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Oral selective serotonin reuptake inhibitors activate vagus nerve dependent gut-brain signalling.
The vagus nerve can transmit signals to the brain resulting in a reduction in depressive behavior as evidenced by the long-term beneficial effects of electrical stimulation of the vagus in patients with intractable depression. The vagus is the major neural connection between gut and brain, and we have previously shown that ingestion of beneficial bacteria modulates behaviour and brain neurochemistry via this pathway. Given the high levels of serotonin in the gut, we considered if gut-brain signaling, and specifically the vagal pathway, might contribute to the therapeutic effect of oral selective serotonin reuptake inhibitors (SSRI). Mesenteric nerve recordings were conducted in mice after treatment with SSRI to ascertain if this class of drugs resulted in increased vagal excitability. Patch clamp recordings of enteric neurons were carried out to measure activity of primary afferent neurons in the gut in response to SSRI and to assess the importance of gut epithelium in transducing signal. The tail suspension test (TST) was used following 14d feeding of SSRI in vagotomised and surgical sham mice to measure depressive-like behaviour. Brain mRNA expression was examined via PCR and the intestinal microbiome was assessed. Mesenteric nerve recordings in BALB/c mice demonstrated that oral treatment with SSRI leads to a significant increase in vagal activity. This effect was not observed in mice treated with a representative noradrenaline-dopamine reuptake inhibitor. It is known that signals from the gut can be transmitted to the vagus via the enteric nervous system. Exposure of the gut to SSRI increased the excitability of intrinsic primary afferent neurons in the myenteric plexus, through an intestinal epithelium dependent mechanism, and alpha-diversity of gut microbiota was altered. Critically, blocking vagal signaling from gut to brain, via subdiaphragmatic vagotomy, abolished the antidepressive effects of oral SSRI treatment as determined by the tail suspension test. This work suggests that vagus nerve dependent gut-brain signaling contributes to the effects of oral SSRI and further, highlights the potential for pharmacological approaches to treatment of mood disorders that focus on vagal stimulation and may not even require therapeutic agents to enter the circulation.
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The microbiota-gut-brain axis in postpartum depression: a review of microbial mechanisms and therapeutic potential.
Postpartum depression (PPD), a common but mechanistically uncertain mood disorder, occurs in 10-15% of mothers and seriously affects maternal and infant health. Recent evidence suggests that alteration of gut microbiota could dysregulate gut-brain axis functioning, which is potentially linked to the pathogenesis of PPD. This review innovatively synthesizes up-to-date preclinical and clinical evidence to illustrate relevant mechanisms, including microbial metabolite signaling, immune-inflammatory pathways, and neuroendocrine disruptors. Furthermore, the therapeutic potential of microbial-targeting approaches, including probiotics, dietary changes, and fecal microbiota transplant, to remedy PPD by restoring microbial health is discussed. Nevertheless, several notable limitations, translational uncertainties and major knowledge gaps still exist in this field. Most current evidence derives from cross-sectional observations, and well-designed longitudinal human studies are urgently needed to confirm causal relationships. In addition, available microbiota-related interventions have not yet developed into mature precision microbiome therapeutics. Against this background, this study proposes a microbiome framework connecting basic science and clinical applications that may help unravel the etiology and treatment of PPD.
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DeepBiomarker: Identifying Important Lab Tests from Electronic Medical Records for the Prediction of Suicide-Related Events among PTSD Patients.
Identifying patients with high risk of suicide is critical for suicide prevention. We examined lab tests together with medication use and diagnosis from electronic medical records (EMR) data for prediction of suicide-related events (SREs; suicidal ideations, attempts and deaths) in post-traumatic stress disorder (PTSD) patients, a population with a high risk of suicide. We developed DeepBiomarker, a deep-learning model through augmenting the data, including lab tests, and integrating contribution analysis for key factor identification. We applied DeepBiomarker to analyze EMR data of 38,807 PTSD patients from the University of Pittsburgh Medical Center. Our model predicted whether a patient would have an SRE within the following 3 months with an area under curve score of 0.930. Through contribution analysis, we identified important lab tests for suicide prediction. These identified factors imply that the regulation of the immune system, respiratory system, cardiovascular system, and gut microbiome were involved in shaping the pathophysiological pathways promoting depression and suicidal risks in PTSD patients. Our results showed that abnormal lab tests combined with medication use and diagnosis could facilitate predicting SRE risk. Moreover, this may imply beneficial effects for suicide prevention by treating comorbidities associated with these biomarkers.
