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Microbiome driven modulation of neurotransmitters: implications for neurotransmission and mood disorders.
The human gut microbiome has emerged as a crucial regulator of neurophysiological processes by engaging with the central nervous system (CNS) via the microbiota-gut-brain (MGB) axis. One of the most significant ways gut microorganisms influence brain functions is by altering the levels of neurotransmitters. A significant relationship exists between microbial activity and mood, behavior, and cognition. Gut microorganisms can make or break down bioactive substances like serotonin, dopamine, γ-aminobutyric acid (GABA), glutamate, acetylcholine, and histamine. These microbial modulations influence precursor availability, receptor sensitivity, synaptic signaling dynamics, and neuroimmune modulation, thereby indirectly shaping neurotransmission within central circuits. These neurochemical effects, particularly involving serotonergic, dopaminergic, GABAergic, and glutamatergic pathways, are mediated through microbial metabolites such as short-chain fatty acids (SCFAs), alterations in tryptophan metabolism, immune system activation, vagal nerve transmission, and the control of the hypothalamic-pituitary-adrenal (HPA) axis. Changes in the composition of the microbiome have been frequently linked to mood disorders, such as depression, anxiety, bipolar disorder, and schizophrenia. The current review integrates findings from preclinical and clinical studies on microbiome-related neurotransmitter modulation, emphasizing novel therapeutics such as probiotics, prebiotics, fecal microbiota transplantation, and dietary alterations. Unlike previous reviews that primarily focus on microbiome composition or therapeutic interventions such as probiotics and fecal microbiota transplantation, this review adopts a neurotransmitter-centered framework, integrating microbial regulation of serotonergic, dopaminergic, GABAergic, glutamatergic, cholinergic, and histaminergic systems with the pathophysiology of mood disorders. Connecting microbiota-driven modulation of neurochemistry to mental outcomes offers a promising adjunctive avenue for mood disorder management, pending rigorous mechanistic and clinical validation.
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Antidepressant Shugan Jieyu Capsule Alters Gut Microbiota and Intestinal Microbiome Function in Rats With Chronic Unpredictable Mild Stress -Induced Depression.
Shugan Jieyu Capsule (SG) has been widely used in China to treat mild to moderate depression. Hypericum perforatum L. (St John's Wort, SJW) is the main ingredient of SG and has been used as herbal medicine to treat depression in western countries. However, it is known that SJW has low bioavailability and does not easily get through the blood-brain barrier. Therefore, how SG plays an antidepressant effect in the central nervous system (CNS) remains an urgent problem to be solved. Mounting research has described the relationship between antidepressants and intestinal microbiota to illuminate antidepressive mechanisms in the CNS. We aimed to investigate the effects of therapy with SG on the function of gut microbiota and intestinal microbiota in rats with chronic unpredictable mild stress (CUMS)-induced depression. The psychophysiological state and the hypothalamic-pituitary-adrenal axis function of rats are evaluated through behavioral experiments, corticosterone levels, serotonin levels, and adrenal index measurements. 16S rDNA amplicon sequencing is used to test the changes in gut microbiota and make functional predictions of genes. With treatment of SG, the depression-like behaviors of CUMS-induced rats were reversed; the corticosterone levels and the adrenal index decreased significantly; the level of serotonin increased significantly; and the alpha and beta diversity analysis of microbiota showed an increase in the richness and uniformity of the flora were increased. SG regulated the relative abundance of Actinobacteria, Erysipelotrichaceae, Bifidobacteriaceae, Atopobiaceae, Dubosiella, and Bifidobacterium; Linear discriminant analysis effect size analysis demonstrated that Lactobacillaceae (family level), Lactobacillus (genus level), Lactobacillales (order level), Bacilli (class level), and Lactobacillus-reuteri (species level) were biomarkers in the SG group samples, and also likely to modulate metabolic pathways, such as those involved in carbohydrate metabolism, amino acid metabolism, and signal transduction. These data clearly illustrated the effect of SG on gut microbiome, thus laying the foundation for uncovering more insights on the therapeutic function of the traditional Chinese antidepressants. The potential of SG on mechanisms of antidepression to alter gut microbiota and intestinal microbiome function exposed to CUMS can be explored.
