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Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: part III - convergence toward clinical trials.
Rapid scientific and technological advances have allowed for a more detailed understanding of the relevance of intestinal microbiota, and the entire body-wide microbiome, to human health and well-being. Rodent studies have provided suggestive evidence that probiotics (e.g. lactobacillus and bifidobacteria) can influence behavior. More importantly, emerging clinical studies indicate that the administration of beneficial microbes, via supplementation and/or fecal microbial transplant (FMT), can influence end-points related to mood state (glycemic control, oxidative status, uremic toxins), brain function (functional magnetic resonance imaging fMRI), and mental outlook (depression, anxiety). However, despite the advances in the area of gastro-biological psychiatry, it becomes clear that there remains an urgent need to explore the value of beneficial microbes in controlled clinical investigations. With the history explored in this series, it is fair to ask if we are now on the cusp of major clinical breakthroughs, or are we merely in the quicksand of Autointoxication II?
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Endometriosis, Pain, and Related Psychological Disorders: Unveiling the Interplay among the Microbiome, Inflammation, and Oxidative Stress as a Common Thread.
Endometriosis (EM), a chronic condition in endometrial tissue outside the uterus, affects around 10% of reproductive-age women, significantly affecting fertility. Its prevalence remains elusive due to the surgical confirmation needed for diagnosis. Manifesting with a range of symptoms, including dysmenorrhea, dyschezia, dysuria, dyspareunia, fatigue, and gastrointestinal discomfort, EM significantly impairs quality of life due to severe chronic pelvic pain (CPP). Psychological manifestations, notably depression and anxiety, frequently accompany the physical symptoms, with CPP serving as a key mediator. Pain stems from endometrial lesions, involving oxidative stress, neuroinflammation, angiogenesis, and sensitization processes. Microbial dysbiosis appears to be crucial in the inflammatory mechanisms underlying EM and associated CPP, as well as psychological symptoms. In this scenario, dietary interventions and nutritional supplements could help manage EM symptoms by targeting inflammation, oxidative stress, and the microbiome. Our manuscript starts by delving into the complex relationship between EM pain and psychological comorbidities. It subsequently addresses the emerging roles of the microbiome, inflammation, and oxidative stress as common links among these abovementioned conditions. Furthermore, the review explores how dietary and nutritional interventions may influence the composition and function of the microbiome, reduce inflammation and oxidative stress, alleviate pain, and potentially affect EM-associated psychological disorders.
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Maternal probiotic supplementation and effects on the fetal placenta.
Increasing number of pregnant women are consumi ng probiotics to promote their own health and that of their unborn fetuses. Such supplements are presumed to be safe for pregnant mothers and their unborn offspring. For pregnant mothers, such bioactive compounds might lower the risk of constipation, diarrhea, other gastrointestinal conditions, and pre-term birth, and prevent adverse pregnancy outcomes, including gestational diabetes mellitus and depression/anxiety. More research is needed to examine potential safety of probiotic consumption during pregnancy and long-term health consequences to offspring. The conceptus can also be indirectly affected by maternal probiotic supplementation through microorganism production of bioactive compounds. The placenta is in direct communication with the underlying uterine tissue. Thus, compounds in the maternal blood can easily transfer across the placenta and impact this hormonally sensitive organ. Select studies suggest that disruptions to the maternal microbiome dramatically affect the placenta. In the current review, we will therefore consider the evidence to date of how maternal probiotic supplementation affects the placenta. Three potential mechanisms we will explore include the possibility that maternal probiotic supplementation might impact the putative placenta microbiome. The second potential mechanism we will consider is that maternal probiotic consumption alters bacterial-derived metabolites, including short-chained fatty acids, polyamines, Vitamin B9, and Vitamin B12. The third potential mechanism to be discussed is that such supplements affect maternal and placental immune responses. Before probiotics are promoted for healthy pregnant women and those with gestational disorders, more studies, including those examining the effects on the placenta, are essential.
