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International Society of Sports Nutrition Position Stand: Probiotics.
Position statement: The International Society of Sports Nutrition (ISSN) provides an objective and critical review of the mechanisms and use of probiotic supplementation to optimize the health, performance, and recovery of athletes. Based on the current available literature, the conclusions of the ISSN are as follows: 1)Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (FAO/WHO).2)Probiotic administration has been linked to a multitude of health benefits, with gut and immune health being the most researched applications.3)Despite the existence of shared, core mechanisms for probiotic function, health benefits of probiotics are strain- and dose-dependent.4)Athletes have varying gut microbiota compositions that appear to reflect the activity level of the host in comparison to sedentary people, with the differences linked primarily to the volume of exercise and amount of protein consumption. Whether differences in gut microbiota composition affect probiotic efficacy is unknown.5)The main function of the gut is to digest food and absorb nutrients. In athletic populations, certain probiotics strains can increase absorption of key nutrients such as amino acids from protein, and affect the pharmacology and physiological properties of multiple food components.6)Immune depression in athletes worsens with excessive training load, psychological stress, disturbed sleep, and environmental extremes, all of which can contribute to an increased risk of respiratory tract infections. In certain situations, including exposure to crowds, foreign travel and poor hygiene at home, and training or competition venues, athletes' exposure to pathogens may be elevated leading to increased rates of infections. Approximately 70% of the immune system is located in the gut and probiotic supplementation has been shown to promote a healthy immune response. In an athletic population, specific probiotic strains can reduce the number of episodes, severity and duration of upper respiratory tract infections.7)Intense, prolonged exercise, especially in the heat, has been shown to increase gut permeability which potentially can result in systemic toxemia. Specific probiotic strains can improve the integrity of the gut-barrier function in athletes.8)Administration of selected anti-inflammatory probiotic strains have been linked to improved recovery from muscle-damaging exercise.9)The minimal effective dose and method of administration (potency per serving, single vs. split dose, delivery form) of a specific probiotic strain depends on validation studies for this particular strain. Products that contain probiotics must include the genus, species, and strain of each live microorganism on its label as well as the total estimated quantity of each probiotic strain at the end of the product's shelf life, as measured by colony forming units (CFU) or live cells.10)Preclinical and early human research has shown potential probiotic benefits relevant to an athletic population that include improved body composition and lean body mass, normalizing age-related declines in testosterone levels, reductions in cortisol levels indicating improved responses to a physical or mental stressor, reduction of exercise-induced lactate, and increased neurotransmitter synthesis, cognition and mood. However, these potential benefits require validation in more rigorous human studies and in an athletic population.
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Acupuncture for hormonal readiness and gut microbiota in obese polycystic ovary syndrome: an open-label, randomized controlled trial.
OBJECTIVE: To explore whether acupuncture combined with clomiphene can reduce the luteinizing hormone-to follicle-stimulating hormone ratio and impact the gut microbiota in patients with obese polycystic ovary syndrome. METHODS: This open-label, randomized, parallel-group controlled trial included 86 women aged 20-40 years with obese polycystic ovary syndrome and 19 healthy controls. Participants were randomly assigned to either an acupuncture combined with clomiphene group or a clomiphene-only group, with a healthy control group for comparison. The treatment lasted three menstrual cycles, with acupuncture administered three times weekly and clomiphene given daily from day five of menstruation for five consecutive days per cycle. The primary outcome was the change in the luteinizing hormone-to-follicle-stimulating hormone (LH/FSH) ratio. Secondary outcomes included levels of other sex hormones, glucose and lipid metabolism parameters, self-rating anxiety and depression scale scores, and gut microbiota composition. RESULTS: Intention-to-treat analysis showed that the adjusted mean luteinizing hormone-to follicle-stimulating hormone ratio decrease was -0.8 (95% CI: -1.14 to -0.46) in the acupuncture combined with clomiphene group and -0.22 (95% CI: -0.47 to 0.01) in the clomiphene group. The adjusted between-group difference was 0.53 (95% CI: 0.24 to 0.82, p < 0.001). The levels of Agathobacter faecis increased, and those of Erysipelatoclostridium spiroforme, Streptococcus lutetiensis, and Lactococcus lactis decreased after acupuncture combined with clomiphene treatment (p < 0.05). CONCLUSION: Acupuncture combined with clomiphene may be safe and effective, reduce the luteinizing hormone-to follicle-stimulating hormone ratio, and improve insulin resistance in obese polycystic ovary syndrome, and these outcomes may be related to the gut microbiota.
