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Endocannabinoid system mediates the association between gut-microbial diversity and anhedonia/amotivation in a general population cohort.
Anhedonia and amotivation are debilitating symptoms and represent unmet therapeutic needs in a range of clinical conditions. The gut-microbiome-endocannabinoid axis might represent a potential modifiable target for interventions. Based on results obtained from animal models, we tested the hypothesis that the endocannabinoid system mediates the association between gut-microbiome diversity and anhedonia/amotivation in a general population cohort. We used longitudinal data collected from 786 volunteer twins recruited as part the TwinsUK register. Our hypothesis was tested with a multilevel mediation model using family structure as random intercept. The model was set using alpha diversity (within-individual gut-microbial diversity) as predictor, serum and faecal levels of the endocannabinoid palmitoylethanolamide (PEA) as mediator, and anhedonia/amotivation as outcome. PEA is considered the endogenous equivalent of cannabidiol, with increased serum levels believed to have anti-depressive effects, while increased stool PEA levels, reflecting increased excretion, are believed to have opposite, detrimental, effects on mental health. We therefore expected that either reduced serum PEA or increased stool PEA would mediate the association between microbial diversity and anhedonia amotivation. Analyses were adjusted for obesity, diet, antidepressant use, sociodemographic and technical covariates. Data were imputed using multiple imputation by chained equations. Mean age was 65.2 ± 7.6; 93% of the sample were females. We found a direct, significant, association between alpha diversity and anhedonia/amotivation (β = -0.37; 95%CI: -0.71 to -0.03; P = 0.03). Faecal, but not serum, levels of the endocannabinoid palmitoylethanolamide (PEA) mediated this association: the indirect effect was significant (β = -0.13; 95%CI: -0.24 to -0.01; P = 0.03), as was the total effect (β = -0.38; 95%CI: -0.72 to -0.04; P = 0.03), whereas the direct effect of alpha diversity on anhedonia/amotivation was attenuated fully (β = -0.25; 95%CI: -0.60 to 0.09; P = 0.16). Our results suggest that gut-microbial diversity might contribute to anhedonia/amotivation via the endocannabinoid system. These findings shed light on the biological underpinnings of anhedonia/amotivation and suggest the gut microbiota-endocannabinoid axis as a promising therapeutic target in an area of unmet clinical need.
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Preface to the Special Issue: "Microbiota and Gut-Brain Axis".
The microbiota-gut-brain axis has emerged as a central framework for understanding how microbial communities influence nervous system development, function, and disease. This Special Issue highlights three interconnected themes: microbial metabolites and neurochemistry, developmental and neuroimmune mechanisms, and translation to neurological and psychiatric disease. The articles in the collection examine how microbial metabolites modulate neuroinflammatory and neurochemical pathways, how stress, development, immune signaling, and gut health shape gut-brain communication across the lifespan, and how these mechanisms contribute to disorders including autism spectrum disorder, depression, Parkinson's disease, spinal cord injury, and addiction. Together, these contributions advance a mechanistic and translational understanding of microbiota-gut-brain interactions and identify important directions for future research.
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Magnetic resonance spectroscopy reveals oral Lactobacillus promotion of increases in brain GABA, N-acetyl aspartate and glutamate.
The gut microbiome has been shown to regulate the development and functions of the enteric and central nervous systems. Its involvement in the regulation of behavior has attracted particular attention because of its potential translational importance in clinical disorders, however little is known about the pathways involved. We previously have demonstrated that administration of Lactobacillus rhamnosus (JB-1) to healthy male BALB/c mice, promotes consistent changes in GABA-A and -B receptor sub-types in specific brain regions, accompanied by reductions in anxiety and depression-related behaviors. In the present study, using magnetic resonance spectroscopy (MRS), we quantitatively assessed two clinically validated biomarkers of brain activity and function, glutamate+glutamine (Glx) and total N-acetyl aspartate+N-acetyl aspartyl glutamic acid (tNAA), as well as GABA, the chief brain inhibitory neurotransmitter. Mice received 1×10(9) cfu of JB-1 per day for 4weeks and were subjected to MRS weekly and again 4weeks after cessation of treatment to ascertain temporal changes in these neurometabolites. Baseline concentrations for Glx, tNAA and GABA were equal to 10.4±0.3mM, 8.7±0.1mM, and 1.2±0.1mM, respectively. Delayed increases were first seen for Glx (~10%) and NAA (~37%) at 2weeks which persisted only to the end of treatment. However, Glx was still elevated 4weeks after treatment had ceased. Significantly elevated GABA (~25%) was only seen at 4weeks. These results suggest specific metabolic pathways in our pursuit of mechanisms of action of psychoactive bacteria. They also offer through application of standard clinical neurodiagnostic techniques, translational opportunities to assess biomarkers accompanying behavioral changes induced by alterations in the gut microbiome.
