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The Gut-Brain Axis: How Microbiota and Host Inflammasome Influence Brain Physiology and Pathology.
The human microbiota has a fundamental role in host physiology and pathology. Gut microbial alteration, also known as dysbiosis, is a condition associated not only with gastrointestinal disorders but also with diseases affecting other distal organs. Recently it became evident that the intestinal bacteria can affect the central nervous system (CNS) physiology and inflammation. The nervous system and the gastrointestinal tract are communicating through a bidirectional network of signaling pathways called the gut-brain axis, which consists of multiple connections, including the vagus nerve, the immune system, and bacterial metabolites and products. During dysbiosis, these pathways are dysregulated and associated with altered permeability of the blood-brain barrier (BBB) and neuroinflammation. However, numerous mechanisms behind the impact of the gut microbiota in neuro-development and -pathogenesis remain poorly understood. There are several immune pathways involved in CNS homeostasis and inflammation. Among those, the inflammasome pathway has been linked to neuroinflammatory conditions such as multiple sclerosis, Alzheimer's and Parkinson's diseases, but also anxiety and depressive-like disorders. The inflammasome complex assembles upon cell activation due to exposure to microbes, danger signals, or stress and lead to the production of pro-inflammatory cytokines (interleukin-1β and interleukin-18) and to pyroptosis. Evidences suggest that there is a reciprocal influence of microbiota and inflammasome activation in the brain. However, how this influence is precisely working is yet to be discovered. Herein, we discuss the status of the knowledge and the open questions in the field focusing on the function of intestinal microbial metabolites or products on CNS cells during healthy and inflammatory conditions, such as multiple sclerosis, Alzheimer's and Parkinson's diseases, and also neuropsychiatric disorders. In particular, we focus on the innate inflammasome pathway as immune mechanism that can be involved in several of these conditions, upon exposure to certain microbes.
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The Effect of A Whey-Protein and Galacto-Oligosaccharides Based Product on Parameters of Sleep Quality, Stress, and Gut Microbiota in Apparently Healthy Adults with Moderate Sleep Disturbances: A Randomized Controlled Cross-Over Study.
People experiencing sleep problems may benefit from nutrients supporting serotonin metabolism and stress reduction. We studied the effect of a dairy-based product (DP) containing protein, galacto-oligosaccharides, vitamins and minerals, on sleep quality, stress, and gut-microbiota. In a cross-over RCT (three weeks intervention; three weeks washout), adults (n = 70; 30-50 y) with sleep disturbances (Pittsburgh Sleep Quality Index (PSQI) ≥ 9) consumed products 1 h before bed-time. Sleep quality (PSQI) was measured weekly, stress at base- and end-line (Depression Anxiety Stress Scale and saliva cortisol). Fecal samples were collected in the 1st intervention period only. Compared to placebo (skimmed milk), PSQI was only lower at day 14 in the 2nd intervention period in intention-to-treat (ITT) (p = 0.017; n = 69) and per-protocol (PP) (p = 0.038; n = 64) analyses. Post-hoc analysis (modified-PP: n=47, with baseline PSQI ≥ 9, and endline day 14), however, showed a decrease in PSQI (-1.60 ± 2.53; p = 0.034). Early morning saliva cortisol decreased versus placebo (p = 0.045). Relative abundance of Bifidobacterium increased (p = 0.02). Redundancy analysis showed an inverse relationship between baseline microbiota composition and baseline PSQI (p = 0.046). Thus, although DP did not improve sleep quality in ITT and PP populations, it did in the modPP. DP reduced salivary cortisol and stimulated Bifidobacterium, which possibly is important for sleep improvement.
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The putative role of the microbiota in the development of neuropsychiatric disorders following early childhood malnutrition.
Early childhood malnutrition (ECM) is robustly associated with increased risk of cognitive impairment and neuropsychiatric disorders across the lifespan, yet the biological mechanisms underlying this vulnerability remain incompletely defined. Accumulating clinical evidence indicates that ECM is associated with delayed maturation and reduced diversity of the intestinal microbiota, including depletion of taxa involved in short-chain fatty acid production and complex carbohydrate fermentation. These microbial alterations coincide with broader metabolic, immune, and barrier dysfunctions - such as reduced availability of neuroactive metabolites, low-grade inflammation, and impaired intestinal and vascular integrity - that plausibly intersect with critical processes in brain development. Experimental studies in animal models demonstrate that perturbation of microbiota-derived signaling during sensitive early periods is sufficient to induce lasting neurodevelopmental and behavioral changes, providing proof of concept for a causal role. However, in human populations, the microbiota remains best viewed as a biologically plausible intermediary rather than a proven determinant of outcome. Future progress will require integrative longitudinal studies and developmentally timed interventions to test whether restoration of microbiota function can modify neurodevelopmental trajectories. Clarifying these relationships has important implications for understanding the long-term consequences of early nutritional adversity and for identifying preventive strategies in settings where ECM remains prevalent.