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A cross comparison between Ayurvedic etiology of Major Depressive Disorder and bidirectional effect of gut dysregulation.
Ayurveda, an Indian medical science has been practiced for thousands of years. What makes Ayurveda relevant today is its subtle understanding of the environment and its focus on the generation of good health through one's own lifestyle choices. The digestive system has long been an area of critical importance within the Ayurvedic system and is only now being acknowledged by modern science as a key component in the regulation of physical and mental well-being. The gut microbiome and enteric nervous system are two particular areas in which the onset of psychiatric disorders, such as depression, have been associated. There are some striking similarities between this biomedical understanding of the gastrointestinal system and the Ayurvedic perspective of disease development. Major Depressive Disorder (MDD) is becoming increasingly linked with gut dysregulation in contemporary literature and is a pathology explored within both the Ayurvedic and Western systems of medicine. This literature review seeks to draw parallels between these two areas of study and highlight the importance of the digestive system when diagnosing and treating MDD.
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Altered metabolome and microbiome features provide clues in understanding irritable bowel syndrome and depression comorbidity.
Irritable bowel syndrome (IBS) is one of the functional gastrointestinal disorders characterized by chronic and/or recurrent symptoms of abdominal pain and irregular defecation. Changed gut microbiota has been proposed to mediate IBS; however, contradictory results exist, and IBS-specific microbiota, metabolites, and their interactions remain poorly understood. To address this issue, we performed metabolomic and metagenomic profiling of stool and serum samples based on discovery (n = 330) and validation (n = 101) cohorts. Fecal metagenomic data showed moderate dysbiosis compared with other diseases, in contrast, serum metabolites showed significant differences with greater power to distinguish IBS patients from healthy controls. Specifically, 726 differentially abundant serum metabolites were identified, including a cluster of fatty acyl-CoAs enriched in IBS. We further identified 522 robust associations between differentially abundant gut bacteria and fecal metabolites, of which three species including Odoribacter splanchnicus, Escherichia coli, and Ruminococcus gnavus were strongly associated with the low abundance of dihydropteroic acid. Moreover, dysregulated tryptophan/serotonin metabolism was found to be correlated with the severity of IBS depression in both fecal and serum metabolomes, characterized by a shift in tryptophan metabolism towards kynurenine production. Collectively, our study revealed serum/fecal metabolome alterations and their relationship with gut microbiome, highlighted the massive alterations of serum metabolites, which empower to recognize IBS patients, suggested potential roles of metabolic dysregulation in IBS pathogenesis, and offered new clues to understand IBS depression comorbidity. Our study provided a valuable resource for future studies, and would facilitate potential clinical applications of IBS featured microbiota and/or metabolites.
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Dietary index for gut microbiota (DIGM) and cardiometabolic, inflammatory, and gut-brain-related biomarkers in adults with obesity: a cross-sectional study.
