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The therapeutic readiness of probiotics in major depressive disorder: A systematic review of randomised controlled trials.
BACKGROUND: Major depressive disorder (MDD) is a globally prevalent psychiatric condition associated with significant morbidity and often suboptimal treatment outcomes. Probiotics have emerged as a promising adjunctive therapy targeting the gut-brain axis in MDD. AIMS: This systematic review aimed to critically evaluate the efficacy of probiotics in the treatment of clinically diagnosed MDD, assess methodological quality and therapeutic readiness, and identify research gaps relevant to clinical application. METHODS: A systematic search of MEDLINE, Web of Science, and PubMed was conducted in June 2023 in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Double-blind, placebo-controlled, randomised controlled trials (RCTs) involving adults with MDD were included. Risk of bias was assessed using the Cochrane Risk of Bias tool. RESULTS: Thirteen RCTs involving 437 adults aged 18-75 years with MDD were included. Most trials reported improvements in depressive symptoms, particularly in outpatients with mild-to-moderate MDD treated with multi-strain formulations containing Lactobacillus and Bifidobacterium over 4-8 weeks. Secondary outcomes across metabolic, inflammatory, cognitive, neurotrophic, and gastrointestinal domains showed variable improvements. Probiotic benefits were most consistent in Iranian outpatients, more modest in European inpatients, and positive but variable in East Asian outpatients. Risk of bias was predominantly low, though attrition, selective reporting, and methodological heterogeneity remained sources of bias. CONCLUSIONS: Probiotics appear safe and well-tolerated, with modest adjunctive benefit in MDD, most evident for multi-strain formulations in younger, outpatient populations with mild-to-moderate symptoms, supporting an individualised, context-dependent approach. Future trials should stratify patients, extend intervention durations, and integrate mechanistic endpoints to refine patient-tailored recommendations.
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No Evidence of Gut Microbiota Alteration in Psoriasis Patients Switching to Brodalumab after Loss of TNFα Inhibition Effect.
Biological agents used to treat severe psoriasis may alter the gut microbiota, though current knowledge is limited. This study examines whether switching from TNFα inhibitors, from which patients had reduced or lost effect, to brodalumab, an IL-17 inhibitor, affects the gut microbiota in patients with psoriasis and how these changes correlate with the clinical variables of psoriasis severity and depressive symptoms. Fecal samples from patients were collected before the treatment switch and 12 weeks after the switch and were analyzed for the microbiota composition using next-generation sequencing targeting the V3-V5 region of the 16S rRNA gene, followed by bioinformatics analysis. No significant changes in overall gut microbiota composition were observed after the treatment switch, although individual variations in the Firmicutes/Bacteroidetes ratio were noted, and no significant correlations with clinical variables were found. These findings suggest that short-term changes in gut microbiota in patients with psoriasis are limited and that dysbiosis may be influenced by the interplay of various microbial populations rather than specific taxa. This study provides a foundation for further research into the effects of biological treatments on the gut microbiota in patients with psoriasis.
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Cannabidiol modulates brain molecular alterations, gut microbiota dysbiosis and alcohol self-administration in a mouse model of fetal alcohol spectrum disorder.
Fetal Alcohol Spectrum Disorder (FASD) is a range of neurodevelopmental abnormalities caused by Perinatal Alcohol Exposure (PAE), leading to profound behavioral and molecular disturbances in the offspring. Unraveling the central and peripheral mechanisms involved, including the microbiota-gut-brain axis, is crucial to improving our understanding of the disease and developing new treatment strategies from a sex perspective. In this study, we investigated the impact of PAE on emotional behavior, brain biomarkers, and gut microbiota composition and diversity in a preclinical C57BL/6 J mouse model, as well as the extent of their vulnerability to alcohol consumption. Furthermore, we have also explored the potential modulatory effects of cannabidiol (CBD) administered chronically (30 mg/kg/day, i.p.) from weaning on PAE-induced sex-dependent emotional and brain molecular impairments, gut microbiota dysbiosis, and increased alcohol reinforcing and motivational actions. FASD model mice showed increased anxiety- and depressive-like behavior accompanied by sex-dependent changes in synaptic density, dopamine D2/D3 receptors availability, cannabinoid receptors 1 and 2 (Cnr1/Cnr2), tyrosine hydroxylase (Th), and serotonin transporter (Slc6a4) gene expression, and gut microbiota dysbiosis. Interestingly, CBD sex-dependently improved and/or normalized PAE-induced behavioral and molecular disturbances. In addition, females but not males exposed to the animal model of FASD showed a higher motivation to drink alcohol, which CBD abolished. Our findings provide new insights into the brain and gut microbiota sex-dependent mechanisms involved in FASD pathophysiology and further highlight the therapeutic potential of CBD to improve the management of FASD-induced emotional disturbances and alcohol addiction from a sex-oriented approach.