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Long-term microbiome and clinical effects of a microbiome-guided personalized diet versus low-FODMAP diet in irritable bowel syndrome: A 12-month follow-up randomized controlled trial.
Dietary therapy is central to irritable bowel syndrome (IBS) management, yet the long-term durability of the low-FODMAP diet (LFD), and of microbiome-guided personalization, remains unclear. We assessed the long-term clinical and gut-microbiome effects of a microbiome-guided personalized diet (PD) compared with a standard LFD in adults meeting Rome IV criteria for IBS. In this multicenter, open-label randomized controlled trial with blinded outcome assessment, participants who completed a 6-week dietary intervention (PD or LFD) were followed at 6 and 12 months without further dietary intervention. Outcomes included the IBS Severity Scoring System (IBS-SSS), IBS Quality of Life (IBS-QOL), and the Hospital Anxiety and Depression Scale (HADS); gut microbiota were profiled by 16S rRNA sequencing. Longitudinal changes were evaluated using linear mixed-effects models, responder analyses, PERMANOVA, and PERMDISP. Both diets reduced IBS-SSS at 6 weeks. PD maintained symptom improvement at 6 and 12 months (-82.0 and -78.3 points from baseline), whereas LFD benefits regressed by 12 months (+29.3 points; between-group p = 0.001). At 12 months, IBS-SSS responder rates were higher with PD than LFD (62.5% vs 34.5%; absolute risk difference +28.0%, 95% CI 4.2-47.7; Fisher p = 0.029), and IBS-QOL, HADS-anxiety, and HADS-depression showed more favourable trajectories with PD. PD was associated with sustained Shannon alpha-diversity gains (+0.488 at 6 weeks; +0.205 at 12 months; both p < 0.01). A modest between-group beta-diversity difference at 6 months (R2 = 0.035; p = 0.011) was not significant at 12 months. This hypothesis-generating follow-up suggests more durable benefit with PD; larger trials powered for long-term clinical and microbiome outcomes are warranted.
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The correlation between gut microbiota and both neurotransmitters and mental disorders: A narrative review.
The gastrointestinal tract is embedded with microorganisms of numerous genera, referred to as gut microbiota. Gut microbiota has multiple effects on many body organs, including the brain. There is a bidirectional connection between the gut and brain called the gut-brain-axis, and these connections are formed through immunological, neuronal, and neuroendocrine pathways. In addition, gut microbiota modulates the synthesis and functioning of neurotransmitters. Therefore, the disruption of the gut microbiota in the composition or function, which is known as dysbiosis, is associated with the pathogenesis of many mental disorders, such as schizophrenia, depression, and other psychiatric disorders. This review aims to summarize the modulation role of the gut microbiota in 4 prominent neurotransmitters (tryptophan and serotonergic system, dopamine, gamma-aminobutyric acid, and glutamate), as well as its association with 4 psychiatric disorders (schizophrenia, depression, anxiety disorders, and autism spectrum disorder). More future research is required to develop efficient gut-microbiota-based therapies for these illnesses.
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Stress, microbiota, and the gut-brain axis in mental and digestive health.
