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Novel Pharmacological Approaches to the Treatment of Depression.
Major depressive disorder is one of the most prevalent mental health disorders. Monoamine-based antidepressants were the first drugs developed to treat major depressive disorder. More recently, ketamine and other analogues were introduced as fast-acting antidepressants. Unfortunately, currently available therapeutics are inadequate; lack of efficacy, adverse effects, and risks leave patients with limited treatment options. Efforts are now focused on understanding the etiology of depression and identifying novel targets for pharmacological treatment. In this review, we discuss promising novel pharmacological targets for the treatment of major depressive disorder. Targeting receptors including N-methyl-D-aspartate receptors, peroxisome proliferator-activated receptors, G-protein-coupled receptor 39, metabotropic glutamate receptors, galanin and opioid receptors has potential antidepressant effects. Compounds targeting biological processes: inflammation, the hypothalamic-pituitary-adrenal axis, the cholesterol biosynthesis pathway, and gut microbiota have also shown therapeutic potential. Additionally, natural products including plants, herbs, and fatty acids improved depressive symptoms and behaviors. In this review, a brief history of clinically available antidepressants will be provided, with a primary focus on novel pharmaceutical approaches with promising antidepressant effects in preclinical and clinical studies.
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Moxidectin Effects on Gut Microbiota of Wistar-Kyoto Rats: Relevance to Depressive-Like Behavior.
BACKGROUND/AIMS: The prevalent comorbidity between neuropsychiatric and gastrointestinal (GI) disorders is believed to be significantly influenced by gut microbiota (GM). GM may also play a substantial role in comorbidity between substance abuse (e.g. Alcohol Use Disorder, AUD) and depression. The anti-parasitic drug Moxidectin (MOX) has been reported to reduce alcohol intake in male and female mice. This effect is purported to be centrally mediated with a significant contribution linked to purinergic, P2X4 purinergic receptors. However, MOX's effects on GM in animal models of depression is not known. METHODS: Adult male Wistar Kyoto (WKY) rats (5/group) were injected intraperitoneally (i.p.) once daily for 7 days with MOX (2.5mg/kg), or saline as control group. On day 8, approximately 20 h after the last MOX injection, animals were sacrificed, intestinal stools were collected and stored at -80°C DNA was extracted from the samples for 16S rRNA gene-based GM analysis using 16S Metagenomics application. RESULTS: At taxa and species level, MOX affected a number of bacteria including a 30-fold increase in Bifidobacterium cholerium, a bacterium with a strong ability to degrade carbohydrates that resist digestion in the small intestine. There was a minimum of 2-fold increase in: five probiotic species of Lactobacillus, butyrate-forming Rosburia Facies and Butyrivibro proteovlasticus. In contrast, MOX depleted 11 species, including 2 species of Ruminoccus, which are positively associated with severity of irritable bowel syndrome, and 4 species of Provettela, which are closely associated with depressive-like behavior. CONCLUSION: Thus, MOX enhanced probiotic species, and suppressed the opportunistic pathogens. Since overall effect of MOX appears to be promoting GM associated with mood enhancement (e.g. Bifidobacterium and Lactobacillus) and suppressing GM associated with inflammation (e.g. Ruminoccus), potential antidepressant and anti-inflammatory effects of MOX in suitable animal models should be investigated.
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Diarrhea-predominant Irritable Bowel Syndrome-like Symptoms in Patients With Quiescent Crohn's Disease: Comprehensive Analysis of Clinical Features and Intestinal Environment Including the Gut Microbiome, Organic Acids, and Intestinal Permeability.
