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Effects of Heat-Treated Lactobacillus helveticus CP790-Fermented Milk on Gastrointestinal Health in Healthy Adults: A Randomized Double-Blind Placebo-Controlled Trial.
Probiotic-fermented milk is commonly used to maintain intestinal health. However, the effects of heat-treated fermented milk, which does not contain live microorganisms, on intestinal function are not yet fully understood. This study aimed to investigate whether heat-treated Lactobacillus helveticus CP790-fermented milk affects fecal microbiota and gut health as a "postbiotic". A randomized, double-blind, placebo-controlled trial was conducted in healthy Japanese individuals aged 20-59 years with a tendency toward constipation. Participants consumed 100 mL of either the test beverage (n = 60) or placebo beverage (n = 60) for four weeks. The test beverages were prepared with heat-treated CP790-fermented milk, while the placebo beverages were prepared with nonfermented milk flavored with lactic acid. Fecal samples were analyzed using 16S rRNA gene sequencing. Constipation symptoms were assessed using defecation logs and the Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaire. Mood state was also assessed using the Profile of Mood States 2 (POMS2) questionnaire to explore its potential as a "psychobiotic". Desulfobacterota were significantly decreased by CP790-fermented milk intake. PICRUSt2 analysis predicted a decrease in the proportion of genes involved in the sulfate reduction pathway following the consumption of CP790-fermented milk. The CP790-fermented milk intervention significantly improved stool consistency and straining during defecation. These improvements were correlated with a decrease in Desulfobacterota. After the intervention, overall mood, expressed as total mood disturbance, and depression-dejection were significantly better in the CP790 group than in the placebo group. These results suggest that the intake of CP790-fermented milk could be effective in modulating gut microbiota and improving constipation symptoms and mood states.
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Brain-gut microbiota multimodal predictive model in patients with bipolar depression.
BACKGROUND: The "microbiota-gut-brain axis" which bridges the brain and gut microbiota is involved in the pathological mechanisms of bipolar disorder (BD), but rare is known about the exact association patterns and the potential for clinical diagnosis and treatment outcome prediction. METHODS: At baseline, fecal samples and resting-state MRI data were collected from 103 BD depression patients and 39 healthy controls (HCs) for metagenomic sequencing and network-based functional connectivity (FC), grey matter volume (GMV) analyses. All patients then received 4-weeks quetiapine treatment and were further classified as responders and non-responders. Based on pre-treatment datasets, the correlation networks were established between gut microbiota and neuroimaging measures and the multimodal kernal combination support vector machine (SVM) classifiers were constructed to distinguish BD patients from HCs, and quetiapine responders from non-responders. RESULTS: The multi-modal pre-treatment characteristics of quetiapine responders, were closer to the HCs compared to non-responders. And the correlation network analyses found the substantial correlations existed in HC between the Anaerotruncus_ unclassified，Porphyromonas_asaccharolytica，Actinomyces_graevenitzii et al. and the functional connectomes involved default mode network (DMN),somatomotor (SM), visual, limbic and basal ganglia networks were disrupted in BD. Moreover, in terms of the multimodal classifier, it reached optimized area under curve (AUC-ROC) at 0.9517 when classified BD from HC, and also acquired 0.8292 discriminating quetiapine responders from non-responders, which consistently better than even using the best unique modality. LIMITATIONS: Lack post-treatment and external validation datasets; size of HCs is modest. CONCLUSIONS: Multi-modalities of combining pre-treatment gut microbiota with neuroimaging endophenotypes might be a superior approach for accurate diagnosis and quetiapine efficacy prediction in BD.
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Ferulic acid as a therapeutic agent in depression: Evidence from preclinical studies.
Depression is a common but severe mood disorder with a very high prevalence across the general population. Depression is of global concern and poses a threat to human physical and mental health. Ferulic acid (FA) is a natural active ingredient that has antioxidative, anti-inflammatory, and free radical scavenging properties. Furthermore, studies have shown that FA can exert antidepressant effects through a variety of mechanisms. The aim of the review was to comprehensively elucidate the mechanisms in FA that alleviate depression using animal models. The in vivo (animal) studies on the mechanism of FA treatment of depression were searched in PubMed, Chinese National Knowledge Infrastructure, Baidu academic, and Wan fang databases. Thereafter, the literature conclusions were summarized accordingly. Ferulic acid was found to significantly improve the depressive-like behaviors of animal models, suggesting that FA is a potential natural product in the treatment of depression. The mechanisms are achieved by enhancing monoamine oxidase A (MOA) activity, inhibiting microglia activation and inflammatory factor release, anti-oxidative stress, promoting hippocampal nerve regeneration, increasing brain-derived neurotrophic factor secretion, regulating gut microbiome, and activating protein kinase B/collapsin response mediator protein 2 (AKT/CRMP2) signaling pathway. Ferulic acid produces significant antidepressant effects in animal depression models through various mechanisms, suggesting its potential value as a treatment of depression. However, clinical research trials involving FA are required further to provide a solid foundation for its clinical application.
