomic alterations. Male C57BL/6 mice were assigned to Normal, CORT, fluoxetine, low-dose BHSST, or high-dose BHSST groups. CORT was administered for 21 days, and immobility-based behavioral responses were assessed using the forced swimming test and tail suspension test. Fecal microbiota were analyzed by 16S rRNA gene sequencing, and serum metabolites were profiled using untargeted UPLC-QTOF-MS. BHSST reduced CORT-induced immobility time in both behavioral tests. Although alpha diversity was not significantly altered, BHSST treatment was associated with changes in fecal microbial community structure and discriminative bacterial taxa. Serum metabolomics revealed BHSST-H-associated changes in metabolites related to amino acid metabolism, energy metabolism, redox-related metabolism, lipid metabolism, and microbial co-metabolism. Integrated microbiome-metabolome analysis identified association-based multi-omics signatures involving selected bacterial taxa, serum metabolites, and immobility-based behavioral outcomes. These findings suggest that BHSST-induced behavioral improvement is accompanied by changes in the microbiome-metabolome profile in CORT-induced mice.
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The effect of fecal microbiota transplantation on psychiatric symptoms among patients with inflammatory bowel disease: an experimental study.
INTRODUCTION: Over the past decade, evidence that supports the relationship between intestinal microbiota and the brain has been obtained. Ageing, stress, nutrition and medicines can alter the composition of bacteria in the intestinal microbiota. This condition, called dysbiosis, can be repaired through prebiotics, probiotics or fecal microbiota transplantation (FMT). FMT is effective in the treatment of inflammatory bowel diseases (IBD). Information on FMT's use with psychiatric disorders is limited. This study aims to investigate changes in the severity of depression, anxiety and obsession of patients who received FMT for the treatment of inflammatory bowel diseases. METHODS: This study was conducted with 10 patients with IBD who underwent FMT between March and September 2017. FMT was performed by an experienced gastroenterologist. The patients completed the Beck Depression Inventory (BDI), Symptom Checklist-90-Revised (SCL-90-R) and Maudsley Obsessive Compulsive Inventory (MOCI) before FMT and again at 1 month after FMT. RESULTS: Significant decreases were found in BDI (Z=2.49, p=0.013), SCL-90-R (Z=-2.09, p=0.037) and MOCI (Z=2.08, p=0.037) scores after 1 month of FMT. Although the SCL-90-R anxiety subscale scores decreased, this decrease was not statistically significant (Z=-1.55, p=0.121). CONCLUSIONS: The severity of anxiety, depression and obsession in IBD patients decreased after FMT. The decrease in psychiatric symptoms may result from the direct neuropsychiatric effect of FMT (primary effect), but also the improvement of gastrointestinal symptoms (secondary effect). Another possibility is that this result is independent of these two conditions. Therefore, the results of our study are not sufficient to establish a cause-effect relationship. More randomised controlled trials with larger samples from patients with anxiety or depression but without comorbid physical illnesses are needed to generalise these results.
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Peripheral aetiopathogenic drivers and mediators of Parkinson's disease and co-morbidities: role of gastrointestinal microbiota.
We seek an aetiopathogenic model for the spectrum of Parkinson's disease (PD), functional bowel disease, depression and cognitive impairment. The adopted concept is that systemic immuno-inflammatory processes mediate neuro-inflammation. The model would be based on phenotype, exposome (including gastrointestinal microbiome), milieu (immuno-inflammatory and metabolome), human genetics and their interactions. It would enable a patient's position, to be understood in terms of drivers, perpetuators and mediators, and a future position, with and without intervention, predicted. Even the cardinal facets of PD may have different drivers: halting one may allow escape down subordinate pathways. Peptic ulceration is prodromal to PD. In our randomised placebo-controlled trial, hypokinesia improved over the year following biopsy-proven Helicobacter pylori eradication and rigidity worsened. This was independent of any (stable, long t½) antiparkinsonian medication. There are pointers to an autoimmune process: for example, surveillance-confirmed hypokinesia effect was indication specific. During surveillance, successive antimicrobial courses, other than for Helicobacter, were associated with cumulative increase in rigidity. Exhibiting laxatives appeared to stem the overall temporal increase, despite antiparkinsonian medication, in rigidity. Thus, intestinal dysbiosis may be a major source of bystander neuronal damage. There are biological gradients of objective measures of PD facets on circulating inflammatory markers and leucocyte subset counts. Moreover, lactulose hydrogen breath test positivity for small-intestinal bacterial overgrowth (present in two thirds of PD patients) is associated with the same subsets: higher natural killer and total CD4+ counts and lower neutrophils. With greater aetiopathogenic understanding, relatively low cost and on-the-shelf medication could have a major impact. A new generation of animal models, based on the gut microbiome, is envisaged.