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Saffron extract (Safr'Inside™) improves anxiety related behaviour in a mouse model of low-grade inflammation through the modulation of the microbiota and gut derived metabolites.
Treatment of anxiety and depression predominantly centres around pharmacological interventions, which have faced criticism for their associated side effects, lack of efficacy and low tolerability. Saffron, which is reportedly well tolerated in humans, has been recognised for its antidepressant and anti-anxiety properties. Indeed, we previously reported upon the efficacy of saffron extract supplementation in healthy adults with subclinical anxiety. However, the molecular aetiology remains unclear. In a rodent model of low-grade chronic inflammation, we explored the impact of a saffron extract (Safr'Inside™) supplemented at a physiological dose, which equated to 22 ± 1.2 mg per day human equivalent dose for a person of 60 kg. Behavioural tests (Open Field task, Y maze, Novel object recognition), caecal 16S rRNA microbial sequencing, caecal 1H NMR metabolomic analysis and 2DE brain proteomic analyses were completed to probe gut-brain axis interactions. Time occupying the centre of the Open Field maze (OF) was increased by 62% in saffron supplemented animals. This improvement in anxiety-related behaviour coincided with gut microbial shifts, notably Akkermansia, Muribaculaceae, Christensenellacae and Alloprevotella which significantly increased in response to saffron supplementation. Akkermansia and Muribaculaceae abundance negatively correlated with the neurotoxic metabolite dimethylamine which was reduced in saffron supplemented animals. Brain proteomic analysis highlighted several significantly altered proteins including ketimine reductase mu-crystallin which also correlated with dimethylamine concentration. Both dimethylamine and ketimine reductase mu-crystallin were associated with OF performance. This may be indicative of a novel interaction across the gut-brain axis which contributes to anxiety-related disorders.
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Exploring the acute and chronic effects of a multistrain probiotic supplement on cognitive function and mood in healthy older adults: a randomized controlled trial.
BACKGROUND: Aging is associated with a decline in cognitive function and vulnerability to depression. Probiotic supplements have shown beneficial effects on cognition and mood in clinical populations, but the potential benefit for healthy older adults experiencing age-related decline in cognition remains unclear. OBJECTIVES: The primary aim of the present work was to explore the effect of a chronic (long-term) multispecies probiotic intervention on cognition in healthy aging adults. Secondary aims included exploring the chronic effect on mood outcomes and gut microbiota community, as well as a novel investigation into the acute effect of supplementation on cognition and mood. METHODS: The study employed a randomized, placebo-controlled, cross-over trial in 30 healthy older adults to explore the acute (1 d) and chronic (8 wk) effects of a probiotic supplement on cognitive domains of memory and executive function, alongside mood measures of stress, anxiety, depression, and cognitive reactivity to sad mood. 16s rRNA sequencing of stool samples was also performed pre- and postchronic intervention to assess potential effects on the gut microbiota. RESULTS: Acute probiotic supplementation was associated with faster reaction times on cognitively demanding trials during a task of executive function [-64.91 ms, 95% confidence interval (CI): -115.70, -14.15]. Chronic supplementation was associated with improvement in cognitive biases such as hopelessness (-0.97, 95% CI: -1.72, -0.23), rumination (-1.58, 95% CI: -2.86, -0.29), and aggression (-1.57, 95% CI: -2.63, -0.51) that contribute to reactivity to sad mood and therefore vulnerability to depression, and may improve executive function under higher cognitive demand (0.43%, 95% CI: -0.53%, 1.38%). CONCLUSIONS: The current work provides novel evidence for an acute effect of probiotics on reaction times during executive function, which should be replicated in future work. Additionally, this work replicates previous findings of improved cognitive reactivity to sad mood following chronic probiotic supplementation, indicating probiotics may reduce risk of developing depression in a healthy aging population. This study was registered at clinicaltrials.gov as NCT04951687.
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Weizmannia coagulans BC99 improved intestinal motility and chronic constipation through regulating gut microbiota: a randomized, double-blind, placebo-controlled trial.