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Lower serum levels of IL-1β and IL-6 cytokines in adolescents with anorexia nervosa and their association with gut microbiota in a longitudinal study.
INTRODUCTION: Anorexia nervosa (AN) is an often chronic and debilitating psychiatric disease whose etiology is not completely understood. Recently, a potential role of inflammation has emerged in other psychiatric diseases, such as depression, PTSD and schizophrenia. The first results in adults with AN seemed to confirm a low-grade proinflammatory state until recent studies presented more differential findings. Studying adolescents with a shorter illness duration and fewer confounding factors might help elucidate the role of inflammation in the underlying pathophysiology of AN; however, the few available studies in adolescents remain ambiguous, and no longitudinal data are available in this age range. METHODS: We examined the proinflammatory cytokines Tumor Necrosis Factor-alpha (TNF-α), Interleukin (IL)-1β, IL-6, IL-15, and the cytokine-receptor IL-6 Receptor alpha (IL-6 Rα) in the serum of twenty-two hospitalized female adolescent patients with AN longitudinally at admission and discharge and compared their results to nineteen healthy controls (HC). We also collected clinical data and stool samples that were analyzed with 16S rRNA amplicon sequencing to explore potential influencing factors of cytokine changes. RESULTS: TNF-α serum levels were significantly elevated in patients with AN at admission, while IL-1β and IL-6 levels were lower at admission and discharge than in HC. After treatment, we also found significantly elevated levels of IL-6 Rα compared to HC, while IL-15 did not show significant changes. Exploratory analyses revealed positive associations of cytokine and genus-level changes between admission and discharge for IL-1β (Bacteroides) and IL-15 (Romboutsia), and negative associations for IL-15 (Anaerostipes) and TNF-α (uncultured Lachnospiraceae). CONCLUSION: We confirmed a previous finding of elevated levels of TNF-α also in adolescents with AN; however, the reduced IL-1β and IL-6 levels differed from the mostly increased levels found in adults. A mixed pro- and anti-inflammatory state appears to be present in adolescents, potentially due to their shorter illness duration. The gut microbiota, with its regulatory function on cytokine production, might play a role in mediating these inflammatory processes in AN and could offer targets for new therapeutic approaches.
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Microbial Dysbiosis as an Emerging Pathology of Suicidal Behaviour? A Critical Review, Passing Through Depression to Chronic Pain.
BACKGROUND: Suicidal behaviour (SB) is one of the most complex neuropsychiatric conditions, with an etiopathogenesis that remains elusive despite a myriad of studies revealing its multifaceted nature, influenced by various biological, psychological, socioeconomic and cultural factors, usually with complex reciprocal and synergistic interactions. Emerging evidence has recently suggested a potential involvement of pathogens and host-tissue derived microbial species in contributing to SB. This review aims to provide a concise synthesis of clinical evidence focusing on the presence of microbial alterations in subjects with SB and in those exhibiting risk factors for SB, thereby exploring a possible new perspective in suicidology. SUMMARY: We conducted a surveillance of the literature in the PUBMED database, from its inception to 10 May 2025, to identify associations between infection/microbial alterations with SB and some of its risk factors (by focusing on two pathologic examples of psychiatric and somatic origins, respectively: depression and chronic pain, two often closely related conditions). Major clinical findings were selected and synthesised into a hypothetical framework to support the presence of a microbe-related origin of SB. We found that SB was associated with selected infections, such as Toxoplasma gondii and Cytomegalovirus. Dysbiosis, including changes in diversity and/or abundance of selected microbial species, in the oral cavity, gastrointestinal tract, and other mucosal tissues, was observed in subjects with SB and individuals with psychiatric (depression) and somatic (chronic pain) risk factors of SB. KEY MESSAGE: Microbial dysbiosis might contribute to SB etiopathogenesis. Further studies in this emerging field of research are expected to provide additional mechanistic insights for an improved understanding, prevention, and therapeutic management of this neuropsychiatric condition.
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Advances in capsule-based fecal microbiota transplantation: clinical applications and innovations.