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Multi-Strain Probiotics Alleviate Food Allergy-Induced Neurobehavioral Abnormalities by Regulating Gut Microbiota and Metabolites.
Background and aim: Neurobehavioral changes associated with food allergies have been reported, but the therapeutic effects of probiotics have not been fully explored. Our study aimed to investigate the impact of multi-strain probiotics on neurobehavioral outcomes and to elucidate the underlying mechanism via the microbiota-gut-brain axis. Methods: C57BL/6J Male mice were randomly divided into the following three groups: (1) control group; (2) OVA-sensitized group; (3) OVA-sensitized group treated with multi-strain probiotics (OVA + P). Anaphylactic reactions and behavioral abnormalities were assessed by histological, immunological, and behavioral analyses. To further elucidate the underlying mechanisms, the prefrontal cortex was collected for microglial morphological analysis, while serum and fecal samples were obtained for untargeted metabolomic profiling and 16S rDNA-based gut microbiota analysis, respectively. Results: Multi-strain probiotics significantly alleviated anaphylactic reactions in OVA-sensitized mice, as evidenced by reduced serum IgE levels, decreased Th2 cytokines, and reduced epithelial damage. Meanwhile, neurobehavioral symptoms were alleviated, including anxiety-like and depression-like behaviors, repetitive behaviors, social avoidance, and impaired attention. Mechanistically, probiotics administration suppressed production of inflammatory cytokines (TNF-α, IL-1β and IL-6) and inhibited activation of M1 microglia in the prefrontal cortex, which might contribute to neuron recovery. Furthermore, multi-omics analysis revealed that amino acid metabolism restoration in OVA + P mice, particularly carboxylic acids and derivatives, which was remarkably correlated with alterations in gut microbiota and behaviors related to FA. Conclusions: Gut microbiota and its amino acid metabolites mediate the therapeutic effects of multi-strain probiotics on FA-induced behavioral abnormalities. These effects occur alongside the suppression of neuroinflammation and microglial activation in the prefrontal cortex. Our findings highlight the neuroimmune regulatory role of the gut-microbiota-brain axis and support the potential use of probiotics as an intervention for FA-induced brain dysfunctions.
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Repeated intermittent administration of 3,4-methylenedioxymethamphetamine mitigates demyelination in the brain from cuprizone-treated mice.
3,4-Methylenedioxymethamphetamine (MDMA), commonly known as a recreational drug, may also offer therapeutic benefits for mental health. Population-based studies suggest that MDMA users have a lower risk of demyelinating diseases, such as depression. Given the role of the gut microbiota in mediating MDMA's effects, we hypothesized that MDMA might confer mental health benefits via the gut-brain axis. Cuprizone (CPZ) induces demyelination by chelating copper, which leads to oligodendrocyte death and subsequent myelin loss. This study investigated the impact of MDMA on brain demyelination in CPZ-treated mice, focusing on the gut-brain axis. Repeated intermittent MDMA administration (10 mg/kg, three times weekly for 6 weeks) significantly reduced demyelination in the corpus callosum (CC) of CPZ-treated mice. Gut microbiota and non-targeted metabolomics analyses revealed notable differences in specific gut bacteria and plasma (β-D-allose and L-sorbose) or fecal metabolite (carnitine) levels between MDMA-treated and vehicle-treated CPZ-exposed mice. Negative correlations were found between the levels of metabolites (β-D-allose, L-sorbose, and carnitine) and the relative abundance of Romboutsia and Romboutsia timonensis. These findings suggest that intermittent MDMA administration may alleviate demyelination in the CC of CPZ-treated mice via the gut-brain axis. Further research is needed to elucidate the roles of gut microbiota and metabolites in MDMA's effects on brain demyelination and to investigate other demyelination models.
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Impact of the gut microbiota and associated metabolites on cardiometabolic traits, chronic diseases and human longevity: a Mendelian randomization study.
