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Review of the microbiome and metabolic pathways associated with psychoneurological symptoms in children with cancer.
Children with cancer often endure a range of psychoneurological symptoms (PNS), including pain, fatigue, cognitive impairment, anxiety, depressive symptoms, and sleep disturbance. Despite their prevalence, the underlying pathophysiology of PNS remains unclear. Hypotheses suggest an interplay between the gut microbiome and the functional metabolome, given the immune, neurological, and inflammatory influences these processes exert. This mini-review aims to provide a synopsis of the literature that examines the relationship between microbiome-metabolome pathways and PNS in children with cancer, drawing insights from the adult population when applicable. While there is limited microbiome research in the pediatric population, promising results in adult cancer patients include an association between lower microbial diversity and compositional changes, including decreased abundance of the beneficial microbes Fusicatenibacter, Ruminococcus, and Odoribacter, and more PNS. In pediatric patients, associations between peptide, tryptophan, carnitine shuttle, and gut microbial metabolism pathways and PNS outcomes were found. Utilizing multi-omics methods that combine microbiome and metabolome analyses provide insights into the functional capacity of microbiomes and their associated microbial metabolites. In children with cancer receiving chemotherapy, increased abundances of Intestinibacter and Megasphaera correlated with six metabolic pathways, notably carnitine shuttle and tryptophan metabolism. Interventions that target the underlying microbiome-metabolome pathway may be effective in reducing PNS, including the use of pre- and probiotics, fecal microbiome transplantation, dietary modifications, and increased physical activity. Future multi-omics research is needed to corroborate the associations between the microbiome, metabolome, and PNS outcomes in the pediatric oncology population.
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Microbiome-Related Indole and Serotonin Metabolites are Linked to Inflammation and Psychiatric Symptoms in People Living with HIV.
BACKGROUND: People living with HIV (PLHIV) exhibit dysregulation of tryptophan metabolism. Altered gut microbiome composition in PLHIV might be involved. Mechanistic consequences within the 3 major tryptophan metabolism pathways (serotonin, kynurenine, and indoles), and functional consequences for platelet, immune and behavioral functions are unknown. We investigated plasma tryptophan metabolites, gut microbiome composition, and their association with platelet function, inflammation, and psychiatric symptoms. METHODS: This study included 211 PLHIV on long-term antiretroviral treatment (ART). Plasma tryptophan pathway metabolites were measured using time-of-flight mass spectrometry. Bacterial composition was profiled using metagenomic sequencing. Platelet reactivity and serotonin levels were quantified by flowcytometry and ELISA, respectively. Circulating inflammatory markers were determined using ELISA. Symptoms of depression and impulsivity were measured by DASS-42 and BIS-11 self-report questionnaires, respectively. RESULTS: Plasma serotonin and indole metabolites were associated with gut bacterial composition. Notably, species enriched in PLHIV were associated with 3-methyldioxyindole. Platelet serotonin concentrations were elevated in PLHIV, without effects on platelet reactivity. Plasma serotonin and indole metabolites were positively associated with plasma IL-10 and TNF-α concentrations. Finally, higher tryptophan, serotonin, and indole metabolites were associated with lower depression and anxiety, whereas higher kynurenine metabolites were associated with increased impulsivity. CONCLUSION: Our results suggest that gut bacterial composition and dysbiosis in PLHIV on ART contribute to tryptophan metabolism, which may have clinical consequences for immune function and behavior.
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The Impact of Disease Comorbidities in Alzheimer's Disease.
A wide range of comorbid diseases is associated with Alzheimer's disease (AD), the most common neurodegenerative disease worldwide. Evidence from clinical and molecular studies suggest that chronic diseases, including diabetes, cardiovascular disease, depression, and inflammatory bowel disease, may be associated with an increased risk of AD in different populations. Disruption in several shared biological pathways has been proposed as the underlying mechanism for the association between AD and these comorbidities. Notably, inflammation is a common dysregulated pathway shared by most of the comorbidities associated with AD. Some drugs commonly prescribed to patients with diabetes and cardiovascular disease have shown promising results in AD patients. Systems-based biology studies have identified common genetic factors and dysregulated pathways that may explain the relationship of comorbid disorders in AD. Nonetheless, the precise mechanisms for the occurrence of disease comorbidities in AD are not entirely understood. Here, we discuss the impact of the most common comorbidities in the clinical management of AD patients.