Capsule-based fecal microbiota transplantation (cFMT) has emerged as a vital tool for modulating gut dysbiosis for therapeutic intervention. This noninvasive alternative to traditional FMT avoids procedural invasiveness while offering logistical advantages in terms of storage, administration, and patient compliance. This review evaluates cFMT as a transformative approach across diverse diseases. Notably, cFMT demonstrates robust efficacy in restoring the microbial balance in Clostridioides difficile infection (CDI), inflammatory bowel disease (IBD), and multidrug-resistant infections, with outcomes comparable to those of conventional methods. It also alleviates symptoms and enhances microbiota diversity in small intestinal bacterial overgrowth (SIBO). However, the clinical benefits remain inconsistent for individuals with in irritable bowel syndrome (IBS) and functional constipation (FC), despite alterations in gut microbial diversity. Emerging applications highlight the potential of cFMT metabolic disorders (e.g., obesity and hypertension) via the modulation of gut-derived metabolites and neuropsychiatric conditions (e.g., depression and autism) through gut–brain axis signaling, in addition to chronic kidney disease and hepatic encephalopathy. Challenges such as donor variability, standardization gaps, and transient adverse effects hinder widespread adoption. Further advancements, including targeted colon-release formulations, synthetic microbial consortia, and single-cell delivery systems, could improve precision and scalability. Despite its transformative potential, the clinical adoption of cFMT hinges on rigorous quality control, mechanistic insights, and long-term safety data. In recent years, the United States Food and Drug Administration (FDA) has officially approved the oral microbiome therapy Vowst for marketing. This marked the gradual transition of fecal microbiota transplantation (FMT)-related therapies from clinical research to standardized clinical application, and at the same time, Vowst has become the world’s first oral fecal microbiome therapy approved by the FDA. This review highlights the role of cFMT in microbiota-targeted therapies while advocating for innovation to address current limitations and expand its therapeutic scope.
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Bipolar Disorder and Immune Dysfunction: Epidemiological Findings, Proposed Pathophysiology and Clinical Implications.
Bipolar disorder (BD) is strongly associated with immune dysfunction. Replicated epidemiological studies have demonstrated that BD has high rates of inflammatory medical comorbidities, including autoimmune disorders, chronic infections, cardiovascular disease and metabolic disorders. Cytokine studies have demonstrated that BD is associated with chronic low-grade inflammation with further increases in pro-inflammatory cytokine levels during mood episodes. Several mechanisms have been identified to explain the bidirectional relationship between BD and immune dysfunction. Key mechanisms include cytokine-induced monoamine changes, increased oxidative stress, pathological microglial over-activation, hypothalamic-pituitary-adrenal (HPA) axis over-activation, alterations of the microbiome-gut-brain axis and sleep-related immune changes. The inflammatory-mood pathway presents several potential novel targets in the treatment of BD. Several proof-of-concept clinical trials have shown a positive effect of anti-inflammatory agents in the treatment of BD; however, further research is needed to determine the clinical utility of these treatments. Immune dysfunction is likely to only play a role in a subset of BD patients and as such, future clinical trials should also strive to identify which specific group(s) of BD patients may benefit from anti-inflammatory treatments.
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Agathobaculum butyriciproducens improves ageing-associated cognitive impairment in mice.