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Vagus nerve stimulation and gut microbiota interactions: A novel therapeutic avenue for neuropsychiatric disorders.
The rising prevalence of treatment-resistant neuropsychiatric disorders underscores the need for innovative and effective treatment strategies. The gut microbiota (GM) plays a pivotal role in the progression of these diseases, influencing the brain and mental health through the gut-brain axis (GBA). The vagus nerve plays a significant role in the GBA, making it a key area of focus for potential novel therapeutic interventions. Vagus nerve stimulation (VNS) was introduced and approved as a treatment for refractory forms of some neuropsychological disorders, such as depression and epilepsy. Considering its impact on several brain regions that play a vital part in mood, motivation, affection, and cognitive function, the VNS has shown significant therapeutic potential for treating a variety of neuropsychiatric disorders. Using VNS to target the bidirectional communication pathways linking the GM and the VN could present an exciting and novel approach to treating neuropsychological disorders. Imbalances in the GM, such as dysbiosis, can impair the communication pathways between the gut and the brain, contributing to the development of neuropsychological disorders. VNS shows potential for modulating these interconnected systems, helping to restore balance. Interestingly, the composition of the GM may also influence the effectiveness of VNS, as it has the potential to modify the brain's response to this therapeutic approach. This study provides a comprehensive analysis of a relatively unexplored but noteworthy interaction between VNS and GM in the treatment of neuropsychiatric disorders. In addition, we discussed the mechanisms, therapeutic potential, and clinical implications of VNS on the GBA across neuropsychiatric disorders.
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Differences in clinical features and gut microbiota between individuals with methamphetamine casual use and methamphetamine use disorder.
BACKGROUND: The transition from methamphetamine (MA) casual use (MCU) to compulsive use is enigmatic as some MA users can remain in casual use, but some cannot. There is a knowledge gap if gut microbiota (GM) play a role in differing MCU from MA use disorder (MUD). We aimed to investigate the clinical features and GM differences between individuals with MCU and MUD. METHOD: We recruited two groups of MA users -MCU and MUD - and matched them according to age and body mass index (n=21 in each group). Participants were accessed using the Semi-Structured Assessment for Drug Dependence and Alcoholism, and their fecal samples were undergone 16S ribosomal DNA sequencing. We compared the hosts' clinical features and GM diversity, composition, and structure (represented by enterotypes) between the two groups. We have identified differential microbes between the two groups and performed network analyses connecting GM and the clinical traits. RESULT: Compared with the casual users, individuals with MUD had higher incidences of MA-induced neuropsychiatric symptoms (e.g., paranoia, depression) and withdrawal symptoms (e.g., fatigue, drowsiness, and increased appetite), as well as stronger cravings for and intentions to use MA, and increased MA tolerance. The GM diversity showed no significant differences between the two groups, but four genera (Halomonas, Clostridium, Devosia, and Dorea) were enriched in the individuals with MUD (p<0.05). Three distinct enterotypes were identified in all MA users, and Ruminococcus-driven enterotype 2 was dominant in individuals with MUD compared to the MCU (61.90% vs. 28.60%, p=0.03). Network analysis shows that Devosia is the hub genus (hub index = 0.75), which is not only related to the counts of the MUD diagnostic criteria (ρ=0.40; p=0.01) but also to the clinical features of MA users such as reduced social activities (ρ=0.54; p<0.01). Devosia is also associated with the increased intention to use MA (ρ=0.48; p<0.01), increased MA tolerance (ρ=0.38; p=0.01), craving for MA (ρ=0.37; p=0.01), and MA-induced withdrawal symptoms (p<0.05). CONCLUSION: Our findings suggest that Ruminococcus-driven enterotype 2 and the genera Devosia might be two influential factors that differentiate MA casual use from MUD, but further studies are warranted.
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Repeated use of 3,4-methylenedioxymethamphetamine is associated with the resilience in mice after chronic social defeat stress: A role of gut-microbiota-brain axis.