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Short-Term Grape Consumption Diminishes UV-Induced Skin Erythema.
Over three million Americans are affected by skin cancer each year, largely as a result of exposure to sunlight. The purpose of this study was to determine the potential of grape consumption to modulate UV-induced skin erythema. With 29 human volunteers, we report that nine demonstrated greater resistance to UV irradiation of the skin after consuming the equivalent of three servings of grapes per day for two weeks. We further explored any potential relationship to the gut-skin axis. Alpha- and beta-diversity of the gut microbiome were not altered, but grape consumption modulated microbiota abundance, enzyme levels, and KEGG pathways. Striking differences in the microbiome and metabolome were discerned when comparing the nine individuals showing greater UV resistance with the 20 non-responders. Notably, three urinary metabolites, 2'-deoxyribonic acid, 3-hydroxyphenyl acetic and scyllo-inositol, were depressed in the UV-resistant group. A ROC curve revealed a 71.8% probability that measurement of urinary 2'-deoxyribonic acid identifies a UV skin non-responder. 2'-Deoxyribonic acid is cleaved from the DNA backbone by reactive oxygen species. Three of the nine subjects acquiring UV resistance following grape consumption showed a durable response, and these three demonstrated unique microbiomic and metabolomic profiles. Variable UV skin sensitivity was likely due to glutathione S-transferase polymorphisms. We conclude that a segment of the population is capable of demonstrating greater resistance to a dermal response elicited by UV irradiation as a result of grape consumption. It is uncertain if modulation of the gut-skin axis leads to enhanced UV resistance, but there is correlation. More broadly, it is reasonable to expect that these mechanisms relate to other health outcomes anticipated to result from grape consumption.
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Drugs and Bugs: The Gut-Brain Axis and Substance Use Disorders.
Substance use disorders (SUDs) represent a significant public health crisis. Worldwide, 5.4% of the global disease burden is attributed to SUDs and alcohol use, and many more use psychoactive substances recreationally. Often associated with comorbidities, SUDs result in changes to both brain function and physiological responses. Mounting evidence calls for a precision approach for the treatment and diagnosis of SUDs, and the gut microbiome is emerging as a contributor to such disorders. Over the last few centuries, modern lifestyles, diets, and medical care have altered the health of the microbes that live in and on our bodies; as we develop, our diets and lifestyle dictate which microbes flourish and which microbes vanish. An increase in antibiotic treatments, with many antibiotic interventions occurring early in life during the microbiome's normal development, transforms developing microbial communities. Links have been made between the microbiome and SUDs, and the microbiome and conditions that are often comorbid with SUDs such as anxiety, depression, pain, and stress. A better understanding of the mechanisms influencing behavioral changes and drug use is critical in developing novel treatments for SUDSs. Targeting the microbiome as a therapeutic and diagnostic tool is a promising avenue of exploration. This review will provide an overview of the role of the gut-brain axis in a wide range of SUDs, discuss host and microbe pathways that mediate changes in the brain's response to drugs, and the microbes and related metabolites that impact behavior and health within the gut-brain axis.
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Emotional distress and clinical response to neoadjuvant chemoimmunotherapy in resectable non-small-cell lung cancer: a protocol for the prospective observational NeoFUSE-Lung cohort study.
BACKGROUND: Neoadjuvant chemoimmunotherapy (NACI) has improved pathological and survival outcomes in patients with resectable non-small-cell lung cancer (NSCLC), yet marked heterogeneity in treatment response persists. Emotional distress (ED) may modulate antitumor immunity through neuroendocrine and immune-related mechanisms, but its association with response to NACI in patients with resectable NSCLC remains insufficiently explored. This study aims to prospectively evaluate the relationship between ED and clinical outcomes in patients with resectable NSCLC receiving NACI, with exploratory analyses of stress-related biomarkers and gut microbiome profiles. METHODS: This single-center, prospective observational cohort study will enroll patients with treatment-naïve, resectable stage II-IIIB NSCLC scheduled to receive first-line NACI at Fujian Medical University Union Hospital. All participants will receive NACI as part of routine clinical care, and no experimental intervention will be assigned. ED will be assessed using the Hospital Anxiety and Depression Scale (HADS) at baseline and after two cycles of NACI, and participants will be classified according to baseline ED status and longitudinal ED trajectories. Clinical, psychological, quality-of-life, biochemical, and fecal microbiome data will be collected at prespecified time points. The primary outcomes are overall survival (OS) and progression-free survival (PFS). Secondary outcomes include objective response rate (ORR), pathological complete response (pCR), major pathological response (MPR), and quality of life (QoL). Associations between ED and clinical outcomes will be analyzed using appropriate regression and survival models, with exploratory analyses of stress-related biomarkers and gut microbiome profiles. DISCUSSION: This trial aims to provide prospective data on the association between ED and response to NACI in patients with resectable NSCLC, while exploring potential neuroimmune-microbiome pathways underlying this association. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR) identifier: ChiCTR2600119872.
