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Gut microbiota-derived indole-3-propionic acid attenuates Arsenic trioxide-induced cognitive impairment by inhibiting ubiquitination and degradation of BRD4.
BACKGROUND AND PURPOSE: Arsenic trioxide (ATO) therapy for acute promyelocytic leukaemia (APL) can induce neurological disorders, including cognitive impairment (CI) and depression, severely impacting patient quality of life, yet effective interventions are lacking. Clinical observations indicate ATO treatment is associated with gut microbiota dysbiosis. Given the crucial role of gut microbes and their metabolites in neurological health, this study investigated indole-3-propionic acid (IPA), a neuroprotective microbiota-derived metabolite capable of crossing the blood-brain barrier. RESULTS: In ATO-treated mice, behavioural tests confirmed significant cognitive decline. 16S rRNA genotyping revealed a reduction in Bifidobacterium abundance, and metabolomics identified a concomitant decrease in its metabolite, IPA, alongside disruptions in the tricarboxylic acid cycle and glycolysis. IPA supplementation alleviated ATO-induced intestinal inflammation and behavioural deficits. Mechanistically, IPA inhibited ATO-induced BRD4 degradation and the associated reduction in H4 acetylation, thereby restoring the expression of the metabolic enzyme PFKM and the synaptic protein PSD95. CONCLUSION: IPA mitigates ATO-induced intestinal injury and glycolytic dysfunction via the 'BRD4-H4ac-PFKM' axis, providing novel insights for preventing and treating ATO-induced neurotoxicity.
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Methodology Considerations in Studying Mental Health, Sleep Quality, and Biopsychosocial Determinants Among Chinese and Korean Americans During the COVID-19 Pandemic.
UNLABELLED: Asians are one of the fastest-growing racial groups in the United States. The mental health of Asian Americans, particularly regarding depression and anxiety, needs significant attention. Various biopsychosocial factors interact to influence the risks of depression, anxiety, and sleep quality among Asian Americans. Currently, multiple methodological issues exist in the research of Asian Americans, such as limited data collection using Asian languages and inconsistent reporting of race and ethnicity data, which may be lacking entirely. All these methodological issues in research may account for the seemingly low prevalence rates of mental health problems among Asian Americans. In our study on mental health and sleep quality among Chinese and Korean Americans, we adopted multiple data collection strategies during the COVID-19 pandemic, including using culturally adaptive and validated measures as well as operating culture-sensitive procedures in the recruitment and data collection. The successful use of these strategies could promote early detection and personalized treatment of depression, anxiety, and sleep disturbance among Asian Americans. These strategies would further improve health care service use in this population. INTERNATIONAL REGISTERED REPORT IDENTIFIER IRRID: RR2-10.1136/bmjopen-2020-047281.
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The clinical outcomes of gut-brain axis (GBA) microbiota influence on psychiatric disorders.
The gut microbiome plays an important role in the health of the body. The study of its effect on mental problems has become the main topic of this study. As a matter of fact, every change in the gut microbiota composition can influence on mood and anxiety and vice versa. So, considering this "microbiota-gut-brain" axis (GBA) is so important. In this narrative review, the most recent reproduced information on GBA roles in neuropsychiatric disorders, and clinical significance have been considered. The gut microbial population is formed from birth and transforms from an immature state to the postnatal period into a more intricate and diverse adult ecosystem. In this review, we had some findings that GBA implicated in some psychiatric problems which can be a dysregulation consequence. In addition, some bacteria have been implicated in causing mental disorders in humans such as depression, obsessive-compulsive disorder, psychiatric disorders, stress disorders, schizophrenia and, autism. The absence of balance in GBA natural state can cause several negative consequences on host health which leads to neurological problems. Possibly, findings were delineating an interesting new etiological pathway for future exploration.
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Predictive model, miRNA-TF network, related subgroup identification and drug prediction of ischemic stroke complicated with mental disorders based on genes related to gut microbiome.