Features of the gut microbiota have been associated with several chronic diseases and longevity in preclinical models as well as in observational studies. Whether these relations underlie causal effects in humans remains to be established. We aimed to determine whether the gut microbiota influences cardiometabolic traits as well as the risk of chronic diseases and human longevity using a comprehensive 2-Sample Mendelian randomization approach. We included as exposures 10 gut-associated metabolites and pathways and 57 microbial taxa abundance. We included as outcomes nine cardiometabolic traits (fasting glucose, fasting insulin, systolic blood pressure, diastolic blood pressure, HDL cholesterol, LDL cholesterol, triglycerides, estimated glomerular filtration rate, body mass index [BMI]), eight chronic diseases previously linked with the gut microbiota in observational studies (Alzheimer's disease, depression, type 2 diabetes, non-alcoholic fatty liver disease, coronary artery disease (CAD), stroke, osteoporosis and chronic kidney disease), as well as parental lifespan and longevity. We found 7 associations with evidence of causality before and after sensitivity analyses, but not after multiple testing correction (1198 tests). Most effect sizes (4/7) were small. The two largest exposure-outcome effects were markedly attenuated towards the null upon inclusion of BMI or alcohol intake frequency in multivariable MR analyses. While finding robust genetic instruments for microbiota features is challenging hence potentially inflating type 2 errors, these results do not support a large causal impact of human gut microbita features on cardiometabolic traits, chronic diseases or longevity. These results also suggest that the previously documented associations between gut microbiota and human health outcomes may not always underly causal relations.
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Exploring gut microbiota diurnal fluctuation in alcohol-dependent patients with sleep disturbance.
Introduction. Alcohol dependence (AD) and sleep disturbance (SD) independently affect gut microbiota, potentially disrupting the circadian rhythm of the microbiota and the host. However, the impact of SD on the composition and rhythmicity of gut flora in AD patients remains poorly understood.Gap Statement. Characteristics of gut flora and diurnal oscillations in AD patients experiencing SD are unknown.Aim. This study aims to explore alterations in gut flora and diurnal oscillations in AD patients experiencing SD.Methodology. Thirty-two AD patients and 20 healthy subjects participated, providing faecal samples at 7 : 00 AM, 11 : 00 AM, 3 : 00 PM and 7 : 00 PM for gut microbiota analysis using 16S rDNA sequencing. AD patients were further categorized into those with poor sleep (ADwPS) and those with good sleep (ADwGS) for further analyses.Results. The ADwPS group demonstrated elevated levels of anxiety, depression and withdrawal severity compared to the ADwGS group (all P<0.05). The β-diversity of gut microbiota in the ADwPS group differed from that in the ADwGS group (P<0.05). Bacterial abundances at various taxonomic levels, including Cyanobacteria and Pseudomonadales, differed between the ADwPS and ADwGS groups (all P<0.05). Utilizing unweighted UniFrac analysis, the β-diversity of gut microbiota in the ADwPS group demonstrated robust diurnal oscillation (P<0.05), whereas this pattern was statistically insignificant in the ADwGS group. Notably, the abundance of pathogenic bacteria like Pseudomonadales and Pseudomonadaceae exhibited marked diurnal fluctuation in the ADwPS group (all P<0.05).Conclusion. SD in AD patients extends beyond alcohol-induced alterations, impacting gut microbiota composition, function and diurnal oscillation patterns. This highlights its add-on influence, supplementing AD-related changes.
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Washed microbiota transplantation targeting both gastrointestinal and extraintestinal symptoms in patients with irritable bowel syndrome.
OBJECTIVE: Fecal microbiota transplantation (FMT) has been reported with the treatment potential for irritable bowel syndrome (IBS). However, the knowledge of its effect on extraintestinal symptoms of IBS is limited. This study aimed to evaluate the efficacy of the improved methodology of FMT, washed microbiota transplantation (WMT), on sleep disturbances, and psychological and gastrointestinal symptoms among patients with IBS. METHODS: This was a prospective observational study involving patients with IBS who underwent WMT. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality. The Gastrointestinal Symptom Rating Scale (GSRS) and IBS Severity Scoring System (IBS-SSS) were used to evaluate gastrointestinal symptoms and IBS severity, respectively. The Self-rating Depression Scale (SDS) and Self-rating Anxiety Scale (SAS) were used to evaluate depression and anxiety, respectively. All the symptoms were evaluated at baseline and one month after WMT. A multiple logistic regression model was used to determine the predictive factors of sleep improvement one month after WMT. RESULTS: Seventy-three patients with IBS were included in the study. Sleep quality (Z = -4.211, P < 0.001), anxiety (Z = -4.775, P < 0.001), depression (Z = -4.610, P < 0.001), gastrointestinal symptoms (Z = -5.364, P < 0.001), and IBS severity (Z = -6.468, P < 0.001) significantly improved one month after WMT in all patients. The scores of the five components of PSQI including subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, and sleep disturbances decreased in 52 patients with poor sleep quality (all P < 0.05). Baseline sleep duration scores were identified as an independent predictive factor of sleep improvement one month after WMT in patients with poor sleep quality (OR 2.180 [95% CI = 1.017-4.673]; P = 0.045). Patients that experienced sleep improvement demonstrated greater alleviation in depression (Z = -1.990, P = 0.047) and IBS severity (Z = -2.486, P = 0.013) compared with patients without sleep improvement. CONCLUSION: This study suggested that WMT might be a promising therapy for patients with IBS, especially those with comorbid sleep and psychological disorders.