OBJECTIVE: This randomized, double-blind, placebo-controlled study aims to evaluate the effects and underlying mechanisms of an 8-week Weizmannia coagulans BC99 intervention in alleviating constipation in adults. METHODS: Constipated adults received BC99 (1 × 1010CFU/day) or a placebo for 8 weeks. Assessment included Completely Spontaneous Bowel Movements (CSBM), Depression Anxiety Stress Scale-21 (DASS-21), and Bristol Fecal Characteristics Scale (BSFS) scores, colonic transit time (CTT), gastrointestinal regulatory factors (ET-1, VIP, GAS, CGRP, SS), gut microbiota composition, and short-chain fatty acids (SCFAs) content in feces. This research was a randomized, double-blind, placebo-controlled study, which received approval from the Ethics Commission of the First Afffliated Hospital of Henan University of Science and Technology at 26 April 2024 (Ethical approval number 2024- 03-K0054), Clinical trial registration number is NCT06637397 ( https://clinicaltrials.gov/ , accessed on 26 April 2024). The present study was conducted from July 2024 to October 2024 at the College of Food and Bioengineering, Henan University of Science and Technology, in accordance with the tenets of the Declaration of Helsinki. RESULTS: BC99 significantly improved bowel movement frequency, stool characteristics, and psychological well-being. It reduced CTT and modulated levels of gastrointestinal peptides. Gut microbiota analysis revealed increased relative abundance of Lactobacillus, Bifidobacterium and decreased Escherichia-Shigella. BC99 also elevated fecal SCFAs levels (acetic, butyric, isovaleric acid) and inferred the key KEGG pathways associated with fatty acid metabolism and pathogen invasion. CONCLUSION: W. coagulans BC99 effectively alleviates constipation by enhancing intestinal motility, regulating gut microbiota, and increasing SCFA production, demonstrating its potential as a therapeutic probiotic.
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Impact of infrared moxibustion for patients with mild hyperlipidemia: a protocol for a randomized controlled trial.
INTRODUCTION: Hyperlipidemia serves as a significant risk factor for cardiovascular diseases and cognitive impairment, making early intervention and management highly necessary. Infrared moxibustion, a modern complementary and alternative therapy, currently lacks high-quality clinical research to substantiate its efficacy and underlying mechanisms. Therefore, this study aims to evaluate the effects of infrared moxibustion on blood lipid levels in patients with hyperlipidemia, and to explore its potential mechanisms by analyzing changes in gut microbiota and their metabolites, as well as alterations in brain gray matter volume. PATIENT AND METHODS: This study will recruit 158 patients with mild hyperlipidemia and randomly assign them to either a genuine infrared moxibustion group or a sham infrared moxibustion group. The intervention will be administered twice weekly for a total of 8 weeks. Blood lipid levels, Montreal Cognitive Assessment scores, Hamilton Depression Rating Scale scores, Hamilton Anxiety Scale scores, and Pittsburgh Sleep Quality Index scores will be compared between the two groups before treatment, and at 4, 8, and 12 weeks post-treatment. Additionally, changes in gut microbiota, the gut microbiota metabolite trimethylamine N-oxide (TMAO), and brain gray matter volume will be detected and compared between the two groups before treatment and at 8 weeks post-treatment (See Graphic Abstract).
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Multifaceted Role of Microbiota-Derived Indole-3-Acetic Acid in Human Diseases and Its Potential Clinical Application.
Indole-3-acetic acid (IAA) is recognized as a common plant growth hormone. It is also detectable in mammals, as it can be produced by gut microbiota in the gut. Current research works have shown that IAA is a multifaceted compound with significant consequences for several physiological and pathological processes. Higher levels of IAA occur in chronic kidney disease because decreased renal clearance contributes to cardiovascular and liver dysfunction. In contrast, IAA demonstrates protective effects by modulating oxidative stress, inflammation, and lipid metabolism in nonalcoholic fatty liver disease. IAA also shows potential therapeutic benefits in lung disorders such as acute lung injury, pulmonary fibrosis, and chronic obstructive pulmonary disease. Furthermore, IAA shows potential as an adjunct in cancer therapy, where it synergizes with chemotherapy regimens by endorsing oxidative stress and autophagy. Beyond cancer-related applications and metabolic disorders, IAA's role in neuroinflammation, mainly in conditions such as sepsis-associated encephalopathy and depression, underscores its potential as a therapeutic agent targeting the gut-brain axis. Furthermore, IAA is a potent oral hypoglycemic agent with mitigating effects on metabolic disorders associated with obesity and diabetes. This review provides an overview of the diverse roles of IAA in disease pathophysiology, its therapeutic promise, and the need for further research to better understand its mechanistic pathways. Understanding these complex effects could pave the way for novel microbiota-based therapies to address a range of chronic diseases and improve patient outcomes.