BACKGROUND/AIMS: Diarrhea-predominant irritable bowel syndrome (IBS-D)-like symptoms frequently occur in patients with quiescent Crohn's disease (CD). To investigate the factors underlying IBS-D-like symptoms in patients with quiescent CD, we performed a comprehensive analysis of the clinical features and intestinal environment in those patients. METHODS: We performed a prospective observational study of 27 patients with quiescent CD (CD activity index [CDAI] ≤ 150; C-reactive protein ≤ 0.3 mg/dL). The presence and severity of IBS-D-like symptoms, health-related quality of life, disease-specific quality of life, and status of depression and anxiety were evaluated. The level of intestinal permeability, fecal calprotectin and organic acids and the profiles of gut microbiome were analyzed. RESULTS: Twelve of the 27 patients with quiescent CD (44.4%) had IBS-like symptoms, and these patients showed a significantly higher CDAI, IBS severity index and anxiety score than those without. The inflammatory bowel disease questionnaire score was significantly lower in the patients with IBS-D-like symptoms. There were no significant differences in small intestinal/colonic permeability or the levels of organic acids between the patients with and without IBS-D-like symptoms. Fusicatenibacter was significantly less abundant in the patients with IBS-D-like symptoms whereas their fecal calprotectin level was significantly higher (384.8 ± 310.6 mg/kg) than in patients without (161.0 ± 251.0 mg/kg). The receiver operating characteristic curve constructed to predict IBS-D-like symptoms in patients with quiescent CD using the fecal calprotectin level (cutoff, 125 mg/kg) showed a sensitivity and specificity of 73.3% and 91.7%, respectively. CONCLUSION: Minimal inflammation is closely associated with the development of IBS-D-like symptoms in patients with quiescent CD.
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Migraine Comorbidities.
Novel knowledge about the interrelationships and reciprocal effects of migraine and epilepsy, migraine and mood disorders, or migraine and irritable bowel syndrome has emerged in recent decades. Over time, comorbid pathologies associated with migraine that share common physiopathological mechanisms were studied. Among these studied pathologies is epilepsy, a disorder with common ion channel dysfunctions as well as dysfunctions in glutamatergic transmission. A high degree of neuronal excitement and ion channel abnormalities are associated with epilepsy and migraine and antiepileptic drugs are useful in treating both disorders. The coexistence of epilepsy and migraine may occur independently in the same individual or the two may be causally connected. The relationship between cortical spreading depression (CSD) and epileptic foci has been suggested by basic and clinical neuroscience research. The most relevant psychiatric comorbidities associated with migraine are anxiety and mood disorders, which influence its clinical course, treatment response, and clinical outcome. The association between migraine and major depressive disorder can be explained by a robust molecular genetic background. In addition to its role as a potent vasodilator, CGRP is also involved in the transmission of nociception, a phenomenon inevitably linked with the stress and anxiety caused by frequent migraine attacks. Another aspect is the role of gut microbiome in migraine's pathology and the gut-brain axis involvement. Irritable bowel syndrome patients are more likely to suffer migraines, according to other studies. There is no precise explanation for how the gut microbiota contributes to neurological disorders in general and migraines in particular. This study aims to show that migraines and comorbid conditions, such as epilepsy, microbiota, or mood disorders, can be connected from the bench to the bedside. It is likely that these comorbid migraine conditions with common pathophysiological mechanisms will have a significant impact on best treatment choices and may provide clues for future treatment options.
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The Role of Gut Mucins in the Etiology of Depression.
Major depressive disorders are global health problems that affect more than 6% of the U.S. population. Despite years of research, the etiology of depression remains unclear. Historically, it was believed that depression started within the central nervous system (CNS), but alternative hypotheses have recently challenged this dogma. Indeed, experimental and clinical evidence show that the gut microbiome could be an active player in depression initiation. The composition of bacterial species in depressed patients is significantly different from control microbiomes, and the transfer of the microbiome from depressed patients is sufficient to initiate depressive symptoms in animals. Additionally, the gut microbiome is known to change in the presence of depression risk factors such as chronic stress. While there is strong evidence delineating a role for microbial dysbiosis in depression, the initiating event for this dysbiosis remains unknown. Within the gut, microbiota reside in the mucus layer, a critical gel-like barrier involved in protecting the host from unwanted pathogen interactions, as well as regulating the immune system. Though the mucus layer is often ignored in the face of dysbiosis, it represents a dynamic and important piece of host machinery that has the potential to impact a wide variety of biological processes. Here, we review evidence supporting the novel concept that stress can modify the delicate mucus-microbiome balance, initiating dysbiosis, and ultimately leading to depression.