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Lactiplantibacillus plantarum WH021 Alleviates Lipopolysaccharide-Induced Neuroinflammation via Regulating the Intestinal Microenvironment and Protecting the Barrier Integrity.
Neuroinflammation is one of the major pathological factors leading to neurodegenerative diseases (NDs). Currently, drug treatment is the main strategy for controlling NDs, but long-term drug use has many side effects. Studies have shown that probiotics can regulate neuroinflammation via the microbiota-gut-brain axis, thereby preventing and alleviating NDs. Our early studies screened several strains with antineuroinflammatory properties through the established microglia-zebrafish fast-screening model, and preliminary animal experiments demonstrated that Lactiplantibacillus plantarum WH021 has good antineuroinflammatory activity. Still, its specific effects and mechanisms need to be further explored. Therefore, this study aimed to investigate the effects of three doses of L. plantarum WH021 on behavioral disorders, brain and intestinal inflammation, and their possible mechanism in model mice with lipopolysaccharide (LPS)-induced neuroinflammation. The results showed that L. plantarum WH021 significantly improved the depression-like state caused by neuroinflammation, inhibited brain inflammation and neuronal damage, and enhanced synaptic function and blood-brain barrier integrity after 28 days of intervention in the high-dose group (109 CFU/day). In addition, pathological damage and inflammation in the colon tissue were effectively alleviated, and the function of the intestinal barrier was improved. From the perspective of gut microbiota and serum metabolites, L. plantarum WH021 was also found to regulate intestinal homeostasis and increase serum metabolic levels of neuroactive components and neurotransmitter metabolites. Ultimately, 5-hydroxytryptaminergic synapses, GABAergic synapses, and the arachidonic acid pathway were identified as potential mechanisms exerting their ability to alleviate neuroinflammation. These findings may provide a possible strategy for preventing neuroinflammation-related diseases.
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Fructus gardeniae ameliorates anxiety-like behaviors induced by sleep deprivation via regulating hippocampal metabolomics and gut microbiota.
Fructus gardeniae (FG) is a traditional Chinese medicine and health food for thousands of years of application throughout Chinese history and is still widely used in clinical Chinese medicine. FG has a beneficial impact on anxiety, depression, insomnia, and psychiatric disorders; however, its mechanism of action requires further investigation. This study aimed to investigate the effects and mechanisms of FG on sleep deprivation (SD)-induced anxiety-like behavior in rats. A model of SD-induced anxiety-like behavior in rats was established by intraperitoneal injection of p-chlorophenylalanine (PCPA). This was accompanied by neuroinflammation and metabolic abnormalities in the hippocampus and disturbance of intestinal microbiota. However reduced SD-induced anxiety-like behavior and decreased levels of pro-inflammatory cytokines including TNF-α and IL-1β were observed in the hippocampus of rats after 7 days of FG intervention. In addition, metabolomic analysis demonstrated that FG was able to modulate levels of phosphatidylserine 18, Phosphatidylinositol 18, sn-glycero-3-phosphocholine, deoxyguanylic acid, xylose, betaine and other metabolites in the hippocampus. The main metabolic pathways of hippocampal metabolites after FG intervention involve carbon metabolism, glycolysis/gluconeogenesis, pentose phosphate, and glycerophospholipid metabolism. 16S rRNA sequencing illustrated that FG ameliorated the dysbiosis of gut microbiota in anxious rats, mainly increased the abundance of Muribaculaceae and Lactobacillus, and decreased the abundance of Lachnospiraceae_NK4A136_group. In addition, the correlation analysis demonstrated that there was a close relationship between hippocampal metabolites and intestinal microbiota. In conclusion, FG improved the anxiety behavior and inhibited of neuroinflammation in sleep-deprived rats, and the mechanism may be related to the FG regulation of hippocampal metabolites and intestinal microflora composition.