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Chronic Visceral Pain: New Peripheral Mechanistic Insights and Resulting Treatments.
Chronic visceral pain is one of the most common reasons for patients with gastrointestinal disorders, such as inflammatory bowel disease or disorders of brain-gut interaction, to seek medical attention. It represents a substantial burden to patients and is associated with anxiety, depression, reductions in quality of life, and impaired social functioning, as well as increased direct and indirect health care costs to society. Unfortunately, the diagnosis and treatment of chronic visceral pain is difficult, in part because our understanding of the underlying pathophysiologic basis is incomplete. In this review, we highlight recent advances in peripheral pain signaling and specific physiologic and pathophysiologic preclinical mechanisms that result in the sensitization of peripheral pain pathways. We focus on preclinical mechanisms that have been translated into treatment approaches and summarize the current evidence base for directing treatment toward these mechanisms of chronic visceral pain derived from clinical trials. The effective management of chronic visceral pain remains of critical importance for the quality of life of suffers. A deeper understanding of peripheral pain mechanisms is necessary and may provide the basis for novel therapeutic interventions.
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Azithromycin preserves adult hippocampal neurogenesis and behavior in a mouse model of sepsis.
The mammalian hippocampus can generate new neurons throughout life. Known as adult hippocampal neurogenesis (AHN), this process participates in learning, memory, mood regulation, and forgetting. The continuous incorporation of new neurons enhances the plasticity of the hippocampus and contributes to the cognitive reserve in aged individuals. However, the integrity of AHN is targeted by numerous pathological conditions, including neurodegenerative diseases and sustained inflammation. In this regard, the latter causes cognitive decline, mood alterations, and multiple AHN impairments. In fact, the systemic administration of Lipopolysaccharide (LPS) from E. coli to mice (a model of sepsis) triggers depression-like behavior, impairs pattern separation, and decreases the survival, maturation, and synaptic integration of adult-born hippocampal dentate granule cells. Here we tested the capacity of the macrolide antibiotic azithromycin to neutralize the deleterious consequences of LPS administration in female C57BL6J mice. This antibiotic exerted potent neuroprotective effects. It reversed the increased immobility time during the Porsolt test, hippocampal secretion of pro-inflammatory cytokines, and AHN impairments. Moreover, azithromycin promoted the synaptic integration of adult-born neurons and functionally remodeled the gut microbiome. Therefore, our data point to azithromycin as a clinically relevant drug with the putative capacity to ameliorate the negative consequences of chronic inflammation by modulating AHN and hippocampal-related behaviors.
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Marked shifts in gut microbial structure and neurotransmitter metabolism in fresh inmates revealed a close link between gut microbiota and mental health: A case-controlled study.
BACKGROUND/OBJECTIVE: The gut microbiota plays a pivotal role in psychological health, but the mechanistic perspective between gut microbiome and mental health remains poorly understood. METHOD: The present case-controlled study recruited 30 unimprisoned subjects and 31 inmates that had been detained in jail for no more than a month. The mental health status, gut microbiota and blood NH3, H2S, 5-hydroxy trptamine and dopamine levels were measured. RESULTS: Compared with unimprisoned controls, the fresh inmates exhibited significantly higher scores on anxiety and depression. Both phylogenetic structure and functional genes of the gut microbiota markedly shifted in inmates. Inmates was more Bacteroides-dominated, while unimprisoned subjects were more Prevotella-dominated. Short-chain fatty acids (SCFAs)-producing genera were largely decreased in inmates and were negatively related to mental disorder scores, while Bacteroidetes and Proteobacteria were positive to anxiety and depression scores. Simultaneously, the inmates possessed reduced genes that participate in amino acids, carbohydrates and vitamin cofactors metabolism, but enriched genes that involved in the neurotransmitter-producing Shikimate pathway. Correlation analysis revealed that Anaerotruncus and Prevotella were negative to depression score, and Enterococcus was negative to anxiety score. CONCLUSIONS: Our results revealed potential link between gut microbiota and mental health, leading further support to the microbiota-gut-brain axis theory.
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Gut mycobiome and neuropsychiatric disorders: insights and therapeutic potential.
BACKGROUND: The human gut mycobiome, a minor but integral component of the gut microbiome, has emerged as a significant player in host homeostasis and disease development. While bacteria have traditionally been the focus of gut microbiome studies, recent evidence suggests that fungal communities (mycobiota) may also play a crucial role in modulating health, particularly in neuropsychiatric disorders. OBJECTIVE: This review aims to provide a comprehensive overview of current knowledge on the relationship between the gut mycobiome and neuropsychiatric disorders, exploring the potential of targeting fungal communities as a novel therapeutic strategy. METHODS: We summarized recent findings from metagenomic analyses that characterize the diversity and composition of gut mycobiota and discuss how these communities interact with the host and other microorganisms via the gut-brain axis. Key methodologies for studying mycobiota, such as high-throughout sequencing and bioinformatics approaches, were also reviewed to highlight advances in the field. RESULTS: Emerging research links gut mycobiota dysbiosis to conditions such as schizophrenia, Alzheimer's disease, autism spectrum disorders, bipolar disorder, and depression. Studies indicate that specific fungal populations, such as Candida and Saccharomyces, may influence neuroinflammation, gut permeability and immune responses, thereby affecting mental health outcomes. CONCLUSION: Understanding the gut mycobiome's role in neuropsychiatric disorders opens new avenues for therapeutic interventions, including antifungal treatments, probiotics, and dietary modifications. Future research should integrate multi-omics approaches to unravel the complex interkingdom interactions within the gut ecosystem, paving the way for personalized medicine in mental health care.