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A discussion of the gut microbiome's development, determinants, and dysbiosis in cancers of the esophagus and stomach.
The microbiome refers to a population of microbes that colonize the skin, nasopharynx, oral cavity, gastrointestinal tract, and urogenital tract. The human microbiome consists of bacteria, archaea, fungi, viruses, and phages. Recent advances in genomic sequencing have catalyzed a deeper understanding of complex microbe-microbe and host-microbe interactions. Dysregulation of these interactions, or dysbiosis of the gastrointestinal tract, has been implicated in a growing list of pathologies including nonalcoholic fatty liver disease, cardiovascular disease, obesity, diabetes, depression, Parkinson's disease, autism, and various gastrointestinal cancers. Gastric and esophageal cancer, for example, continue to remain as two of the most common causes of cancer-related deaths worldwide, therefore there is an increased emphasis on investigating the role of dysbiosis on these cancers. In this review, we discuss the development and structure of the gut microbiome, its homeostatic and dysbiotic mechanisms, and the key microbes in esophageal and gastric carcinogenesis with a focus on bacterial biology. Further clarification of these pathways and discovery of diagnostic or therapeutic targets could have broad impacts on global subpopulations. It is important to understand the nature of the gastrointestinal tract microbiome and its potentional risk factors for dysbiosis in order to tailor its application to the individual patient and create an era of highly personalized, precision medicine.
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Mixed probiotics reduce the severity of stress-induced depressive-like behaviors.
In recent years, the gut microbiome has gained significant attention in the spheres of research and public health. As a result, studies have increasingly explored the potential of probiotic dietary supplements as treatment interventions for conditions such as anxiety and depression. The present study examined the effect of mixed probiotics (Lacticaseibacillus rhamnosus and Enterococcus faecium) on inflammation, microbiome composition, and depressive-like behaviors in a macaque monkey model. The mixed probiotics effectively reduced the severity of depressive-like behaviors in macaque monkeys. Further, treatment with mixed probiotics gradually increased the abundance of beneficial bacteria in the gut, improving the balance of the gut microbiota. Additionally, macaques treated with the mixed probiotics showed decreased serum levels of inflammatory factors (P < 0.05), an increased rate of L-tryptophan metabolism (P < 0.05), and the restoration of 5-HT and 5-HTP levels (P < 0.05). Correlation analysis confirmed that Lacticaseibacillus and other beneficial bacteria exhibited a negative correlation with inflammation in the body (P < 0.05), and a positive correlation with tryptophan metabolism (P < 0.05). In conclusion, the mixed probiotics effectively restored intestinal homeostasis in macaques and enhanced tryptophan metabolism, ultimately alleviating inflammation and depressive-like behaviors.
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Predictors of Treatment Response to Fecal Microbiota Transplantation in Irritable Bowel Syndrome: A Pilot Study.