The prevailing mind-body dualism in contemporary medicine, rooted in reductionism and the fragmentation of knowledge, has impeded the development of a conceptual model that can adequately address the complexity of illnesses. Integrating biomedical data into a cohesive model that considers the mind-body-context interconnections is essential. This integration is not merely theoretical; rather, it has significant clinical implications. This is exemplified by chronic stress-related mental and digestive disorders. The onset and development of these disorders are intimately linked to chronic psychological stress via the brain-gut-microbiota axis. The present article examines the evidence and mechanisms indicating that stress is a primary factor and a potentiator of symptom severity in common mental health and digestive diseases, with a particular focus on human studies. However, due to space limitations, only a very general overview of preventive and therapeutic clinical strategies is provided. It is hoped that the recurring phrase, "Everything that happens to you is due to stress," will become more comprehensible to the physician after reading this manuscript.
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Fecal transplantation from humans with obesity to mice drives a selective microbial signature without impacting behavioral and metabolic health.
Obesity is associated with alterations in the gut microbiome that may contribute to metabolic and mental health disturbances. Fecal microbiota transplantation (FMT) from humans to mice is a model proposed to study human microbiota-associated disorders. In this study, we investigated whether gut microbiota from human donors with obesity could affect behavior and metabolomic profiles of mice. Stools from donors with obesity and from lean donors were inoculated to antibiotic-pretreated mice fed a standard low-fat diet throughout the experiment. Obese-recipient mice exhibited a lower bacterial alpha-diversity and limited changes in specific taxa (e.g., an increase in Eubacterium) but were similar to lean-recipient mice in terms of dietary intake, body weight, fat mass, anxiety/depression-like behavior and glucose homeostasis. Non-targeted LC-MS metabolomic analysis revealed no change in the portal and cava serum samples. However, 1-methylnicotinamide, indole-3-acetic acid (I3A) and methyllysine were increased in the cecal content of obese-recipient compared to lean-recipient mice. Microbial metabolites derived from amino acids were positively correlated with Eubacterium. These results indicate that FMT from donors with obesity to mice fed chow diet (low in lipids) leads to minor but persistent change in intestinal microbial-derived metabolites, without recapitulating the metabolic and behavioral alterations of obesity.
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Effect of fecal microbiota transplantation on patients with sporadic amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled trial.
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder marked by the progressive loss of motor neurons. Recent insights into ALS pathogenesis underscore the pivotal role of the gut microbiome, prompting an investigation into the potential therapeutic impact of fecal microbiota transplantation (FMT) on sporadic ALS patients. METHODS: Conducted as a double-blind, placebo-controlled, parallel-group, randomized clinical trial, the study enrolled 27 participants from October 2022 to April 2023. The participants were followed up for 6 months from February 2023 to October 2023, during in-person visits at baseline, week 15, week 23, and week 35. The participants, evenly randomized, received either healthy donor FMT (FMT, n = 14) or a mixture of 0.9% saline and food coloring (E150c) as sham transplantation (placebo, n = 13). The primary outcome measured the change in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score from baseline to week 35. Secondary outcomes included changes in gastrointestinal and respiratory functions, muscle strength, autonomic function, cognition, quality of life, intestinal microbiome composition, and plasm neurofilament light chain protein (NFL). Efficacy and safety outcomes were assessed in the intention-to-treat population. RESULTS: A total of 27 randomized patients (47% women; mean age, 67.2 years), 24 participants completed the entire study. Notably, ALSFRS-R score changes exhibited no significant differences between FMT (6.1 [SD, 3.11]) and placebo (6.41[SD, 2.73]) groups from baseline to week 35. Secondary efficacy outcomes, encompassing respiratory function, muscle strength, autonomic function, cognition, quality of life, and plasm NFL, showed no significant differences. Nevertheless, the FMT group exhibited improvements in constipation, depression, and anxiety symptoms. FMT induced a shift in gut microbiome community composition, marked by increased abundance of Bifidobacterium, which persisted until week 15 (95% CI, 0.04 to 0.28; p = 0.01). Gastrointestinal adverse events were the primary manifestations of FMT-related side effects. CONCLUSIONS: In this clinical trial involving 27 sporadic ALS patients, FMT did not significantly slow the decline in ALSFRS-R score. Larger multicenter trials are needed to confirm the efficacy of FMT in sporadic ALS patients and to explore the underlying biological mechanisms. TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR 2200064504.
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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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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.