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Therapeutic Interventions of Gut-Brain Axis as Novel Strategies for Treatment of Alcohol Use Disorder Associated Cognitive and Mood Dysfunction.
Alcohol use disorders (AUD) is characterized by persistent or intermittent alcohol cravings and compulsive drinking. The functional changes in the central nervous system (CNS) after alcohol consumption are alcohol-associated cognitive impairment and mood disorders, which are major health issues reported in AUDs. Studies have shown that transferring the intestinal microbiota from AUDs patients to germ-free animals causes learning and memory dysfunction, depression and anxiety-like behavior, indicating the vital role of intestinal microbiota in development of neuropsychiatric disorders in AUD. Intestinal flora composition of AUD patients are significantly different from normal people, suggesting that intestinal flora imbalance orchestrate the development of neuropsychiatric disorders in AUD. Studies suggests that gut microbiome links bidirectional signaling network of the enteric nervous system (ENS) to central nervous system (CNS), forming gut-microbe-brain axis (brain-gut axis). In this review, we discussed pathogenesis and possible treatment of AUD-induced cognitive deficits, anxiety, and depression disorders. Further, we described the mechanism of intestinal flora imbalance and dysfunction of hippocampus-amygdala-frontal cortex (gut-limbic circuit system dysfunction). Therefore, we postulate therapeutic interventions of gut-brain axis as novel strategies for treatment of AUD-induced neuropsychiatric disorders.
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Anxiety and Depression in Pancreatitis: Mechanisms, Assessment, and Treatment.
BACKGROUND: Numerous studies have detailed that patients with pancreatitis frequently experience comorbid anxiety and depression, which may arise from physiological factors or psychosocial influences, and these conditions adversely affect daily functioning and quality of life. However, there is still a lack of reviews on epidemiological and mechanistic studies of anxiety and depression in patients with pancreatitis. SUMMARY: Patients with pancreatitis commonly present with comorbid anxiety and depression, with chronic pancreatitis patients being more susceptible than those with acute pancreatitis. The mechanisms underlying this comorbidity are complex and likely multifactorial. Biological factors encompass inflammation-driven cytokine signaling to the brain, hypothalamic-pituitary-adrenal axis hyperactivity, gut microbiome dysbiosis, and altered central nervous system plasticity. Psychosocial factors include the emotional burden of pancreatitis, persistent sleep disturbances, substance abuse, and diminished family and social support. Assessment primarily relies on various types of scales, while treatment encompasses a comprehensive approach involving medication, psychological interventions, and family and social support. KEY MESSAGES: This paper reviews the epidemiological characteristics of anxiety and depression in patients with pancreatitis, explores their biological and psychosocial mechanisms, and summarizes key points for the assessment and treatment of this comorbidity.
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Si-Ni-San alleviates depression-like behavior via regulating the gut microbiota-tryptophan metabolism-AhR/NF-κB pathway axis.
BACKGROUND: Si-Ni-San (SNS), a classic herbal formula from the Treatise on Cold Damage Diseases, is used to treat depression by relieving "liver qi stagnation". However, the underlying mechanism remains unclear. PURPOSE OF THE RESEARCH: This study aimed to investigate the mechanism by which SNS alleviates depression-like behavior, specifically focusing on its role in modulating gut microbiota and host tryptophan metabolism. METHODS: A depression model was induced in mice by chronic unpredictable mild stress (CUMS). The antidepressant effects of SNS were evaluated through behavioral tests. Integrated untargeted and targeted metabolomics, alongside 16S rRNA sequencing, were utilized to identify potential gut-brain signaling molecules. Molecular interactions between the gut-brain signaling molecule and its target were validated by surface plasmon resonance (SPR) and molecular docking. Key protein expression was measured via Western blot and ELISA. Finally, the function of gut microbiome-derived indole-3-acetic acid (IAA) as a key gut-brain signaling molecule was confirmed by oral supplementation experiments. RESULTS: SNS significantly alleviated CUMS-induced depression-like behaviors. Multi-omics analysis revealed that SNS reversed tryptophan metabolic disorders and elevated gut microbiome-derived IAA levels in both the colon and prefrontal cortex, which was attributed to the enrichment of Lactobacillus. Further investigations confirmed that IAA directly binds to and activates the aryl hydrocarbon receptor (AhR), thereby inhibiting NF-κB pathway-mediated neuroinflammation. Moreover, oral supplementation with IAA replicated the antidepressant effects of SNS and suppressed CUMS-induced neuroinflammation via the AhR/NF-κB signaling pathway. CONCLUSION: SNS alleviates depression-like behavior by modulating gut microbiota-mediated tryptophan metabolism to enhance IAA production, thereby activating central AhR signaling and suppressing NF-κB-mediated neuroinflammation.