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Prenatal amoxicillin exposure induces depressive-like behavior in offspring via gut microbiota and myristic acid-mediated modulation of the STING pathway.
Amoxicillin is a widely used antibiotic globally, and its pervasive environmental presence poses significant risks to human health and ecosystems. Notably, prenatal amoxicillin exposure (PAmE) may have long-term neurodevelopmental toxicity for offspring. In this study, we investigated the lasting effects of PAmE on depressive-like behaviors in offspring rats, emphasizing the biological mechanisms mediated by changes in gut microbiota and its metabolite, myristic acid. Our results showed that PAmE significantly disrupted the gut microbiota composition in offspring, particularly through the reduction of Lachnospiraceae, leading to decreased levels of myristic acid. This disruption hindered the N-myristoylation of ADP-ribosylation factor 1 (ARF1), impaired the normal degradation of the stimulator of interferon genes protein, inhibited autophagic processes, and promoted M1 polarization of microglia, ultimately leading to depressive-like behaviors in the offspring. Remarkably, supplementation with Lachnospira or myristic acid effectively reversed the PAmE-induced neurodevelopmental and behavioral abnormalities, alleviating depressive-like symptoms. This study reveals how PAmE affects offspring neurodevelopment and behavior through gut microbiota and myristic acid, highlighting the crucial role of the gut-brain axis in the modulation of depressive symptoms. Supplementing Lachnospira or myristic acid could represent a novel strategy to mitigate PAmE-induced fetal-originated depression, providing new biological evidence and potential therapeutic avenues.
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Comprehensive metagenomic and lipidomic analysis showed that baicalin could improve depressive behaviour in atherosclerotic mice by inhibiting nerve cell ferroptosis.
BACKGROUND: Atherosclerosis (AS) concomitant depression is a serious clinical problem with unclear mechanisms of co-morbidity. Baicalin (BA) can resist atherosclerosis and depression by regulating intestinal flora and host lipid metabolism. Therefore, based on intestinal microorganisms and lipid metabolism, this study explored the mechanism of baicalin against AS concomitant depression. METHODS: 16 C57BL/6 mice were fed with normal diet as blank control group. 48 ApoE-/-mice were randomly divided into 3 groups (model group and BAL, BAH two treatment groups). The mouse model of atherosclerosis concomitant depression was established by high-fat feeding combined with restraint stimulation for 16 weeks. Behavioural experiments and biochemical indexes were used to detect the antidepressant effect and anti-atherosclerosis effect of baicalin. Metagenomic sequencing technology combined with metabolomics analysis was used to detect the effects of BA on intestinal microflora structure and brain lipids in AS co-depressed mice. Erastin was used to induce HT-22 hippocampal neurons to construct a model of ferroptosis. The inhibition of baicalin on ferrotosis was verified by detecting the cell viability, ROS production, and expression levels of glutathione, SLC7A11, GPX4 and ACSL4 in each group. RESULTS: Baicalin could effectively improve the indexes of AS co-depressed mice, and the results of metagenomics and lipidomics showed that there were disorders of intestinal flora represented by Helicobacter_typhlonius and Escherichia_coli and disorders of lipid metabolism represented by PE in the AS co-depressed model mice. The correlation analysis showed that the lipid metabolism disorders in the model mice were closely related to the intestinal flora disorders, and baicalin intervention could effectively improve the intestinal flora and lipid metabolism disorders in the AS co-depressed mice. Metabolic pathway enrichment analysis showed that differential lipid PEs were significantly enriched in the iron death pathway, and our further in vitro cellular experiments showed that baicalin could inhibit Erastin-induced Ferroptosis in the hippocampal neuronal cell line HT-22 by promoting the expression of SLC7A11, GSH, and GPX4, inhibiting the expression of ACSL4, and decreasing the cellular ROS. CONCLUSION: Baicalin improves intestinal microbiota and brain lipid metabolism and inhibits ferroptosis of nerve cells, which possesses the application value of anti-atherosclerotic concomitant depression.