Background The gut microbiota plays an important role in metabolic homeostasis and systemic inflammation, and dietary habits are major determinants of its composition and function. This study investigated the association between adherence to the Dietary Index for Gut Microbiota (DIGM) and cardiometabolic, inflammatory, and gut microbiota-related biomarkers in adults with obesity. Methods In this cross-sectional study conducted from January to December 2025, 637 adults with obesity aged 20-55 years were recruited from clinics affiliated with Mansoura University, Egypt, through clinic-based recruitment and public advertisements. Dietary intake was assessed using a semi-quantitative food frequency questionnaire, and the DIGM score was calculated based on predefined favorable and unfavorable dietary components according to the original scoring framework. Participants were categorized into tertiles according to their DIGM score. Anthropometric measurements, blood pressure, glycemic indices, lipid profile, lipopolysaccharide (LPS) and brain-derived neurotrophic factor (BDNF) and C-reactive protein (CRP) were assessed. Multivariable analyses were adjusted for age, sex, body mass index (BMI), smoking status, physical activity, dietary energy intake, education, occupation, marital status, and history of depression. Results Higher DIGM adherence was associated with lower SBP and higher high density lipoprotein cholesterol (HDL-C) after multivariable adjustment. Participants in the highest DIGM tertile showed lower circulating LPS and CRP concentrations and higher BDNF levels compared with lower tertiles (all adjusted P < 0.001). In multivariable linear regression models adjusted for confounders, higher DIGM scores were independently associated with lower SBP (β = -0.057; 95% CI: -0.011 to - 0.006), higher HDL-C (β = 0.100; 95% CI: 0.004 to 0.011), higher BDNF (β = 0.504; 95% CI: 0.295 to 0.407), and lower LPS (β = -0.468; 95% CI: -0.208 to - 0.146) and CRP (β = -0.048; 95% CI: -0.028 to - 0.003). Conclusion Greater adherence to the DIGM was independently associated with a more favorable inflammatory profile, higher circulating BDNF concentrations, lower LPS and CRP levels, and lower blood pressure among adults with obesity. These findings suggest that dietary patterns characterized by higher DIGM adherence may be associated with cardiometabolic and inflammatory profiles. Further prospective studies incorporating direct assessment of gut microbiota composition, microbial metabolites, and clinical outcomes are warranted to clarify the underlying mechanisms and temporal relationships. Keywords: Gut microbiota, Diet score, Obesity, Inflammation, Blood pressure, BDNF, Metabolic profile, Cardiometabolic risk.
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Effect of Chaihu-Shugan-San on functional dyspepsia and gut microbiota: A randomized, double-blind, placebo-controlled trial.
ETHNOPHARMACOLOGICAL RELEVANCE: Chaihu-Shugan-San (CSS) is a classic traditional Chinese medicine (TCM) formula from the Ming Dynasty "Jingyue's Complete Works". In China, it is prevalent for the treatment of a wide range of ailments, with a particular emphasis on functional gastrointestinal disorders (FGIDs). Clinical evidence suggests that CSS has been found to be a highly effective therapeutic approach for the treatment of Functional Dyspepsia (FD), however, there is a limited amount of high-quality clinical evidence, particularly randomized, double-blind, placebo-controlled trials to support this claim. AIM OF THE STUDY: To evaluate the therapeutic efficacy of Chaihu-Shugan-San (CSS) for treating functional dyspepsia (FD) by comparing it to placebos, as well as to investigate the impact of CSS on the gut microbiota in individuals diagnosed with FD. MATERIALS AND METHODS: This was a randomized double-blind, placebo-controlled clinical trial implemented at Shuguang Hospital in Shanghai. Between May 2021 and December 2022, 94 participants satisfying the Rome IV diagnostic criteria for FD were enrolled. They were assigned randomly to either the CSS group or the placebo group, with an equal allocation ratio of 1:1. Patients in both groups received the intervention for four weeks. The primary outcome was the dyspepsia symptom scores evaluated by using single dyspepsia symptom scale (SDS) after four weeks of treatment. The secondary outcomes were the solid gastric empties rate measured by a barium strip method, Hamilton anxiety scale (HAMA), Hamilton depression scale (HAMD), and Functional dyspepsia Quality of life scale (FDDQL). In addition, after unblinding, 30 patients in the CSS group were randomly selected and divided into before and after treatment of the FD groups (FD1, FD2), and 30 healthy participants were selected as healthy control group (HC), and the gut microbiota was analyzed by 16S rRNA sequencing. RESULTS: After four weeks of treatment, the SDS score exhibited a significant improvement in the CSS group compared to the placebo group (t = 4.882; P ＜0.001). The difference in barium strip gastric emptying rate in the CSS group showed a significant ascent compared to the control group (P < 0.01). The HAMA, HAMD, and FDDQL scores in the CSS group showed a statistically significant increase compared to the control group (all P < 0.01). The results of 16S rRNA sequencing revealed that FD patients had less diverse and abundant microbiota than the healthy people. Additionally, the application of CSS resulted in the modulation of certain bacterial populations, leading to both up-regulation and down-regulation of their quantities. CONCLUSIONS: These findings suggested that CSS is more effective compared to a placebo in treating FD, relieves anxiety and depression, increases gastric emptying rate in FD patients, and that CSS also affects the bacterial community structure in FD patients. TRIAL REGISTRATION: ChiCTR, ChiCTR2100045793. Registered 25 Mach 2021.