3,4-Methylenedioxymethamphetamine (MDMA), the most widely used illicit compound worldwide, is the most attractive therapeutic drug for post-traumatic stress disorder (PTSD). Recent observational studies of US adults demonstrated that lifetime MDMA use was associated with lower risk of depression. Here, we examined whether repeated administration of MDMA can affect resilience versus susceptibility in mice exposed to chronic social defeat stress (CSDS). CSDS produced splenomegaly, anhedonia-like phenotype, and higher plasma levels of interleukin-6 (IL-6) in the saline-treated mice. In contrast, CSDS did not cause these changes in the MDMA-treated mice. Analysis of gut microbiome found several microbes altered between saline + CSDS group and MDMA + CSDS group. Untargeted metabolomics analysis showed that plasma levels of N-epsilon-methyl-L-lysine in the saline + CSDS group were significantly higher than those in the control and MDMA + CSDS groups. Interestingly, there were positive correlations between plasma IL-6 levels and the abundance of several microbes (or plasma N-epsilon-methyl-L-lysine) in the three groups. Furthermore, there were also positive correlations between the abundance of several microbes and N-epsilon-methyl-L-lysine in the three groups. In conclusion, these data suggest that repeated administration of MDMA might contribute to stress resilience in mice subjected to CSDS through gut-microbiota-brain axis.
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Effects of (R)-ketamine on reduced bone mineral density in ovariectomized mice: A role of gut microbiota.
Depression is a high risk for osteoporosis, suggesting an association between depression and low bone mineral density (BMD). We reported that the novel antidepressant (R)-ketamine could ameliorate the reduced BMD in the ovariectomized (OVX) mice which is an animal model of postmenopausal osteoporosis. Given the role of gut microbiota in depression and bone homeostasis, we examined whether gut microbiota plays a role in the beneficial effects of (R)-ketamine in the reduced BMD of OVX mice. OVX or sham was operated for female mice. Subsequently, saline (10 ml/kg/day, twice weekly) or (R)-ketamine (10 mg/kg/day, twice weekly) was administered intraperitoneally into OVX or sham mice for the six weeks. The reduction of cortical BMD and total BMD in the OVX mice was significantly ameliorated after subsequent repeated intermittent administration of (R)-ketamine. Furthermore, there were significant changes in the α- and β-diversity between OVX + saline group and OVX + (R)-ketamine group. There were correlations between several OTUs and cortical (or total) BMD. There were also positive correlations between the genera Turicibacter and cortical (or total) BMD. Moreover, there were correlations between several metabolites in blood and cortical (or total) BMD. These data suggest that (R)-ketamine may ameliorate the reduced cortical BMD and total BMD in OVX mice through anti-inflammatory actions via gut microbiota. Therefore, it is likely that (R)-ketamine would be a therapeutic drug for depressed patients with low BMD or patients with osteoporosis.
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Analysis of gut microbiota in Restless Legs Syndrome: searching for a metagenomic signature.
STUDY OBJECTIVES: We aim to analyze the microbiota composition in Restless Legs Syndrome (RLS) patients and its relationship with the different RLS phenotypes. METHODS: We recruited idiopathic RLS (RLS) and insomnia (INS) patients and healthy subjects (CTRL). Validated questionnaires (Pittsburg Sleep Quality Index, International Restless Legs Syndrome Study Group Rating Scale, Insomnia Severity Index, Beck Depression Inventory-II) were administered in the RLS and INS. Fecal microbiota was analyzed by 16S rRNA gene sequencing according to Illumina metagenomics standard procedure on MiSeq Platform. Dada2 pipeline was used to process sequencing data, while DESeq2 and Aldex2 tools were used to calculate differential abundance taxa, correcting for age, sex, body mass index, sequencing run, and presence of mood disorders. RESULTS: The sample included 37 RLS (28 females, mean age 64.78 years), 31 INS (22 females, mean age 60.64 years), and 33 CTRL (24 females, mean age 62.54 years). Differential abundance analysis revealed a statistically significant decrease in the abundance of Lachnoclostridium and Flavonifractor genera in RLS compared to CTRL and INS, but not in the INS compared to CTRL. Lachnoclostridium abundance tended to decrease with long disease duration and a predominant motor phenotype. In the RLS group, several genera were identified as significantly associated with International Restless Legs Syndrome Study Group Rating Scale and Pittsburg Sleep Quality Index scores. CONCLUSIONS: Although only a few previous studies have reported the presence of small intestinal bacterial overgrowth in RLS, to the best of our knowledge this is the first study to highlight significant differences in the gut microbiota composition of RLS compared to both CTRL and INS, identifying a specific RLS metagenomic signature. Statement of Significance This is the first study to comprehensively characterize the gut microbiota in patients with Restless Legs Syndrome (RLS), identifying a distinct microbial signature compared to insomnia patients and healthy controls. We observed alterations alpha and beta diversity and specific changes in bacterial families and genera, some of which significantly correlated with RLS clinical features. In particular, Lachnoclostridium genus was significantly reduced in RLS and tended to be less abundant in patients with longer disease duration and without sensory symptoms. This genus is known to modulate systemic inflammation through the production of short-chain fatty acids, suggesting a potential link between gut dysbiosis, inflammation, and dopaminergic dysfunction. These findings support a role for gut microbiota alterations in RLS pathogenesis and open new avenues for microbiota-based diagnostic and therapeutic strategies.