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Effects of Probiotic Supplementation on Depressive Symptoms, Sleep Quality, and Modulation of Gut Microbiota and Inflammatory Biomarkers: A Randomized Controlled Trial.
Background: More than merely determining our sleep pattern, our body's internal clock also improves the quality of our sleep, alleviates the symptoms of depression, and maintains the balance of our gut flora. Methods: We carried out a 12-week randomized controlled trial with 99 adults from Kolkata, New Delhi, and Pune who reported sleep problems and symptoms of depression or anxiety. Participants received either a probiotic formulated to improve sleep quality and reduce depressive symptoms or a placebo. We tracked sleep using overnight studies and wearable devices, assessed depressive symptoms with standardized questionnaires, and analyzed stool samples to profile gut bacteria and their metabolites using gene sequencing and metabolomics. Advanced statistics and machine learning helped us pinpoint the key microbial and metabolic factors tied to sleep and mental health. Results: At the start, participants with disrupted sleep and depressive symptoms had fewer beneficial gut bacteria like Bifidobacterium and Lactobacillus, more inflammation-related microbes, and lower levels of helpful short-chain fatty acids. These imbalances were linked to poorer sleep efficiency, less REM sleep, and higher depression and anxiety scores. After 12 weeks, those taking the circadian-supporting probiotic saw a statistically significant increase in beneficial gut bacteria, improved sleep efficiency (+7.4%, p = 0.02), and greater reductions in depression and anxiety compared to the placebo. Increases in SCFA-producing bacteria most strongly predicted improvements. Conclusions: Our results show that taking a probiotic supplement can help bring your gut back into balance, support better sleep, and lift symptoms of depression and anxiety. This offers a hopeful and practical option for people looking for real relief from these deeply connected challenges.
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From Gut to Mind: Impact of Probiotics on Depression, Anxiety, Mood, Gut Microbiota, Sleep and Stress-A Systematic Review of RCTs.
BACKGROUND: Probiotic supplementation may influence mental health through the gut-brain axis, with potential effects on depression, anxiety, sleep, cognition, stress hormones, and gut microbial composition. This systematic review aimed to evaluate the effects of probiotics on psychological, physiological, and gut microbiome-related outcomes across diverse populations. SUMMARY: A comprehensive search of PubMed, MEDLINE, PsycINFO, and ScienceDirect identified randomized controlled trials evaluating probiotic supplementation. Twenty RCTs were included, of which 15 were assessed as having a low risk of bias and five as having a high risk of bias. Commonly assessed outcomes included depression (n = 17), anxiety (n = 10), sleep quality (n = 9), stress (n = 6), cortisol (n = 7), cognitive function (n = 5), quality of life (n = 5), gut microbial composition (n = 11), and other neuroendocrine and inflammatory markers. Overall, probiotics were associated with improvements in depression, anxiety, sleep quality, mood, cognition, quality of life, and beneficial gut microbial populations, although findings for cortisol and stress-related outcomes were inconsistent. KEY MESSAGE: Probiotic supplementation may provide beneficial effects on psychological well-being and gut microbial composition. However, heterogeneity among interventions, populations, outcome measures, and study quality warrants further well-designed RCTs.
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Bipolar disorder and the gut microbiota: a bibliometric analysis.