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Gut Microbiota Modulation as a Therapeutic Strategy for Insomnia: A Systematic Review of Nutritional and Botanical Interventions.
Background: Insomnia and stress-related sleep disorders are increasingly recognized as systemic conditions linked to the microbiota-gut-brain axis (MGBA). With growing clinical interest in natural products that modulate the gut environment, this systematic review evaluates the efficacy and mechanisms of non-pharmacological interventions, specifically probiotics, prebiotics, dietary indices, and botanicals, in alleviating insomnia, restoring circadian rhythms, and modulating neurochemical markers. Methods: In strict accordance with PRISMA 2020 guidelines, we searched PubMed, ScienceDirect, Scopus, and The Cochrane Library for English language studies published from inception to March 31, 2026. Eligibility was restricted to studies with rigorously controlled designs, specifically randomized controlled trials (RCTs) and controlled in vivo animal studies. Interventions had to target the gut microbiota, with primary outcomes measuring sleep quality (subjective or objective) or sleep-related neurochemical markers. We excluded uncontrolled, single-arm, or observational designs; in vitro studies; non-original research; and studies involving subjects with severe medical or psychiatric comorbidities (e.g., cancer, ADHD, severe psychiatric disorders) to prevent confounding variables, though mild-to-moderate anxiety and depression were permitted. Risk of bias was assessed using the Cochrane RoB 2.0 and SYRCLE tools. Due to significant methodological heterogeneity, a narrative synthesis stratified by intervention and population was conducted. This review was not registered in PROSPERO. Results: A total of 56 studies (33 humans, 23 animals) met the inclusion criteria. Taxonomic nomenclature was updated to reflect 2020 reclassifications (e.g., Lactiplantibacillus plantarum). In human trials, interventions significantly improved subjective sleep metrics (PSQI, ISI). Recent additions demonstrated the efficacy of the Dietary Index for Gut Microbiota (DI-GM) and the improvement in N3 sleep latency by yeast mannan. Furthermore, whole-food patterns (e.g., the MIND diet) and Traditional Chinese Medicine (TCM) decoctions successfully enriched beneficial taxa, such as Bacteroides coprophilus, and increased short-chain fatty acid (SCFA) production. Animal models demonstrated that "psychobiotic" strains (Bifidobacterium breve, Lacticaseibacillus paracasei), prebiotics (GOS/PDX), and TCM formulas effectively restored GABA/5-HT profiles, lowered morning cortisol, and facilitated REM rebound in PCPA-induced models, while also consolidating non-rapid eye movement (NREM) sleep and downregulating clock genes (Per1/Per2). Conclusions: Psychobiotics, prebiotics, and botanicals represent a highly viable non-pharmacological strategy for treating insomnia. However, current evidence is constrained by a heavy reliance on subjective human questionnaires, short follow-up durations limiting insight into long-term stability, and a substantial translational gap between mechanistic rodent models and human clinical outcomes.
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Cell-Type-Specific WTAP and ALKBH5-Mediated m6A Methylation Orchestrates Mental Disorders via Gut-Brain Axis Metabolite Signaling: Multi-Omics Evidence and Pyroptosis-Associated Loop Mechanism.