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Gut-brain axis volatile organic compounds derived from breath distinguish between schizophrenia and major depressive disorder.
BACKGROUND: Signatures from the metabolome and microbiome have already been introduced as candidates for diagnostic and treatment support. The aim of this study was to investigate the utility of volatile organic compounds (VOCs) from the breath for detection of schizophrenia and depression. METHODS: Patients with a diagnosis of major depressive disorder (MDD) or schizophrenia, as well as healthy controls, were recruited to participate. After being clinically assessed and receiving instruction, each participant independently collected breath samples for subsequent examination by proton transfer-reaction mass spectrometry. RESULTS: The sample consisted of 104 participants: 36 patients with MDD, 34 patients with schizophrenia and 34 healthy controls. Through mixed-model and deep learning analyses, 5 VOCs contained in the participants' breath samples were detected that significantly differentiated between diagnostic groups and healthy controls, namely VOCs with mass-to-charge ratios (m/z) 60, 69, 74, 88 and 90, which had classification accuracy of 76.8% to distinguish participants with MDD from healthy controls, 83.6% to distinguish participants with schizophrenia from healthy controls and 80.9% to distinguish participants with MDD from those with schizophrenia. No significant associations with medication, illness duration, age of onset or time in hospital were detected for these VOCs. LIMITATIONS: The sample size did not allow generalization, and confounders such as nutrition and medication need to be tested. CONCLUSION: This study established promising results for the use of human breath gas for detection of schizophrenia and MDD. Two VOCs, 1 with m/z 60 (identified as trimethylamine) and 1 with m/z 90 (identified as butyric acid) could then be further connected to the interworking of the microbiota-gut-brain axis.
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Fecal Microbiota Transplantation Improves Clinical Symptoms of Fibromyalgia: An Open-Label, Randomized, Nonplacebo-Controlled Study.
Fibromyalgia (FM) is a complex and poorly understood disorder characterized by chronic and widespread musculoskeletal pain, of which the etiology remains unknown. Now, the disorder of the gut microbiome is considered as one of the main causes of FM. This study aimed to investigate the potential benefits of fecal microbiota transplantation (FMT) in patients with FM. A total of 45 patients completed this open-label, randomized, nonplacebo-controlled clinical study. The numerical rating scale scores in the FMT group were slightly lower than the control group at 1 month (P > .05), and they decreased significantly at 2, 3, 6, and 12 months after treatment (P < .001). Besides, compared with the control group, the Widespread Pain Index, Symptom Severity, Hospital Anxiety and Depression Scale, and Pittsburgh Sleep Quality Index scores were significantly lower in the FMT group at different time points (P < .001). After 6 months of treatment, there was a significant increase in serotonin (5-hydroxytryptamine) and gamma-aminobutyric acid levels (P < .001), while glutamate levels significantly decreased in the FMT group (P < .001). The total effective rate was higher in the FMT group (90.9%) compared to the control group (56.5%) after 6 months of treatment (P < .05). FMT can effectively improve the clinical symptoms of FM. With the close relations between the changes in neurotransmitters and FM, certain neurotransmitters may serve as a diagnostic marker or potential target for FM patients. PERSPECTIVE: FMT is a novel therapy that aims to restore the gut microbial balance and modulate the gut-brain axis. It is valuable to further explore the therapeutic effect of FMT on FM. Furthermore, certain neurotransmitters may become a diagnostic marker or a new therapeutic target for FM patients.