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Associations of self-reported and actigraphic sleep with gut microbiome composition and diversity among older adults.
STUDY OBJECTIVES: Poor sleep is linked to adverse health outcomes. Animal studies suggest the gut microbiome may influence sleep, but human findings remain inconsistent. We examined associations of self-reported insomnia symptoms, daytime sleepiness, and actigraphy-measured sleep with gut microbiome diversity and composition in older adults. METHODS: We studied 869 Baltimore Longitudinal Study of Aging participants with self-reported sleep and shotgun metagenomic sequencing; 332 also had actigraphy. We tested associations of sleep with alpha diversity, beta diversity, and species composition using regression, PERMANOVA, and ANCOM-BC2, adjusting for age, sex, BMI, physical activity, education, and depressive symptoms. RESULTS: Participants had mean age 70.7 years; 54.8% were female and 66.9% White. Trouble falling asleep ≥5 times/week was associated with higher Shannon diversity (β=0.41 SD; 95% CI: 0.09, 0.73) and Pielou's evenness, but not richness metrics. No actigraphy-measured sleep variables were associated with alpha or beta diversity. Beta diversity analyses suggested excessive sleepiness (1-2 o 3-4 times/week) was associated with different microbial composition, though variance explained was small. In species-level analyses, frequent insomnia symptoms or excessive sleepiness were associated with depleted or undetected Eubacterium sp. CAG:251. In exploratory actigraphy models, each doubling of sleep efficiency was associated with higher Eubacterium sp. CAG:251 prevalence (PR=2.15; 95% CI: 1.47, 3.14), while each 30-minute increase in wake after sleep onset was associated with lower prevalence (PR=0.49; 95% CI: 0.29, 0.81). CONCLUSIONS: Global diversity findings were limited and inconsistent, whereas subjective and objective sleep disturbances converged on Eubacterium sp. CAG:251. Findings are exploratory and require longitudinal replication.
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Maternal anxiety, depression and stress affects offspring gut microbiome diversity and bifidobacterial abundances.
Uncovering mechanisms underlying fetal programming during pregnancy is of critical importance. Atypical neurodevelopment during the pre- and immediate postnatal period has been associated with long-term adverse health outcomes, including mood disorders and aberrant cognitive ability in offspring. Maternal factors that have been implicated in anomalous offspring development include maternal inflammation and tress, anxiety, and depression. One potential mechanism through which these factors perturb normal offspring postnatal development is through microbiome disruption. The mother is a primary source of early postnatal microbiome seeding for the offspring, and the transference of a healthy microbiome is key in normal neurodevelopment. Since psychological stress, mood disorders, and inflammation have all been implicated in altering maternal microbiome community structure, passing on aberrant microbial communities to the offspring that may then affect developmental outcomes. Therefore, we examined how maternal stress, anxiety and depression assessed with standardized instruments, and maternal inflammatory cytokine levels in the pre- and postnatal period are associated with the offspring microbiome within the first 13 months of life, utilizing full length 16S sequencing on infant stool samples, that allowed for species-level resolution. Results revealed that infants of mothers who reported higher anxiety and perceived stress had reduced alpha diversity. Additionally, the relative taxonomic quantitative abundances of Bifidobacterium dentium and other species that have been associated with either modulation of the gut-brain axis, or other beneficial health outcomes, were reduced in the offspring of mothers with higher anxiety, perceived stress, and depression. We also found associations between bifidobacteria and prenatal maternal pro-inflammatory cytokines IL-6, IL-8, and IL-10. In summary, specific microbial taxa involved in maintaining proper brain and immune function are lower in offspring born to mothers with anxiety, depression, or stress, providing strong evidence for a mechanism by which maternal factors may affect offspring health through microbiota dysregulation.
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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.