Multi-Probiotics ameliorate Major depressive disorder and accompanying gastrointestinal syndromes via serotonergic system regulation.

INTRODUCTION: Major depressive disorder (MDD) is a leading global psychiatric disease. MDD is highly comorbid with gastrointestinal abnormalities, such as gut motility dysfunction. An effective strategy to manage depression and its accompanying gastrointestinal symptoms is warranted. OBJECTIVES: Three probiotic strains (Bifidobacterium breve CCFM1025, Bifidobacterium longum CCFM687, and Pediococcus acidilactici CCFM6432) had previously been validated in mice to possess antidepressant-like potential. This study investigated the potential psychotropic effects of a combined three-strain probiotic intervention for human MDD patients. The mechanism of action was further investigated in the stress-induced depression mice model. METHODS: MDD patients were given a freeze-dried, mixed probiotic formula for four weeks. The patients' psychometric and gastrointestinal conditions were evaluated using clinical rating scales before and after treatment. Their gut microbiome was also analysed using 16S rRNA gene amplicon sequencing. The mechanisms underlying the beneficial probiotic effects were determined using a chronic stress-induced depressive mouse model. RESULTS: Multi-probiotics significantly reduced depression scores, and to a greater extent than the placebo (based on the Hamilton Depression Rating, Montgomery-Asberg Depression Rating, and Brief Psychiatric Rating Scales). Multi-probiotics also significantly improved the patients' gastrointestinal functions (based on self-evaluation using the Gastrointestinal Symptom Rating Scale). Serotonergic system modification was demonstrated as the key mechanism behind the probiotics' benefits for the brain and the gut. CONCLUSION: Our findings suggest a novel and promising treatment to manage MDD and accompanying gut motility problems, and provide options for treating other gut-brain axis-related disorders.

Lactobacillus paracasei CCFM1229 and Lactobacillus rhamnosus CCFM1228 Alleviated Depression- and Anxiety-Related Symptoms of Chronic Stress-Induced Depression in Mice by Regulating Xanthine Oxidase Activity in the Brain.

Depression is a common mood disorder that affects around 350 million people worldwide. We studied the effect of supplementation with Lactobacillus strains for the treatment of depression. Except for control group (n = 8), C57BL/6J mice were treated with Lactobacillus during six weeks of chronic unpredictable stress (depression group: n = 9, Lactobacillus intervention group: n = 7). L. paracasei CCFM1229 and L. rhamnosus CCFM1228 significantly reduced depressive behaviour in the forced swimming test and tail suspension test, significantly reduced anxiety behaviour in the open field test, and reduced anxiety behaviour in the marble burying test and light/dark box test. L. paracasei CCFM1229 and L. rhamnosus CCFM1228 significantly increased the brain serotonin and brain-derived neurotrophic factor concentrations, and CCFM1229 significantly decreased the serum corticosterone concentration, all of which are closely associated with the relief of depressive symptoms. Furthermore, CCFM1229 and CCFM1228 were shown to regulate purine metabolism in mice, as indicated by decreases in brain xanthine oxidase activity and an increase in liver adenosine deaminase activity. Anxiety- and depression-related indicators were significantly associated with xanthine oxidase activity in the cerebral cortex. The strains CCFM1229 and CCFM1228 reduced anxiety- and depression-related behaviour in a mouse model of chronic stress-induced depression, which may be achieved by regulating the activity of brain xanthine oxidase.

Bifidobacterium breve CCFM1025 attenuates major depression disorder via regulating gut microbiome and tryptophan metabolism: A randomized clinical trial.

OBJECTIVE: Psychobiotics, as a novel class of probiotics mainly acting on the gut-brain axis, have shown promising prospects in treating psychiatric disorders. Bifidobacterium breve CCFM1025 was validated to have an antidepressant-like effect in mice. This study aims to assess its psychotropic potential in managing major depression disorder (MDD) and unravel the underlying mechanisms. METHODS: Clinical Trial Registration: https://www.chictr.org.cn/index.aspx (identifier: NO. ChiCTR2100046321). Patients (n = 45) diagnosed with MDD were randomly assigned to the Placebo (n = 25) and CCFM1025 (n = 20) groups. The freeze-dried CCFM1025 in a dose of viable bacteria of 1010 CFU was given to MDD patients daily for four weeks, while the placebo group was given maltodextrin. Changes from baseline in psychometric and gastrointestinal symptoms were evaluated using Hamilton Depression Rating scale-24 Items (HDRS-24), Montgomery-Asberg Depression Rating Scale (MADRS), Brief Psychiatric Rating Scale (BPRS), and Gastrointestinal Symptom Rating Scale (GSRS). Serum measures were also determined, i.e., cortisol, TNF-α, and IL-ß. Serotonin turnover in the circulation, gut microbiome composition, and tryptophan metabolites were further investigated for clarifying the probiotics' mechanisms of action. RESULTS: CCFM1025 showed a better antidepressant-like effect than placebo, based on the HDRS-24 (placebo: M = 6.44, SD = 5.44; CCFM1025: M = 10.40, SD = 6.85; t(43) = 2.163, P = 0.036, d = 0.640) and MADRS (placebo: M = 4.92, SD = 7.15; CCFM1025: M = 9.60, SD = 7.37; t(43) = 2.152, P = 0.037, d = 0.645) evaluation. The factor analysis of BPRS and GSRS suggested that patients' emotional and gastrointestinal problems may be affected by the serotonergic system. Specifically, CCFM1025 could significantly and to a larger extend reduce the serum serotonin turnover compared with the placebo (placebo: M = -0.01, SD = 0.41; CCFM1025: M = 0.27, SD = 0.40; t(43) = 2.267, P = 0.029, d = 0.681). It may be due to changes in gut microbiome and gut tryptophan metabolism under the probiotic treatment, such as changes in alpha diversity, tryptophan, and indoles derivatives. CONCLUSION: B. breve CCFM1025 is a promising candidate psychobiotic strain that attenuates depression and associated gastrointestinal disorders. The mechanisms may be relevant to the changes in the gut microbiome and tryptophan metabolism. These findings support the future clinical applications of psychobiotics in the treatment of psychiatric disorders.