BACKGROUND: Patients with comorbid schizophrenia, depression, drug use, and multiple psychiatric diagnoses have a greater risk of carotid revascularization following stroke. The gut microbiome (GM) plays a crucial role in the attack of mental illness and IS, which may become an index for the diagnosis of IS. A genomic study of the genetic commonalities between SC and IS, as well as its mediated pathways and immune infiltration, will be conducted to determine how schizophrenia contributes to the high prevalence of IS. According to our study, this could be an indicator of ischemic stroke development. METHODS: We selected two datasets of IS from the Gene Expression Omnibus (GEO), one for training and the other for the verification group. Five genes related to mental disorders and GM were extracted from Gene cards and other databases. Linear models for microarray data (Limma) analysis was utilized to identify differentially expressed genes (DEGs) and perform functional enrichment analysis. It was also used to conduct machine learning exercises such as random forest and regression to identify the best candidate for immune-related central genes. Protein-protein interaction (PPI) network and artificial neural network (ANN) were established for verification. The receiver operating characteristic (ROC) curve was drawn for the diagnosis of IS, and the diagnostic model was verified by qRT-PCR. Further immune cell infiltration analysis was performed to study the IS immune cell imbalance. We also performed consensus clustering (CC) to analyze the expression of candidate models under different subtypes. Finally, miRNA, transcription factors (TFs), and drugs related to candidate genes were collected through the Network analyst online platform. RESULTS: Through comprehensive analysis, a diagnostic prediction model with good effect was obtained. Both the training group (AUC 0.82, CI 0.93-0.71) and the verification group (AUC 0.81, CI 0.90-0.72) had a good phenotype in the qRT-PCR test. And in verification group 2 we validated between the two groups with and without carotid-related ischemic cerebrovascular events (AUC 0.87, CI 1-0.64). Furthermore, we investigated cytokines in both GSEA and immune infiltration and verified cytokine-related responses by flow cytometry, particularly IL-6, which played an important role in IS occurrence and progression. Therefore, we speculate that mental illness may affect the development of IS in B cells and IL-6 in T cells. MiRNA (hsa-mir-129-2-3p, has-mir-335-5p, and has-mir-16-5p) and TFs (CREB1, FOXL1), which may be related to IS, were obtained. CONCLUSION: Through comprehensive analysis, a diagnostic prediction model with good effect was obtained. Both the training group (AUC 0.82, CI 0.93-0.71) and the verification group (AUC 0.81, CI 0.90-0.72) had a good phenotype in the qRT-PCR test. And in verification group 2 we validated between the two groups with and without carotid-related ischemic cerebrovascular events (AUC 0.87, CI 1-0.64). MiRNA (hsa-mir-129-2-3p, has-mir-335-5p, and has-mir-16-5p) and TFs (CREB1, FOXL1), which may be related to IS, were obtained.
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Relation between Mood and the Host-Microbiome Co-Metabolite 3-Indoxylsulfate: Results from the Observational Prospective NutriNet-Santé Study.
Gut microbiota metabolizes tryptophan into indole, which can influence brain and behavior. Indeed, some oxidized derivatives of indole, formed in the liver, have neuroactive properties, and indole overproduction by the gut microbiota induces an anxio-depressive phenotype in rodents. The aim of this study was to investigate in humans whether there was a relationship between recurrent depressive symptoms and indole production by the gut microbiota. A case-control study was conducted in 45-65-year-old women, who were participants in the observational prospective NutriNet-Santé Study. Cases were defined as having two Center for Epidemiological Studies-Depression Scales (CES-D) scores ≥ 23 at a two-year interval (recurrent depressive symptoms, n = 87). Each case was matched with two controls (two CES-D <23; n = 174). Urinary excretion of 3-indoxylsulfate, the major final metabolite of indole, was used as a biomarker of indole production by the gut microbiota. Conditional logistic regression models for paired data showed a positive association between urinary 3-indoxylsulfate concentrations, grouped in tertiles, and recurrent depressive symptoms (odds ratio = 2.46, p for trend = 0.0264 in the final model adjusted for confounding factors). This association suggested that indole production by the gut microbiota may play a role in the onset of mood disorders in humans.
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A global atlas of the gut virome reveals subtype-specific and functional alterations in irritable bowel syndrome.
