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Chronic stress in mice: how gut bacteria influence gene activity in key brain neurons.
Major depressive disorder (MDD) is a serious mental disorder. Increasing evidence suggests that changes of gut microbiota are involved in pathogenesis of depression, yet the underlying mechanisms remains unknown. Here, chronic unpredictable mild stress (CUMS) mice model was constructed to mimic depression. We characterized the microbial composition and function of control, bedding exchange, and CUMS mice through 16S rRNA gene and metagenomic sequencing. Additionally, single-nucleus RNA sequencing (snRNA-seq) was used to compare the transcriptomic changes in the hypothalamus of these three groups. We found that replacing the bedding of CUMS mice with that of control mice could reverse the depressive-like behaviors. The microbial signatures of bedding exchange group trended towards the control group at the genus level. The abundance of g_norank_f_Muribaculaceae significantly increased in the bedding exchange group compared to CUMS group. Meanwhile, we found that the CUMS mice were characterized by cell-specific transcriptomic changes in hypothalamus. Notably, the transcriptomes of excitatory neurons in the hypothalamus were mainly affected, and these changes could be effectively reversed by bedding exchange treatment. The gene modules analysis revealed that the gut microbiota mainly modulated glyoxylate and dicarboxylate metabolism as well as arginine biosynthesis in hypothalamic excitatory neurons. Our findings provide new insights into the pathogenesis of depression.
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Probiotics for the treatment of depressive symptoms: An anti-inflammatory mechanism?
During the past decade, there has been renewed interest in the relationship between brain-based disorders, the gut microbiota, and the possible beneficial effects of probiotics. Emerging evidence suggests that modifying the composition of the gut microbiota via probiotic supplementation may be a viable adjuvant treatment option for individuals with major depressive disorder (MDD). Convergent evidence indicates that persistent low-grade inflammatory activation is associated with the diagnosis of MDD as well as the severity of depressive symptoms and probability of treatment response. The objectives of this review are to (1) evaluate the evidence supporting an anti-inflammatory effect of probiotics and (2) describe immune system modulation as a potential mechanism for the therapeutic effects of probiotics in populations with MDD. A narrative review of studies investigating the effects of probiotics on systemic inflammation was conducted. Studies were identified using PubMed/Medline, Google Scholar, and clinicaltrials.gov (from inception to November 2017) using the following search terms (and/or variants): probiotic, inflammation, gut microbiota, and depression. The available evidence suggests that probiotics should be considered a promising adjuvant treatment to reduce the inflammatory activation commonly found in MDD. Several controversial points remain to be addressed including the role of leaky gut, the role of stress exposure, and the role of blood-brain-barrier permeability. Taken together, the results of this review suggest that probiotics may be a potentially beneficial, but insufficiently studied, antidepressant treatment intervention.
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Targeting the endocannabinoid system with microbial interventions to improve gut integrity.
The endocannabinoid system is a metabolic pathway involved in the communication between the gut microbiota and the host. In the gut, the endocannabinoid system regulates the integrity of the intestinal barrier. A compromised integrity of the intestinal barrier is associated with several disorders such as inflammatory bowel disorder, obesity and major depressive disorder. Decreasing the integrity of the intestinal barrier results in an increased translocation of bacterial metabolites, including lipopolysaccharides, across the epithelial layer of the gut, causing the subsequent inflammation. Targeting the endocannabinoid system in the gut can improve the integrity of the intestinal barrier. Currently, microbial interventions in the form of probiotics are under investigation for the treatment of diseases related to a compromised integrity of the intestinal barrier. However, the role of the endocannabinoid system in the gut is ambiguous since activity of the endocannabinoid system is increased in obesity and decreased in inflammatory bowel disease, emphasizing the need for development of personalized microbial interventions. This review discusses the role of the endocannabinoid system in regulating the gut barrier integrity and highlights current efforts to develop new endocannabinoid-targeted microbial interventions.