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Acceptability, tolerability, and safety of fecal microbiota transplantation in patients with active ulcerative colitis (AT&S Study).
BACKGROUND AND AIM: Fecal microbiota transplantation (FMT) targets gut microbiome dysbiosis and is an emerging therapy for ulcerative colitis (UC). Although initial results with FMT in patients with active UC are encouraging, data regarding its acceptability, tolerability, and safety are scant. METHODS: A retrospective analysis of patients with active UC (Mayo clinic score ≥ 4), who received multisession FMT (at weeks 0, 2, 6, 10, 14, 18, and 22) via colonoscopy between June 2016 and June 2018, was performed. Patient acceptability, tolerability, and immediate and long-term safety of the therapy were assessed. RESULTS: Of the 129 patients with active UC who were offered FMT, 101 patients consented, giving acceptability of 78.3%. Fecal slurry retention time improved with each session (3.27 ± 1.06 h for the first session vs 5.12 ± 0.5 h for the seventh session). Abdominal discomfort, flatulence, abdominal distension, borborygmi, and low-grade fever (30.8%, 15.9%, 9.8%, 7.9%, and 7.6%, respectively) were the most common post-procedural short-term adverse events. Long-term adverse events included new-onset urticaria (n = 2, 4.3%), arthritis/arthralgia (n = 3, 6.5%), depression (n = 1, 2.2%), partial sensorineural hearing loss (n = 1, 2.2%), and allergic bronchitis (n = 1, 2.2%). Thirteen (12.9%) patients dropped out because of adverse events. CONCLUSION: Fecal microbiota transplantation appears to be a safe and well-tolerated procedure, with good acceptability in patients with active UC.
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The Brain-Intestinal Mucosa-Appendix- Microbiome-Brain Loop.
The brain and the gut are connected from early fetal life. The mother's exposure to microbial molecules is thought to exert in utero developmental effects on the fetus. These effects could importantly underpin the groundwork for subsequent pathophysiological mechanisms for achieving immunological tolerance and metabolic equilibrium post birth, events that continue through to 3-4 years of age. Furthermore, it is understood that the microbiome promotes cues that instruct the neonate's mucosal tissues and skin in the language of molecular and cellular biology. Post birth mucosal lymphoid tissue formation and maturation (most probably including the vermiform appendix) is microbiota-encouraged co-establishing the intestinal microbiome with a developing immune system. Intestinal mucosal tissue maturation loops the brain-gut-brain and is postulated to influence mood dispositions via shifts in the intestinal microbiome phyla. A plausible appreciation is that dysregulated pro-inflammatory signals from intestinal resident macrophages could breach the loop by providing adverse mood signals via vagus nerve afferents to the brain. In this commentary, we further suggest that the intestinal resident macrophages act as an upstream traffic controller of translocated microbes and metabolites in order to maintain local neuro-endocrine-immunological equilibrium. When macrophages are overwhelmed through intestinal microbiome and intestinal epithelial cell dysbiosis, pro-inflammatory signals are sustained, which may then lead to mood disorders. The administration of probiotics as an adjunctive medicine co-administered with antidepressant medications in improving depressed mood may have biological and clinical standing.
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Sex Differences and Emerging New Risk Factors for Atherosclerosis and Its Thrombotic Complications.
Cardiovascular diseases (CVD) remain the world's leading cause of death and disability in both men and women, but with different prognostics and outcomes between sexes. Although the burden of CVD is generally related to the conventional risk factors, the relevance of non-traditional risk factors is increasingly being recognized to explain the so-called "residual risk". Men and women share many similarities regarding classical cardiovascular risk factors but have different disease pathophysiology, clinical presentations, prevalence, and outcomes of CVDs. How sex-specificities regarding the effects of non-traditional risk factors may contribute to the evolution of atherosclerosis and its clinical manifestations in males and females remain largely underanalyzed. The present review summarizes the current knowledge for sex differences in atherosclerotic plaque composition and clinical evolution in association with risk factors, such as inflammation, lipoprotein(a), hemostasis, intraplaque calcification, and depression. We further discuss the potential sex-differential impact of chronic infectious diseases, gut microbiome and, epigenetic gene expression regulation for atherosclerosis and the effect of female-specific disorders in CVD.
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Capitalizing on the GLP-1 RA revolution for behavioral health through digital companions.
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Neuroimmune mechanisms of the gut-brain axis in treatment-resistant depression: Implications for microbiome-based therapeutic strategies.