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Effect of fecal microbiota transplantation in patients with slow transit constipation and the relative mechanisms based on the protein digestion and absorption pathway.
BACKGROUND: Fecal microbiota transplantation (FMT) is considered an effective treatment for slow transit constipation (STC); nevertheless, the mechanism remains unclear. METHODS: In this study, eight patients with STC were selected according to the inclusion and exclusion criteria; they then received three treatments of FMT. The feces and serum of STC patients were collected after each treatment and analyzed by integrating 16 s rRNA microbiome and metabolomic analyses. RESULTS: The results showed that the percentage of clinical improvement reached 62.5% and the rates of patients' clinical remission achieved 75% after the third treatment. At the same time, FMT improved the Wexner constipation scale (WCS), the Gastrointestinal Quality-of-Life Index (GIQLI) and Hamilton Depression Scale (HAMD). Fecal microbiome alpha diversity and beta diversity altered significantly after FMT. Analysis of the 16 s rRNA microbiome showed that the numbers of Bacteroidetes (Prevotell/Bacteroides) and Firmicute (Roseburia/Blautia) decreased, whereas Actinobacteria (Bifidobacterium), Proteobacteria (Escherichia), and Firmicute (Lactobacillus) increased after FMT. The metabolomics analyses showed that the stool of FMT-treated patients were characterized by relatively high levels of N-Acetyl-L-glutamate, gamma-L-glutamyl-L-glutamic acid, Glycerophosphocholine, et al., after FMT. Compared with baseline, the serum of treated patients was characterized by relatively high levels of L-Arginine, L-Threonine, Ser-Arg, Indoleacrylic acid, Phe-Tyr, 5-L-Glutamyl-L-alanine, and lower levels of Erucamide after the treatment. The correlation analysis between the metabolites and gut microbiota showed a significant correlation. For example, L-Arginine was positively correlated with lactobacillus, et al. L-Threonine was positively correlated with Anaerovibrio, Sediminibacterium but negatively correlated with Phascolarctobacterium. Erucamide had significant negative correlations with Sediminibacterium and Sharpea, while being positively correlated with Phascolarctobacterium. Enriched KEGG pathways analysis demonstrated that the protein digestion and absorption pathways gradually upregulated with the increase of FMT frequency. The L-Arginine and L-Threonine were also involved in the pathway. A large amount of Na + was absorbed in the pathway, so that it might increase mucus secretion and electrical excitability of GI smooth muscle. CONCLUSIONS: Therefore, we speculated that FMT changed the patients' gut microbiota and metabolites involved in the protein digestion and absorption pathways, thereby improving the symptoms of STC. Study on the effectiveness and safety of FMT in the treatment of STC. The study was reviewed and approved by Ethics Committee of Tianjin People's Hospital (ChiCTR2000033227) in 2020.
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Metagenomic insights into the composition and function of the gut microbiota of mice infected with Toxoplasma gondii.
INTRODUCTION: Despite Toxoplasma gondii infection leading to dysbiosis and enteritis, the function of gut microbiota in toxoplasmosis has not been explored. METHODS: Here, shotgun metagenomics was employed to characterize the composition and function of mouse microbial community during acute and chronic T. gondii infection, respectively. RESULTS: The results revealed that the diversity of gut bacteria was decreased immediately after T. gondii infection, and was increased with the duration of infection. In addition, T. gondii infection led to gut microbiota dysbiosis both in acute and chronic infection periods. Therein, several signatures, including depression of Firmicutes to Bacteroidetes ratio and infection-enriched Proteobacteria, were observed in the chronic period, which may contribute to aggravated gut inflammation and disease severity. Functional analysis showed that a large amount of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and carbohydrate-active enzymes (CAZy) family displayed distinct variation in abundance between infected and healthy mice. The lipopolysaccharide biosynthesis related pathways were activated in the chronic infection period, which might lead to immune system imbalance and involve in intestinal inflammation. Moreover, microbial and functional spectrums were more disordered in chronic than acute infection periods, thus implying gut microbiota was more likely to participate in disease process in the chronically infected mice, even exacerbated immunologic derangement and disease progression. DISCUSSION: Our data indicate that the gut microbiota plays a potentially important role in protecting mice from T. gondii infection, and contributes to better understand the association between gut microbiota and toxoplasmosis.