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Neurobiological effects of a probiotic-supplemented diet in chronically stressed male Long-Evans rats: Evidence of enhanced resilience.
Probiotics that regulate the microbiome-gut-brain axis and provide mental health benefits to the host are referred to as psychobiotics. Preclinical studies have demonstrated psychobiotic effects on early life stress-induced anxiety- and depression-related behavior in rodents; however, the specific mechanisms remain ill-defined. In the current study, we investigated the effects of probiotic supplementation on neurobiological responses to chronic stress in adult male Long-Evans rats. Twenty-four rats were randomly assigned to probiotic (PB) or vehicle control (VEH) groups, then to either chronic unpredictable stress (CUS) or no-stress control (CON) conditions within each group (n = 6/subgroup). We hypothesized that PB supplementation would reduce markers of anxiety and enhance emotional resilience, especially in the CUS animals. In the cognitive uncertainty task, a nonsignificant trend was observed indicating that the PB-supplemented animals spent more time oriented toward the food reward than VEH animals. In the open-field task, CUS-PB animals spent more time in the center of the arena than CUS-VEH animals, an effect not observed between the two CON groups. In the swim task, the PB animals, regardless of stress assignment, exhibited increased floating, suggesting a conserved response in a challenging context. Focusing on the endocrine measures, higher dehydroepiandrosterone (DHEA)-to-corticosterone fecal metabolite ratios, a correlate of emotional resilience, were observed in PB animals. Further, PB animals exhibited reduced microglia immunoreactivity in the basolateral amygdala, possibly indicating a neuroprotective effect of PB supplements in this rodent model. These results provide evidence that PB supplementation interacts with stress exposure to influence adaptive responses associated with endocrine, neural, and behavioral indices of anxiety.
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Exploring the Relationship between Psychoneuroimmunology and Oral Diseases: A Comprehensive Review and Analysis.
The relationship between psychoneuroimmunology (PNI) and oral health has recently garnered increasing attention due to the intricate interaction among psychological factors, the nervous system, immune responses, and oral diseases. This comprehensive review aims to elucidate the multifaceted connections between PNI and various oral conditions and conduct an in-depth analysis. Psychological factors, such as stress, anxiety, and depression, have been linked to oral microbiome alterations and immune function and the development and progression of oral diseases, such as periodontal disorders, oral ulcers, and temporomandibular disorders. Conversely, oral health conditions, particularly chronic periodontitis, have been associated with systemic inflammation, affecting mental health and overall well-being through neuroendocrine-immune pathways. Moreover, neural mechanisms, including the brain-gut axis and the autonomic nervous system, significantly influenced oral health through immune modulation and inflammatory responses. Understanding these complex interactions has implications for therapeutic interventions that target both psychological well-being and oral health outcomes. This review synthesizes current research findings from various disciplines, including immunology, neuroscience, dentistry, and psychology, to offer a comprehensive understanding of the bidirectional relationship between PNI and oral diseases. The implications of these interactions on treatment strategies, preventive measures, and interdisciplinary approaches underscore the need for integrated healthcare models that address psychological and oral health aspects to improve outcomes and quality of life in patients.
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Probiotic Mixture Containing Lactobacillus helveticus, Bifidobacterium longum and Lactiplantibacillus plantarum Affects Brain Responses Toward an Emotional Task in Healthy Subjects: A Randomized Clinical Trial.