The gut virome is a critical component of the microbiome-gut-brain axis; however, its role in irritable bowel syndrome (IBS) remains poorly understood due to limited sample sizes and geographic bias. We aimed to construct a comprehensive global atlas of the IBS gut virome to elucidate its composition, functional potential, and clinical relevance across diverse populations and IBS subtypes. We integrated multi-cohort data comprising 1,104 samples (790 IBS patients and 314 healthy controls) from 11 cohorts across 10 geographic regions. A standardized bioinformatic pipeline was employed to perform viral mining from metagenomic and virus-like particle-enriched metaviromic data. The IBS virome exhibited significant taxonomic alterations, with specific viral signatures distinguishing IBS-D, IBS-C, and IBS-M subtypes. Geographic region was identified as a significant factor influencing the viral community structure. Functionally, the IBS virome was enriched in auxiliary metabolic genes involved in carbon metabolism and neurotransmitter precursor synthesis (histidine and tryptophan metabolism), as well as a distinct profile of virulence factors and antibiotic resistance genes. Furthermore, in a specific cohort, certain viral taxa were significantly correlated with the severity of anxiety and depression. Machine learning models based on viral signatures achieved robust performance for IBS subtyping (area under the curve = 0.92). This study establishes a global baseline for the IBS gut virome, demonstrating that viral communities are dynamically shaped by geography and disease subtypes while encoding gene repertoires with the potential to influence host physiology, thereby providing a foundational resource for precision medicine.IMPORTANCEResearch on the human gut microbiome in IBS has focused primarily on bacteria, leaving the viral component as a vast and poorly understood reservoir. By profiling over 1,000 human samples globally, this study characterizes the taxonomic and functional features of the IBS gut virome. We demonstrate that these viral communities vary across geographic populations and IBS subtypes and are enriched in specific auxiliary metabolic genes, virulence factors, and antibiotic resistance genes. In addition, certain viral profiles show significant correlations with patient psychological symptoms such as anxiety and depression. This study also evaluates the potential of virome-based diagnostic biomarkers. Consequently, our findings provide a valuable reference for future in-depth research into the specific roles and mechanistic contributions of the gut virome in the pathogenesis of IBS.
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Pubertal probiotics mitigate lipopolysaccharide-induced programming of the hypothalamic-pituitary-adrenal axis in male mice only.
Puberty is a period of rapid cortical and neuronal development. Stress exposure during puberty programs the hypothalamic-pituitary-adrenal (HPA) axis responsiveness to future stressors. However, programming can result in an enduring maladaptation of the HPA axis activity and can be associated with long-term anxiety- and depression-like behaviours. Probiotic treatment mitigates the effect of stress on mental health, suggesting that the gut microbiome may mediate the programming of the HPA axis. However, the mechanism underlying this effect remains elusive. Thus, we investigated the effect of probiotic exposure on lipopolysaccharide (LPS)-induced programming of the HPA axis and glucocorticoid receptor (GR) expression in the paraventricular (PVN), basolateral amygdala (BLA), piriform cortex (PIR), and medial prefrontal cortex (mPFC). Male and female mice were exposed to either probiotics or control skim milk and were treated with either saline or LPS during puberty. Prior to euthanasia in adulthood, mice were restrained for 30 min. The results showed that pubertal LPS treatment permanently decreased GR expression in the PVN in milk fed control males. However, pubertal probiotic treatment blocked the LPS-induced decrease in GR expression in males. Given that this effect is limited to males, further research is required to better understand sex differences in the interactions between the gut microbiome and the programming of the HPA axis during puberty. Nevertheless, our findings suggest that the gut microbiome influences the neurophysiology of the HPA axis and mediates its programming in pubertal males. The prevention of GR reduction in the male PVN and PIR using probiotics illustrates the complexity of the gut-brain communication and compels continued investigation.
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Intermittent Fasting, Dietary Modifications, and Exercise for the Control of Gestational Diabetes and Maternal Mood Dysregulation: A Review and a Case Report.
Gestational diabetes mellitus (GDM) is a common pregnancy-related condition afflicting 5-36% of pregnancies. It is associated with many morbid maternal and fetal outcomes. Mood dysregulations (MDs, e.g., depression, distress, and anxiety) are common among women with GDM, and they exacerbate its prognosis and hinder its treatment. Hence, in addition to early detection and proper management of GDM, treating the associated MDs is crucial. Maternal hyperglycemia and MDs result from a complex network of genetic, behavioral, and environmental factors. This review briefly explores mechanisms that underlie GDM and prenatal MDs. It also describes the effect of exercise, dietary modification, and intermittent fasting (IF) on metabolic and affective dysfunctions exemplified by a case report. In this patient, interventions such as IF considerably reduced maternal body weight, plasma glucose, and psychological distress without any adverse effects. Thus, IF is one measure that can control GDM and maternal MDs; however, more investigations are warranted.
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The gut microbiota, HPA axis, and brain in adolescent-onset depression: Probiotics as a novel treatment.