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Resilience and the Gut Microbiome: Insights from Chronically Socially Stressed Wild-Type Mice.
The microbiome is an important player within physiological homeostasis of the body but also in pathophysiological derailments. Chronic social stress is a challenge to the organism, which results in psychological illnesses such as depression in some individuals and can be counterbalanced by others, namely resilient individuals. In this study, we wanted to elucidate the potential contribution of the microbiome to promote resilience. Male mice were subjected to the classical chronic social defeat paradigm. Defeated or undefeated mice were either controls (receiving normal drinking water) or pre-treated with antibiotics or probiotics. Following social defeat, resilient behavior was assessed by means of the social interaction test. Neither depletion nor probiotic-shifted alteration of the microbiome influenced stress-associated behavioral outcomes. Nevertheless, clear changes in microbiota composition due to the defeat stress were observed such as elevated Bacteroides spp. This stress-induced increase in Bacteroides in male mice could be confirmed in a related social stress paradigm (instable social hierarchy) in females. This indicates that while manipulation of the microbiome via the antibiotics- and probiotics-treatment regime used here has no direct impact on modulating individual stress susceptibility in rodents, it clearly affects the microbiome in the second line and in a sex-independent manner regarding Bacteroides.
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Food & mood: a review of supplementary prebiotic and probiotic interventions in the treatment of anxiety and depression in adults.
BACKGROUND: A bidirectional relationship exists between the brain and the gastrointestinal tract. Foods containing bacteria that positively influence the gastrointestinal microbiome are termed, probiotics; compounds that promote the flourishing of these bacteria are termed, prebiotics. Whether microbiome influencing therapies could treat psychiatric conditions, including depression and anxiety, is an area of interest. Presently, no established consensus for such treatment exists. METHODS: This systematic review analyses databases and grey literature sites to investigate pre and/or probiotics as treatments for depression and/or anxiety disorders. Articles included are from within 15 years. Pre-determined inclusion exclusion criteria were applied, and articles were appraised for their quality using a modified-CASP checklist. This review focuses specifically on quantitative measures from patients with clinical diagnoses of depression and/or anxiety disorders. RESULTS: 7 studies were identified. All demonstrated significant improvements in one or more of the outcomes measuring the of effect taking pre/probiotics compared with no treatment/placebo, or when compared to baseline measurements. DISCUSSION: Our review suggests utilising pre/probiotic may be a potentially useful adjunctive treatment. Furthermore, patients with certain co-morbidities, such as IBS, might experience greater benefits from such treatments, given that pre/probiotic are useful treatments for other conditions that were not the primary focus of this discourse. Our results are limited by several factors: sample sizes (adequate, though not robust); short study durations, long-term effects and propensity for remission undetermined. CONCLUSION: Our results affirm that pre/probiotic therapy warrants further investigation. Efforts should aim to elucidate whether the perceived efficacy of pre/probiotic therapy in depression and/or anxiety disorders can be replicated in larger test populations, and whether such effects are maintained through continued treatment, or post cessation. Interventions should also be investigated in isolation, not combination, to ascertain where the observed effects are attributable to. Efforts to produce mechanistic explanations for such effect should be a priority.
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Xiaoyaosan Improves Antibiotic-Induced Depressive-Like and Anxiety-Like Behavior in Mice Through Modulating the Gut Microbiota and Regulating the NLRP3 Inflammasome in the Colon.
Disturbance of the gut microbiota plays an essential role in mental disorders such as depression and anxiety. Xiaoyaosan, a traditional Chinese medicine formula, has a wide therapeutic spectrum and is used especially in the management of depression and anxiety. In this study, we used an antibiotic-induced microbiome-depleted (AIMD) mouse model to determine the possible relationship between imbalance of the intestinal flora and behavioral abnormalities in rodents. We explored the regulatory effect of Xiaoyaosan on the intestinal flora and attempted to elucidate the potential mechanism of behavioral improvement. We screened NLRP3, ASC, and CASPASE-1 as target genes based on the changes in gut microbiota and explored the effect of Xiaoyaosan on the colonic NLRP3 pathway. After Xiaoyaosan intervention, AIMD mice showed a change in body weight and an improvement in depressive and anxious behaviors. Moreover, the gut flora diversity was significantly improved. Xiaoyaosan increased the abundance of Lachnospiraceae in AIMD mice and decreased that of Bacteroidaceae, the main lipopolysaccharide (LPS)-producing bacteria, resulting in decreased levels of LPS in feces, blood, and colon tissue. Moreover, serum levels of the inflammatory factor, IL-1β, and the levels of NLRP3, ASC, and CASPASE-1 mRNA and DNA in the colon were significantly reduced. Therefore, Xiaoyaosan may alleviate anxiety and depression by modulating the gut microbiota, correcting excessive LPS release, and inhibiting the immoderate activation of the NLRP3 inflammasome in the colon.