BACKGROUND: Evidence from preclinical studies suggests that probiotics affect brain function via the microbiome-gut-brain axis, but evidence in humans remains limited. OBJECTIVE: The present proof-of-concept study investigated if a probiotic product containing a mixture of Bifidobacterium longum R0175, Lactobacillus helveticus R0052 and Lactiplantibacillus plantarum R1012 (in total 3 × 109 CFU/day) affected functional brain responses in healthy subjects during an emotional attention task. DESIGN: In this double-blinded, randomized, placebo-controlled crossover study (Clinicaltrials.gov, NCT03615651), 22 healthy subjects (24.2 ± 3.4 years, 6 males/16 females) were exposed to a probiotic intervention and a placebo for 4 weeks each, separated by a 4-week washout period. Subjects underwent functional magnetic resonance imaging while performing an emotional attention task after each intervention period. Differential brain activity and functional connectivity were assessed. RESULTS: Altered brain responses were observed in brain regions implicated in emotional, cognitive and face processing. Increased activation in the orbitofrontal cortex, a region that receives extensive sensory input and in turn projects to regions implicated in emotional processing, was found after probiotic intervention compared to placebo using a cluster-based analysis of functionally defined areas. Significantly reduced task-related functional connectivity was observed after the probiotic intervention compared to placebo. Fecal microbiota composition was not majorly affected by probiotic intervention. CONCLUSION: The probiotic intervention resulted in subtly altered brain activity and functional connectivity in healthy subjects performing an emotional task without major effects on the fecal microbiota composition. This indicates that the probiotic effects occurred via microbe-host interactions on other levels. Further analysis of signaling molecules could give possible insights into the modes of action of the probiotic intervention on the gut-brain axis in general and brain function specifically. The presented findings further support the growing consensus that probiotic supplementation influences brain function and emotional regulation, even in healthy subjects. Future studies including patients with altered emotional processing, such as anxiety or depression symptoms are of great interest. CLINICAL TRIAL REGISTRATION: [http://clinicaltrials.gov/], identifier [NCT03615651].
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Protein Intake Across the Lifespan: Optimizing Health, Function, and Longevity.
Lifestyle Medicine leverages evidence-based health behaviors: nutrition, physical activity, restorative sleep, stress management, social connection, and avoidance of risky substances to prevent, treat, and often reverse chronic disease. Nutrition is underutilized in routine care. A growing body of evidence demonstrates that a whole-food, plant-predominant diet (WFPD) confers broad benefits across cardiometabolic, reproductive, and mental health domains. Mechanistic and clinical studies link WFPDs to reduced risk of cardiovascular disease, diabetes, cancer, and depression through improved microbiome diversity, increased short-chain fatty acid production, reduced oxidative stress and inflammation, and enhanced insulin sensitivity. Beyond disease prevention, plant-forward diets improve psychological well-being via nutrient pathways that modulate neurotransmitter synthesis and the gut-brain axis. Some patients can benefit from protein intakes above the Recommended Daily Allowance (RDA) of 0.8g/kg/day for adults in a variety of settings. Well-planned plant-based diets can achieve significantly higher levels of protein intake, achieved through diverse sources such as legumes, soy, grains, nuts, and seeds. Adequate and well-distributed protein supports fertility, fetal growth, lactation, and preservation of lean mass through perimenopause and aging. Implementing WFPDs with individualized protein guidance can extend health span, enhance functional independence, and reduce medication dependence, reaffirming wholesome food as a cornerstone of modern medicine.
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Postbiotics Unveiled: The Next Emerging Trend in Functional Foods.
The global population is expected to reach 9.7 billion by 2050, with demand for food increasing by up to 56%. Postbiotics are a safe and reliable substitute for probiotics, which are described as preparations of non-viable bacteria and/or their metabolic byproducts. Data for this narrative review was collected using Goggle scholar and PubMed from 2006 to 2026. Major bioactive compounds such as short-chain fatty acids, peptides, polysaccharides, vitamins, and cell fragments contribute to immunomodulatory, antioxidant, metabolic, and gut-brain axis effects. Preclinical and clinical research shows that they can improve insulin sensitivity, control cytokine signaling, strengthen epithelial barrier integrity, and protect against obesity, type 2 diabetes mellitus, and depression. Postbiotics have also been found to improve mineral absorption and folate synthesis, and possess anti-sarcopenic actions. Several commercial products are available because of their health benefits. Thus, postbiotics are a revolutionary development in microbiome-based treatments; however, to completely understand their therapeutic potential, it is necessary to standardize, achieve mechanistic clarity, and ensure regulatory alignment.