AIMS: The gut microbiota is increasingly recognised as a pivotal regulator of immune system homeostasis and brain health. Recent research has implicated the gut microbiota in age-related cognitive impairment and dementia. Agathobaculum butyriciproducens SR79 T (SR79), which was identified in the human gut, has been reported to be beneficial in addressing cognitive deficits and pathophysiologies in a mouse model of Alzheimer's disease. However, it remains unknown whether SR79 affects age-dependent cognitive impairment. MAIN METHOD: To explore the effects of SR79 on cognitive function during ageing, we administered SR79 to aged mice. Ageing-associated behavioural alterations were examined using the open field test (OFT), tail suspension test (TST), novel object recognition test (NORT), Y-maze alternation test (Y-maze), and Morris water maze test (MWM). We investigated the mechanisms of action in the gut and brain using molecular and histological analyses. KEY FINDINGS: Administration of SR79 improved age-related cognitive impairment without altering general locomotor activity or depressive behaviour in aged mice. Furthermore, SR79 increased mature dendritic spines in the pyramidal cells of layer III and phosphorylation of CaMKIIα in the cortex of aged mice. Age-related activation of astrocytes in the cortex of layers III-V of the aged brain was reduced following SR79 administration. Additionally, SR79 markedly increased IL-10 production and Foxp3 and Muc2 mRNA expression in the colons of aged mice. SIGNIFICANCE: These findings suggest that treatment with SR79 may be a beneficial microbial-based approach for enhancing cognitive function during ageing.
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Regulation of prefrontal cortex myelination by the microbiota.
The prefrontal cortex (PFC) is a key region implicated in a range of neuropsychiatric disorders such as depression, schizophrenia and autism. In parallel, the role of the gut microbiota in contributing to these disorders is emerging. Germ-free (GF) animals, microbiota-deficient throughout life, have been instrumental in elucidating the role of the microbiota in many aspects of physiology, especially the role of the microbiota in anxiety-related behaviours, impaired social cognition and stress responsivity. Here we aim to further elucidate the mechanisms of the microbial influence by investigating changes in the homeostatic regulation of neuronal transcription of GF mice within the PFC using a genome-wide transcriptome profiling approach. Our results reveal a marked, concerted upregulation of genes linked to myelination and myelin plasticity. This coincided with upregulation of neural activity-induced pathways, potentially driving myelin plasticity. Subsequent investigation at the ultrastructural level demonstrated the presence of hypermyelinated axons within the PFC of GF mice. Notably, these changes in myelin and activity-related gene expression could be reversed by colonization with a conventional microbiota following weaning. In summary, we believe we demonstrate for the first time that the microbiome is necessary for appropriate and dynamic regulation of myelin-related genes with clear implications for cortical myelination at an ultrastructural level. The microbiota is therefore a potential therapeutic target for psychiatric disorders involving dynamic myelination in the PFC.
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Loss of diurnal behavioral rhythms and impaired lipid metabolism in growing pigs with mistimed feeding.
The misalignment of eating time and the endogenous circadian rhythm impairs the body's ability to maintain homeostasis. Although it is well established that children and growing animals differ from adults in their energy metabolism and behavioral patterns, little is known about how mistimed feeding disturbs the diurnal rhythms of behavior and metabolism in children and growing diurnal animals. In this study, growing pigs (diurnal animal) were randomly assigned to the daytime-restricted feeding (DRF) and nighttime-restricted feeding (NRF) groups for 5 weeks. Compared with observations in the DRF group, NRF disrupted the diurnal rhythm of behavior and clock genes and lowered the serum ghrelin, dopamine, and serotonin levels during the daytime and nighttime. Microbiome analysis results suggested that NRF altered the diurnal rhythm and composition of the gut microbiota, and increased log-ratios of Catenibacterium:Butyrivibrio and Streptococcus:Butyrivibrio. Based on the serum proteome, the results further revealed that rhythmic and upregulated proteins in NRF were mainly involved in oxidative stress, lipid metabolism, immunity, and cancer biological pathways. Serum physiological indicators further confirmed that NRF decreased the concentration of melatonin and fibroblast growth factor 21 during the daytime and nighttime, increased the diurnal amplitude and concentrations of very-low-density lipoprotein cholesterol, triglyceride, and total cholesterol, and increased the apolipoprotein B/ApoA1 ratio, which is a marker of metabolic syndrome. Taken together, this study is the first to reveal that mistimed feeding disrupts the behavioral rhythms of growing pigs, reprograms gut microbiota composition, reduces the serum levels of hormones associated with fighting depression and anxiety, and increases the risk of lipid metabolic dysregulation.