BACKGROUND: Previous studies have explored the relationship between bipolar disorder and gut microbiota. However, there has been no bibliometric analysis to summarize and analyze these publications. Our objective was to perform a bibliometric analysis to investigate the current status and frontiers of the publications in the field of the association between bipolar disorder and the gut microbiota. METHODS: We retrieved publications concerning the interplay between the gut microbiota and bipolar disorder from the Web of Science Core Collection (WoSCC). The analysis was executed using WoSCC's literature analysis tool and VOSviewer 1.6.16. RESULTS: In total, we identified 177 publications originating from 362 institutions across 39 countries/regions, and these articles were disseminated in 104 different journals. The most productive institutions, authors, countries/regions, and journals were Zhejiang University contributing 18 publications, Shaohua Hu authoring 12 publications, China with 53 publications, and Frontiers in Psychiatry with 11 publications. The first high-cited document was published in the Journal of Psychiatric Research in 2017, and authored by Evans. In this article, they found gut microbiome composition was associated with BD and its illness severity, and they concluded that targeting the gut microbiota may be helpful to develop the effective treatment for bipolar disorder. The top 5 keywords with the highest frequency except for bipolar disorder and gut microbiota were as follows: depression, inflammation, probiotic, gut-brain axis, and anxiety. CONCLUSION: In conclusion, this is the first bibliometric analysis to explore the publications in the field of the association between bipolar disorder and the gut microbiota. The main research hotspots regarding this field were the characteristics, abundance, and diversity of gut microbiome in bipolar disorder, the role of treatment and gut microbiome in bipolar disorder, microbiome-brain connections in bipolar disorder, and interventions for bipolar disorder based on microbiota composition modification. The number of studies about the association between gut microbiota and bipolar disorder is relatively small, and more studies are needed to expand our understanding the association between gut microbiota and bipolar disorder.
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Chronic Unpredictable Mild Stress in Rats Induces Colonic Inflammation.
Chronic psychological stress is associated with an increased risk for relapse of inflammatory bowel diseases (IBD) and impedes the treatment of this condition. However, the impact of stress on the risk of IBD onset remains unclear. The goal of the present study was to examine whether chronic unpredictable mild stress (CUMS) could initiate or aggravate the onset of colon inflammation in rats which, in turn, would be capable of triggering bowel disease. We found that CUMS exposure increased infiltration of CD-45 positive cells and MPO activity, as well as augmented the expression of the inflammatory cytokines, IFN-γ and IL-6 within the colon of these rats. In addition, CUMS treatment changed the composition and diversity of gut microbiota and enhanced intestinal epithelial permeability, indicating the presence of a defect in the intestinal barrier. This CUMS-induced disruption of mucosal barrier integrity was associated with a reduction in expression of the tight junction protein, occludin 1, and an inhibition in mucosal layer functioning via reductions in goblet cells. Results from bacterial cultures revealed an increased presence of bacterial invasion after CUMS treatment as compared with that observed in controls. Thus, our data indicate that CUMS treatment induces alterations of the fecal microbiome and intestinal barrier defects, which facilitates bacterial invasion into colonic mucosa and further exacerbates inflammatory reactions within the colon. Accordingly, chronic stress may predispose patients to gastrointestinal infection and increase the risk of inflammation-related gut diseases.
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Prospecting the theragnostic potential of the psycho-neuro-endocrinological perturbation of the gut-brain-immune axis for improving cardiovascular diseases outcomes.
Biological derivatives and their effective influence on psychological parameters are increasingly being deciphered to better understand body-mind perspectives in health. Recent evidence suggests that the gut-brain immune axis is an attractive theragnostic target due to its innate capacity to excite the immune system by activating monocyte exosomes. These exosomes induce spontaneous alterations in the microRNAs within the brain endothelial cells, resulting in an acute inflammatory response with physiological and psychological sequelae, evidenced by anxiety and depression. Exploring the role of the stress models that influence anxiety and depression may reflect on the effect and role of exosomes, shedding light on various physiological responses that explain the contributing factors of cardiovascular disorders. The pathophysiological effects of gut-microbiome dysbiosis are further accentuated by alterations in the glucose metabolism, leading to type 2 diabetes, which is known to be a risk factor for cardiovascular disorders. Understanding the role of exosomes and their implications for cell-to-cell communication, inflammatory responses, and neuronal stress reactions can easily provide insight into the gut-brain immune axis and downstream cardiovascular sequelae.