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Mental health in early pregnancy: Interplay of objectively measured lifestyles, gut microbiota, and metabolomics.
Prenatal anxiety symptoms (AS) and depression symptoms (DS) in early pregnancy substantially impact maternal-infant health, but their pathophysiological mechanisms remain unclear. We conducted a multimodal assessment of 161 early-pregnant women. DS exhibited significantly longer standing/sitting durations and shorter nocturnal sleep and nap times (p < 0.05). AS was associated with lower fiber intake (p = 0.018). AS and DS had more complex microbial co-occurrence networks with more extensive metabolomic changes. DS was characterized by dysregulated cysteine/methionine metabolism and Bifidobacterium-mediated modulation of standing/sleep effects. Machine learning achieved best DS discrimination by combining physical activity, diet, and microbiome data (AUC = 0.877), while metabolomics alone best discriminated AS (AUC = 0.844). In conclusion, AS is associated with metabolomic dysregulation and fiber deficiency, while DS is associated with sedentary behavior and microbiota-metabolite disruption. This study establishes a precision framework prioritizing fiber interventions for AS and activity/sleep modulation targeting microbiota-metabolite pathways for DS.
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Effect of faecal microbial transplant via colonoscopy in patients with severe obesity and insulin resistance: A randomized double-blind, placebo-controlled Phase 2 trial.
AIM: To assess the effects of faecal microbial transplant (FMT) from lean people to subjects with obesity via colonoscopy. MATERIAL AND METHODS: In a double-blind, randomized controlled trial, subjects with a body mass index ≥ 35 kg/m2 and insulin resistance were randomized, in a 1:1 ratio in blocks of four, to either allogenic (from healthy lean donor; n = 15) or autologous FMT (their own stool; n = 13) delivered in the caecum and were followed for 3 months. The main outcome was homeostatic model assessment of insulin resistance (HOMA-IR) and secondary outcomes were glycated haemoglobin levels, lipid profile, weight, gut hormones, endotoxin, appetite measures, intestinal microbiome (IM), metagenome, serum/faecal metabolites, quality of life, anxiety and depression scores. RESULTS: In the allogenic versus autologous groups, HOMA-IR and clinical variables did not change significantly, but IM and metabolites changed favourably (P < 0.05): at 1 month, Coprococcus, Bifidobacterium, Bacteroides and Roseburia increased, and Streptococcus decreased; at 3 months, Bacteroides and Blautia increased. Several species also changed significantly. For metabolites, at 1 month, serum kynurenine decreased and faecal indole acetic acid and butenylcarnitine increased, while at 3 months, serum isoleucine, leucine, decenoylcarnitine and faecal phenylacetic acid decreased. Metagenomic pathway representations and network analyses assessing relationships with clinical variables, metabolites and IM were significantly enhanced in the allogenic versus autologous groups. LDL and appetite measures improved in the allogenic (P < 0.05) but not in the autologous group. CONCLUSIONS: Overall, in those with obeisty, allogenic FMT via colonoscopy induced favourable changes in IM, metabolites, pathway representations and networks even though other metabolic variables did not change. LDL and appetite variables may also benefit.
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Serum Cyclic Pentapeptide Cyclo(D-Trp-D-Asp-Pro-D-Val-Leu) as a Candidate Diagnostic Biomarker for Depression-Anxiety Comorbidity.