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Intestinal Dysbiosis, Gut Hyperpermeability and Bacterial Translocation: Missing Links Between Depression, Obesity and Type 2 Diabetes.
The comorbid prevalence of major depressive disorder (MDD) with obesity and type II diabetes mellitus reflects the existence of a subset of individuals with a complex common pathophysiology and overlapping risk factors. Such comorbid disease presentations imply a number of difficulties, including: decreased treatment responsivity and adherence; altered glycemic control and increased risk of wider medical complications. A number of factors link MDD to metabolic-associated disorders, including: higher rates of shared risk factors such as poor diet and physical inactivity and biological elements including increased inflammation; insulin resistance; oxidative and nitrosative stress; and mitochondrial dysfunction. All of these biological factors have been extensively investigated in the pathophysiology of obesity and type 2 diabetes mellitus as well as MDD. In this review, we aim to: (1) overview the epidemiological links between MDD, obesity and type 2 diabetes mellitus; (2) discuss the role of synergistic neurotoxic effects in MDD comorbid with obesity, and type 2 diabetes mellitus; (3) review evidence of intestinal dysbiosis, leaky gut and increased bacterial translocation, in the pathophysiology of MDD, obesity and type 2 diabetes mellitus; and (4) propose a model in which the gut-brain axis could play a pivotal role in the comorbidity of these disorders.
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The association between gut microbiota and functional connectivity in cognitive impairment of first-episode major depressive disorder.
The pathogenesis of major depressive disorder(MDD) and cognitive impairment has been linked to gut microbiota; however, the relationship between cognitive impairment and gut microbiota in patients with MDD and their underlying mechanisms remain unclear. This study aimed to investigate the brain-gut axis involved in cognitive impairment among patients with first-episode MDD through neuroimaging and microbiome analyses. 43 microbial species were different between patients with first-episode MDD and healthy controls. Notably, the relative abundances of Amycolatopsis sp. Hca4 and Shewanella livingstonensis were lower in patients with MDD compared to healthy controls, with Amycolatopsis sp. Hca4 negatively correlated with processing speed and Shewanella livingstonensis positively correlated with verbal learning. Brain network analysis revealed significant connectivity between subnetworks in patients with MDD, with cognitive function closely associated with connections between somatomotor-limbic, default mode-limbic and frontoparietal-limbic networks. Additionally, Amycolatopsis sp. Hca4 was found to modulate the relationship between the functional connectivity of the middle frontal gyrus and parahippocampal gyrus and working memory, with this correlation varying according to the abundance of Amycolatopsis sp. Hca4. These findings suggest that gut microbiota disturbances in patients with first-episode MDD serve as a regulatory factor for brain dysfunction and cognitive impairment.
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Immune-to-Brain Communication Pathways in Inflammation-Associated Sickness and Depression.
A growing body of evidence now highlights a key role for inflammation in mediating sickness behaviors and depression. Systemic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and chronic liver disease have high comorbidity with depression. How the periphery communicates with the brain to mediate changes in neurotransmission and thereby behavior is not completely understood. Traditional routes of communication between the periphery and the brain involve neural and humoral pathways with TNFα, IL-1β, and IL-6 being the three main cytokines that have primarily been implicated in mediating signaling via these pathways. However, in recent years communication via peripheral immune-cell-to-brain and the gut-microbiota-to-brain routes have received increasing attention for their ability to modulate brain function. In this chapter we discuss periphery-to-brain communication pathways and their potential role in mediating inflammation-associated sickness behaviors and depression.
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Probiotics and Fecal Microbiota Transplantation in Major Depression: Doxa or Episteme?