Treatment-resistant depression (TRD) represents a major clinical challenge characterised by inadequate response to conventional antidepressant therapies and high relapse rates. Emerging evidence suggests that TRD may extend beyond monoaminergic dysfunction and may involve dysregulation of the HPA axis, neuroinflammation, impaired neuroplasticity, and disruption of the gut-brain axis (GBA). Gut dysbiosis has been associated with treatment resistance through alterations in monoamine turnover, immune signalling, intestinal barrier integrity, and drug-microbiome interactions affecting antidepressant bioavailability. This review integrates emerging evidence supporting targeted modulation of the GBA as a mechanistically informed strategy for TRD. Specific microbial strains (e.g., Christensenella minuta, Akkermansia muciniphila, Bifidobacterium breve CCFM1025), microbial metabolites (e.g., indole-3-propionic acid, indole-3-lactic acid, anserine), and phytochemicals (e.g., curcumin, matrine, salidroside) are discussed for their proposed roles in modulating neuroendocrine signalling, neuroinflammation, and synaptic plasticity. The review also highlights emerging peripheral biomarkers, including the kynurenine/tryptophan ratio, serum metabolomics, and lymphocyte serotonin transporter clustering, as candidate tools for stratified psychiatry. Most of the evidence discussed in this review comes from animal studies, in vitro systems, and computational analyses, while direct evidence in patients with treatment-resistant depression remains limited. These findings provide important mechanistic insights into gut-brain axis dysfunction but require further validation in human TRD populations. Biomarker-guided and endotype-based approaches targeting the gut-brain axis may offer a useful framework for future research, although their clinical utility has yet to be established.
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L. rhamnosus improves the immune response and tryptophan catabolism in laying hen pullets.
In mammals, early-life probiotic supplementation is a promising tool for preventing unfavourable, gut microbiome-related behavioural, immunological, and aromatic amino acid alterations later in life. In laying hens, feather-pecking behaviour is proposed to be a consequence of gut-brain axis dysregulation. Lactobacillus rhamnosus decreases stress-induced severe feather pecking in adult hens, but whether its effect in pullets is more robust is unknown. Consequently, we investigated whether early-life, oral supplementation with a single Lactobacillus rhamnosus strain can prevent stress-induced feather-pecking behaviour in chickens. To this end, we monitored both the short- and long-term effects of the probiotic supplement on behaviour and related physiological parameters. We hypothesized that L. rhamnosus would reduce pecking behaviour by modulating the biological pathways associated with this detrimental behaviour, namely aromatic amino acid turnover linked to neurotransmitter production and stress-related immune responses. We report that stress decreased the proportion of cytotoxic T cells in the tonsils (P = 0.047). Counteracting this T cell depression, birds receiving the L. rhamnosus supplementation significantly increased all T lymphocyte subset proportions (P < 0.05). Both phenotypic and genotypic feather peckers had lower plasma tryptophan concentrations compared to their non-pecking counterparts. The probiotic supplement caused a short-term increase in plasma tryptophan (P < 0.001) and the TRP:(PHE + TYR) ratio (P < 0.001). The administration of stressors did not significantly increase feather pecking in pullets, an observation consistent with the age-dependent onset of pecking behaviour. Despite minimal changes to behaviour, our data demonstrate the impact of L. rhamnosus supplementation on the immune system and the turnover of the serotonin precursor tryptophan. Our findings indicate that L. rhamnosus exerts a transient, beneficial effect on the immune response and tryptophan catabolism in pullets.
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Microbiome: A Potential Component in the Origin of Mental Disorders.
It is not surprising to find microbiome abnormalities present in psychiatric disorders such as depressive disorders, bipolar disorders, etc. Evolutionary pressure may provide an existential advantage to the host eukaryotic cells in that it survives in an extracellular environment containing non-self cells (e.g., bacteria). This phenomenon is both positive and negative, as with other intercellular processes. In this specific case, the phenomenal amount of information gained from combined bacterial genome could enhance communication between self and non-self cells. This can be coupled to both pathological processes and healthy ones. In this review, we chose to examine potential associated disorders that may be coupled to the microbiome, from the perspective of their bidirectional communication with eukaryotic cells in the gut. Cognition, being the newest neural networking functionality to evolve, consumes a good amount of organismic energy, 30% of which arises from the gut flora. Furthermore, the mammalian gut is highly innervated and has a highly developed immune component, reflecting brain complexity. The brain-gut axis uses similar molecular messengers as the brain, which affects bacterial processes as well. Thus, any modification of normal bacterial processes may manifest itself in altered behavior/cognition, originating from the gut. The origin of some disorders associated with this bidirectional communication may be harnessed to restore normal functioning.