Stress-associated disruptions in the development of frontolimbic regions may play a critical role in the emergence of adolescent-onset depression. These regions are particularly sensitive to Hypothalamic-Pituitary-Adrenal (HPA) axis signaling. The HPA axis is hyperactive in adolescent depression, and interventions that attenuate such hyperactivity hold promise as potential treatments. The Microbiome-Gut-Brain (MGB) axis is an important pathway through which stress dysregulates HPA-axis activity and thus exerts deleterious effects on the adolescent brain. Probiotic agents, which alter the gut microbiota composition by introducing bacterial strains with beneficial physiological effects, normalize aberrant HPA-axis activity and reduce depressive symptoms in both animal studies and adult clinical trials. While the potential utility of such agents in treating or preventing adolescent depression remains largely unexplored, recent data suggest the existence of an adolescent sensitive window during which probiotics may be especially efficacious in reducing depressive symptoms compared to effects observed in adult populations. In this review, we outline evidence that probiotic use may attenuate stress effects on frontolimbic development, providing a novel means of improving depressive symptoms among adolescent populations.
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A Randomised, Double-Blind, Placebo-Controlled Trial of Probiotic and Postbiotic Strains in Healthy Adults with Self-Reported Anxiety: Effects on Mood, Vitality, Quality of Life and Perceived Stress.
Background: Subclinical psychological symptoms-such as low mood, perceived stress, and poor sleep-affect a large portion of the population and can impair quality of life despite remaining below clinical thresholds. The gut-brain axis has emerged as a promising target for interventions that support emotional and psychological resilience. Probiotics and postbiotics are gaining attention for their potential to modulate mood and stress via microbiome-related mechanisms, but human evidence remains limited, particularly in non-clinical populations. Objectives: We aimed to assess the effects of a two-strain combination of live microorganisms alongside a two-strain combination of heat-treated inactivated microorganisms on outcomes associated with anxiety, mood, perceived stress, and quality of life in healthy adults experiencing mild stress. Methods: This study was conducted in two parts. In Part I, a randomized, double-blind, placebo-controlled study, 100 participants were randomized to receive either a blend of live microorganisms (Bifidobacterium longum CECT 7347 and Lactobacillus rhamnosus CECT 8361) or an identical placebo once daily for 12 weeks. In Part II, a pilot feasibility study, a subset of eight placebo non-responders from Part I received the heat-inactivated preparation of the same bacterial strains in a 6-week trial extension phase. For Parts I and II, the primary outcome was the change in the Hamilton Anxiety Rating Scale (HAM-A). Secondary outcomes included measures of mood (Beck Depression Inventory (BDI); Patient Health Questionnaire-9 (PHQ-9)), stress (state and trait anxiety inventory (STAI); Perceived Stress Scale (PSS)), sleep (Pittsburgh Sleep Quality Index (PSQI)), quality of life (36-item Short Form Survey (SF-36)), gastrointestinal symptoms (Gastrointestinal Symptom Rating Scale (GSRS)), salivary cortisol and microbiome modulation. Results: In Part I, there were no significant effects of the live blend on the HAM-A, indicating that the primary endpoint was not met. In addition, no significant effects were seen on the STAI or PSS scores when compared to the placebo. However, participants consuming the live blend trended toward a reduction in total PHQ-9 scores compared to placebo (p = 0.089), whilst preliminary exploratory analyses suggested an improvement in anhedonia (p = 0.045). Furthermore, there was a significant improvement in the vitality domain of the SF-36 compared to placebo (p = 0.017). On microbiome analysis, it was noted that consumption of the live blend was linked to the preservation of butyrate-producing bacteria, particularly members of the Pseudoflavonifractor genus and the Clostridium SGB6179 species. Furthermore, the abundance of B. longum species was found to be inversely associated with the total PSS Scores. In Part II, supplementation with the inactivated preparation resulted in significant within-group improvements for the vitality (p = 0.006) and social functioning (p = 0.010) domains of the SF-36 and improvements in PSS scores compared to baseline (p = 0.050). Conclusions: Supplementation with either the dual-strain live or inactivated formulations was associated with significant improvements in the vitality domain of the SF-36, whilst participants receiving the inactivated formulation demonstrated lower perceived stress and improved social functioning compared to baseline. Overall, the findings from this pilot study suggest that these two biotic consortia are well-tolerated and may be associated with improvements in measures of vitality in individuals with subclinical psychological symptoms. The subtle observations detected for stress and anhedonia suggest that further well-powered trials are needed to better characterize these findings, potentially in populations with greater baseline symptomatology.