In the human body, eukaryotic somatic cells and prokaryotic microorganisms live together. In this state, the body can be viewed as a "superorganism." Symbiotic life with commensal microorganisms can be observed in almost every part of the body. Intestinal microbiota plays an important role in health and disease, and in shaping and regulating neuronal functions from the intrauterine period to the end of life. Microbiota-based treatment opportunities are becoming more evident in both understanding the etiopathogenesis and treatment of neuropsychiatric disorders, especially depression. Antidepressant drugs, which are the first choice in the treatment of depression, also have antimicrobial and immunomodulatory mechanisms of action. From these perspectives, direct probiotics and fecal microbiota transplantation are treatment options to modulate microbiota composition. There are few preclinical and clinical studies on the effectiveness and safety of these applications in depression. The information obtained from these studies may still be at a doxa level. However, the probability that this information will become episteme in the future seems to be increasing.
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Potential of Probiotics as an Adjunct for Patients with Major Depressive Disorder.
Major depressive disorder (MDD) is an enfeebling disease with a lifetime incidence of 20%. While accumulating studies implicate a correlation between the disease and gut microbiota, data show that not every patient responded to probiotic treatments. To comprehensively assess the potential role of probiotics in MDD, this study first summarizes the current pathological hypothesis of the disease from a life-stage perspective, focuses on the potential role of "depression gut microbiota." Currently available managements are then briefly summarized and novel bio-materials having potential therapeutic effects on MDD are also evaluated. To harness the positive effect of probiotics, prebiotics, and postbiotics, clinical evidence and their applications on MDD patients are listed. Factors that may counteract the pre/probiotic applications, such as diet, physiology, gender difference, and use of antibiotics and antidepressants are also discussed. The endocannabinoid (eCBs) system may be promising targets for probiotic therapy. More evidence is needed to demonstrate the hierarchical factors in the complex network driving the disease, and probiotic can be one promising adjunct for patients with MDD.
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Gut microbial changes of patients with psychotic and affective disorders: A systematic review.
BACKGROUND: Many diverse inflammatory pathophysiologic mechanisms have been linked to mental disorders, and through the past decade an increasing interest in the gut microbiota and its relation to mental health has been arising. We aimed to systematically review studies of alterations in gut microbiota of patients suffering from psychotic disorders, bipolar disorder or depression compared to healthy controls. METHODS: We systematically searched the databases CENTRAL, PubMed, EMBASE, PsycINFO and LILACS. Primary outcome was to compare the gut microbiota of patients suffering from psychotic disorders, bipolar disorder or depression with healthy controls. RESULTS: We identified 17 studies, covering 744 patients and 620 healthy controls. The most consistent microbiota changes were a tendency towards higher abundance of Actinobacteria and lower abundance of Firmicutes at the phylum level, lower abundance of Lachnospiraceae at family level and lower abundance of Faecalibacterium at genus level for the mental disorders overall. However, we found that all studies had risk of bias and that the included studies displayed great variability in methods of storage, analysis of the fecal samples, reporting of results and statistics used. CONCLUSION: Due to the many limitations of the included studies the findings should be interpreted with caution. Larger studies (especially of schizophrenia and major depressive disorder) are needed, but it is also of great importance to gather information of and control for factors that influence the result of a microbiota analysis including body mass index (BMI), smoking, alcohol consumption, diet habits, antibiotics, sample handling, wet laboratory methods and statistics.
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Antibiotic exposure and depression incidence: A cohort study of the Korean population.
Recent research highlights the crucial role of the gut-brain axis in understanding depression etiologies. While burgeoning studies suggest an association between disruptions in gut microbiota and the development of depression, limited longitudinal studies have investigated this link. To address this gap, we conducted a retrospective cohort study using National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) data in South Korea, involving 199,144 individuals aged 40-79. We examined the impact of cumulative antibiotic exposure (2004-2008) on subsequent depression incidence (2009-2013) by conducting Cox proportional hazards regressions. Our findings show an increasing depression risk with extended antibiotic exposure after adjusting for comorbidities and behavioral covariates. A broader antibiotic spectrum was associated with a higher depression risk. These trends persisted after adjusting for the original antibiotic indications. In conclusion, our study highlights the duration-dependent association between antibiotic exposure and increased depression risk, offering insights into depression etiologies and relevant novel therapeutic tools, and advocating for heightened antibiotic stewardship considering their impact on mental health.