Pediococcus acidilactici CCFM6432 mitigates chronic stress-induced anxiety and gut microbial abnormalities.

The discovery of psychobiotics has improved the therapeutic choices available for clinical mental disorders and shows promise for regulating mental health in people by combining the properties of food and medicine. A Pediococcus acidilactici strain CCFM6432 was previously isolated and its mood-regulating effect was investigated in this study. Viable bacteria were given to chronically stressed mice for five weeks, and then the behavioral, neurobiological, and gut microbial changes were determined. CCFM6432 significantly reduced stress-induced anxiety-like behaviors, mitigated hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, and reversed the abnormal expression of hippocampal phosphorylated CREB and the c-Fos protein. In particular, CCFM6432 improved the gut microbial composition by inhibiting the over-proliferated pathogenic bacteria (e.g., Escherichia-shigella) and promoting beneficial bacteria growth (e.g., Bifidobacterium). Lactic acid, rather than bacteriocin, was further confirmed as the key compound that determined the antimicrobial activity of CCFM6432. Collectively, these results first proved the psychobiotic potential of the Pediococcus acidilactici strain. Ingestion of CCFM6432, or fermented food containing it, may facilitate mental health management in daily life, especially during the COVID-19 pandemic.

An in vitro screening method for probiotics with antidepressant-like effect using the enterochromaffin cell model.

Certain probiotics can regulate the host's neurobehavioral function through the microbiota-gut-brain axis. However, screening these probiotics is mainly carried out in animal models, and is costly and inefficient. Herein, a putative enterochromaffin cell line (RIN14B) was used as an in vitro pre-screening model; 30 bacterial strains were tested for bacteria-stimulated tryptophan hydroxylase 1 gene (Tph1) expression and 5-hydroxytryptophan/5-hydroxytryptamine secretion. All strains were further validated for their neurobehavioral effects in chronic stress-induced depressive mice. Using partial least squares (PLS) modeling of in vitro and in vivo datasets, we found that the level of Tph1 mRNA in RIN14B significantly correlated with the performance of a forced swim test and sucrose preference test, and serum corticosterone level in chronically stressed mice. Four strains were identified as the best candidates among 30 strains using principal component analysis on all in vivo measures, and unsurprisingly, three of them could enhance Tph1 expression in RIN14B, which further proved that the RIN14B-based screening method (especially the detection of bacteria-stimulated Tph1 mRNA) has good predictive validity and screening efficiency for the strain's antidepressant-like capacity. Collectively, this study provides a novel in vitro method for screening probiotics (or other related bioproducts) with antidepressant-like potential.

Ingestion of Bifidobacterium longum subspecies infantis strain CCFM687 regulated emotional behavior and the central BDNF pathway in chronic stress-induced depressive mice through reshaping the gut microbiota.

Increasing evidence points to the effect of the gut microbiota on central nervous system functions. Supplementation of certain microbial strains has been demonstrated to alleviate depressive behaviors and neurological abnormalities. This study took the approach to screen for an anti-depressive Bifidobacterium longum strain from fourteen candidates and systematically verified its effect in a chronic stress-induced depression mice model. B. longum subsp. infantis strain CCFM687 could significantly enhance the biosynthesis of 5-hydroxytryptamine (5-HTP) in vitro in RIN14B cells through up-regulation of the Tph1 gene expression. Administration of CCFM687 in mice significantly improved the scores in behavioral tests and increased the level of 5-HTP and serotonin (5-HT) in the prefrontal cortex (PFC) of the brain. The brain-derived neurotrophic factor (BDNF) in the PFC was also increased, possibly through the 5-HT1A-CREB-BDNF pathway. In addition, CCFM687 alleviated the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis response and accordingly reversed the peripheral inflammation status. Moreover, the stress-induced structural and functional dysbiosis of the gut microbiome was improved by CCFM687, through increased alpha diversity and abundance of butyrate-producing bacteria, in conjunction with inhibition of pathogenic gene expression. In summary, these results indicate that supplementation of B. longum subsp. infantis strain CCFM687 may prevent the onset of depression from chronic stress, and RIN14B could serve as an efficient cell model for rapid screening of anti-depressive probiotics.