INTRODUCTION: Mental disorders affect one billion people and contribute 5% of global DALYs. Although N6-methyladenosine (m6A) modification, gut microbiota, cerebrospinal fluid (CSF) metabolites, and pyroptosis have been implicated in disease pathogenesis, the directionality and magnitude of causal links remain elusive. We integrated two-sample Mendelian randomization (MR) with single-cell eQTL data to generate hypotheses regarding these relationships. METHODS: Using large-scale GWAS summary statistics, we estimated the causal effects of m6A regulators, gut microbiota, CSF metabolites, and pyroptosis on depression, schizophrenia (SZ), bipolar disorder (BD), attention-deficit/hyperactivity disorder (ADHD), and post-traumatic stress disorder (PTSD). Mediation analysis quantified hypothesized microbiota- and metabolite-mediated proportions; single-cell eQTL from 14 immune subsets localized genetic associations to cell types. RESULTS: MR analysis suggested distinct causal associations of m6A modifiers (WTAP/ALKBH5) with mental disorders. Gut microbiota (e.g., GCA-900066755, Bacillus) and CSF metabolites (e.g., theophylline, isoleucine) were estimated to potentially mediate 5.06%-45.28% of these effects, forming pathways such as WTAP → GCA-900066755 → theophylline → ADHD and ALKBH5 → CAG-390 → isoleucine → PTSD. These represent statistically inferred associations rather than experimentally validated pathways. Notably, these proportions were not based on multiple-testing-corrected associations. Single-cell eQTL mapping associated WTAP's ADHD risk with XCL1-NK cells (OR = 1.445). Bidirectional MR suggested potential reciprocal associations between mental disorders and microbial/metabolite profiles. Pyroptosis demonstrated a tentative statistical association (3.99% explanatory power), though its specific biological role remains undefined. CONCLUSION: This multi-omics integration generates a hypothesis regarding a potential m6A-microbiota-metabolite axis that may be associated with mental disorders, with pyroptosis as a potentially related peripheral factor. Should these associations prove causal, the identified relationships could suggest peripheral intervention nodes, while combinatorial targeting might provide directions for preventive psychiatry. Experimental validation is required to confirm the biological mechanisms implied by these genetic associations.
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IL-1β pathway-dependent regulation of glutamate receptor activity by gut microbiota in bipolar depression.
OBJECTIVES: Neuroinflammation may disrupt neurotransmitter signaling. This study investigated whether gut microbiota-induced neuroinflammation can regulate glutamate pathways in bipolar disorder (BD). METHODS: Fecal microbiota transplantation (FMT) was performed to observe behavioral changes in the antibiotic-treated C57BL/6J male mouse model of bipolar depression. Gut microbial structure, circulating, and prefrontal levels of inflammatory factors, microglial activation, and transcription levels of N-methyl- d-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4 isoxazole receptor (AMPAR) genes were measured in the "BD" and control mice. Furthermore, the effects of interleukin-1 (IL-1) receptor antagonist (IL-1RA) on the glutamate pathways were assessed. RESULTS: Compared with the control mice, "BD" mice displayed depression-like behaviors, with a lower diversity of gut bacteria and a decreased abundance of certain species. In addition, "BD" mice showed increased levels of inflammatory factors (e.g., IL-1β) in the serum and prefrontal cortex, microglial activation, and changes in the messenger RNA (mRNA) levels of NMDAR and AMPAR. Treatment with IL-1RA partially reversed the behavioral patterns, neuroinflammation, and transcription levels of glutamate receptors. CONCLUSIONS: The findings suggest that gut microbiota may influence glutamate receptor gene expression via an IL-1β-dependent pathway in a mouse model of BD, potentially contributing to neuroinflammatory mechanisms relevant to this disorder.
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Variations in the oral microbiome are associated with depression in young adults.
A growing body of evidence supports an important role for alterations in the brain-gut-microbiome axis in the aetiology of depression and other psychiatric disorders. The potential role of the oral microbiome in mental health has received little attention, even though it is one of the most diverse microbiomes in the body and oral dysbiosis has been linked to systemic diseases with an underlying inflammatory aetiology. This study examines the structure and composition of the salivary microbiome for the first time in young adults who met the DSM-IV criteria for depression (n = 40) and matched controls (n = 43) using 16S rRNA gene-based next generation sequencing. Subtle but significant differences in alpha and beta diversity of the salivary microbiome were observed, with clear separation of depressed and healthy control cohorts into distinct clusters. A total of 21 bacterial taxa were found to be differentially abundant in the depressed cohort, including increased Neisseria spp. and Prevotella nigrescens, while 19 taxa had a decreased abundance. In this preliminary study we have shown that the composition of the oral microbiome is associated with depression in young adults. Further studies are now warranted, particuarly investigations into whether such shifts play any role in the underling aetiology of depression.