BACKGROUND/AIMS: We aim to investigate the effectiveness, safety, and predictors of treatment response to fecal microbiota transplantation (FMT) in Korean irritable bowel syndrome (IBS) patients. METHODS: Patients with moderate to severe diarrhea-predominant IBS (IBS-D) or mixed-type IBS (IBS-M) received FMT from one healthy donor via esophagogastroduodenoscopy. IBS-symptom severity score (IBS-SSS), Bristol stool form scale (BSFS), IBS Quality of Life (IBS-QoL) questionnaires, Hospital Anxiety and Depression Scale (HADS), and gut microbiome profiles were assessed at baseline, 4 weeks and 12 weeks post-FMT. RESULTS: Among the 46 enrolled IBS patients, 37 patients (IBS-D:IBS-M = 28:9) completed a 12-week follow-up. Significant improvements were observed in IBS-SSS, IBS-QoL, and BSFS after 12 weeks. FMT led to increased microbial diversity and a sustained increase in beneficial bacterial genera, including Holdemanella, Ruminococcus, and Faecalibacterium. In terms of β-diversity, the distance between the patient's gut microbiome and that of the donor decreased after FMT; greater reduction in distance to donor microbiota was associated with greater symptom improvement (Unweighted UniFrac distance, P < 0.05). Responders (IBS-SSS reduction > 50 points) exhibited lower baseline relative abundances of Roseburia and Subdoligranulum, and more profound microbiome shifts toward the donor profile after FMT. CONCLUSIONS: FMT appears to be a potentially effective treatment for moderate to severe IBS, with significant symptom relief and gut microbiota changes. Lower baseline abundances of Roseburia and Subdoligranulum and greater shifts of gut microbiome profile toward donor microbiota after FMT may predict favorable FMT response. Long-term follow-up is on the way to assessing the durability of these effects.
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Relationship between psychosocial stress-induced prefrontal cortex activity and gut microbiota in healthy Participants-A functional near-infrared spectroscopy study.
Brain and gut microbes communicate in a bidirectional manner with each affecting a person's response to psychosocial stress. Although human studies demonstrated that the intake of probiotics can alter stress-related behavior in both patients and healthy participants, the association between stress-related brain functions and the gut microbiota has mostly been investigated in patients with depression. However, the response to psychosocial stress differs, even among healthy individuals, and elucidating the natural state of the gut microbiota would broaden the understanding of responses to psychosocial stress. We investigated the relationship between psychosocial stress response in the prefrontal cortex and the abundance of gut microbes in healthy male participants. The participants were exposed to psychosocial stress during a task while brain activation data were recorded using functional near-infrared spectroscopy. The heart rate and subjective stress were recorded, and fecal samples were collected. The stressful condition was accompanied by high subjective stress, high heart rate, and higher prefrontal activation in the right pre-motor cortex/supplementary motor area, right dorsolateral prefrontal cortex, right frontal pole, and right inferior prefrontal gyrus. The psychosocial stress response in the prefrontal cortex was also associated with changes in the gut microbiota abundance. The abundance of Alistipes, Clostridium IV, Clostridium XI, Faecalibacterium, and Blautia in healthy participants who had high psychosocial stress resembled that noted in patients with depression. These results suggest that the gut microbiota differs, among healthy participants, depending on the psychosocial stress response. We believe that this study is the first to report a direct relationship between brain function and the gut microbiota in healthy participants, and our findings would shed a new light on this field in the near future.
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Parabacteroides distasonis induces depressive-like behavior in a mouse model of Crohn's disease.
Patients with inflammatory bowel disease (IBD) are particularly susceptible to behavioral diagnoses, and the microbiome has been repeatedly implicated in the pathogenesis of IBD. The intestinal microbiome's ability to affect behavior has become increasingly recognized and studied. The so-called 'psychobiome' has been linked to a plethora of neurological and psychological diagnoses, including autism and Parkinson's disease. Despite the ability of many bacterial species within the human intestinal microbiome to synthesize neurotransmitters, it has never been previously reported that a single bacterial species is sufficient to induce depression. Here, we demonstrate that our mouse model of Crohn's disease (CD)-like ileitis, the SAMP1/YitFc (SAMP1), does not exhibit baseline behavioral abnormalities. By comparison, SAMP6 mice develop depressive-like behavior that is associated with a rise in the GABA-producing bacterial genus Parabacteroides. We finally demonstrate that administration of Parabacteroides distasonis into our SAMP1 mice induces depressive-like behavior. Colonization with P. distasonis was not associated with increased intestinal inflammation or alterations in other measures of behavior. The intestinal environment of CD may be particularly conducive to colonization with P. distasonis and subsequent induction of depressive-like behavior. To our knowledge, this is the first report of a bacterial species specifically inducing depressive-like behavior.