INTRODUCTION: The comorbidity rate of depression and anxiety disorders is as high as 50%, with patients suffering from both conditions facing an elevated risk of suicide. Given the challenges in clinical diagnosis, there is an urgent need for objective diagnostic biomarkers to accurately identify patients with comorbid depression and anxiety disorders. METHODS: The case-control study enrolled 77 participants, including healthy controls (n = 38) and patients with comorbid depression and anxiety disorders (n = 39). Serum levels of short peptides were assessed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Binary logistic regression and receiver operating characteristic analysis (ROC) were employed to identify potential biomarkers, while decision curve analysis (DCA) was performed to evaluate the clinical utility of the candidate cyclic pentapeptide. RESULTS: A total of 25 differentially expressed short peptides were identified, among which 19 were significantly downregulated, and 6 were upregulated. Logistic regression analysis revealed that reduced levels of cyclo (D-trp-D-asp-pro-D-val-leu) were associated with an increased risk of comorbid depression and anxiety disorders. The area under the ROC curve (AUC) for this cyclic pen-tapeptide in diagnosing comorbid depression and anxiety disorders was 0.941 (95% CI, 0.884-0.997; P < 0.0001). DCA demonstrated that the cyclic pentapeptide provides meaningful net benefits when the threshold probability exceeded 0.11. Notably, this cyclic pentapeptide is an endothelin A receptor antagonist, which is implicated in vasoconstriction, hypertension, and anxiety, and elevated blood pressure was indeed observed in the patient cohort. DISCUSSION: The identified cyclic pentapeptide serves as a potential diagnostic tool, linking the pathophysiology of comorbid depression and anxiety disorders to the endothelin system. This association offers a novel integrative perspective on the co-occurring psychiatric and cardiovascular manifestations observed in these patients. CONCLUSION: In conclusion, this study identifies a specific cyclic pentapeptide as a promising serum biomarker that may facilitate the objective diagnosis of patients with comorbid depression and anxiety disorders. Its biological role as an endothelin A receptor antagonist not only provides a potential tool for clinical differentiation but also suggests a novel pathophysiological link to cardiovascular comorbidities, thereby offering new directions for elucidating the underlying mechanisms of these conditions.
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Gut Microbial β-Glucuronidase Inhibition via Catalytic Cycle Interception.
Microbial β-glucuronidases (GUSs) cause severe gut toxicities that limit the efficacy of cancer drugs and other therapeutics. Selective inhibitors of bacterial GUS have been shown to alleviate these side effects. Using structural and chemical biology, mass spectrometry, and cell-based assays, we establish that piperazine-containing GUS inhibitors intercept the glycosyl-enzyme catalytic intermediate of these retaining glycosyl hydrolases. We demonstrate that piperazine-based compounds are substrate-dependent GUS inhibitors that bind to the GUS-GlcA catalytic intermediate as a piperazine-linked glucuronide (GlcA, glucuronic acid). We confirm the GUS-dependent formation of inhibitor-glucuronide conjugates by LC-MS and show that methylated piperazine analogs display significantly reduced potencies. We further demonstrate that a range of approved piperazine- and piperidine-containing drugs from many classes, including those for the treatment of depression, infection, and cancer, function by the same mechanism, and we confirm through gene editing that these compounds selectively inhibit GUS in living bacterial cells. Together, these data reveal a unique mechanism of GUS inhibition and show that a range of therapeutics may impact GUS activities in the human gut.
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Dysregulation of Oral Microbial Eicosapentaenoic Acid Induced by Chronic Restraint Stress Exacerbates Periodontitis via M1 Macrophage Polarization.
The intricate interplay between chronic psychological stress and periodontitis, mediated by oral microbiota and macrophage polarization, remains largely enigmatic. Here, we demonstrate that chronic restraint stress (CRS) exacerbates periodontitis by inducing oral microbial dysbiosis and a consequential shift in host metabolism. Clinical observations reveal a significant correlation between depressive symptoms and the severity of periodontitis, which is underpinned by a distinct oral microbiome. Crucially, fecal microbiota transplantation from CRS-exposed mice into germ-free mice was sufficient to transmit the heightened periodontitis phenotype, establishing a causal role for the stress-altered microbiota. Metabolomic profiling identified a depletion of eicosapentaenoic acid (EPA) in stressed, ligature-induced periodontitis mice. Mechanistically, supplementation with EPA ameliorates periodontitis by suppressing the NF-κB signaling pathway, thereby inhibiting the pro-inflammatory M1 polarization of macrophages. Our findings unveil a novel gut-oral axis mediated by microbiota and metabolites under stress, and position the omega-3 fatty acid EPA as a promising therapeutic agent for mitigating stress-aggravated inflammatory disorders.