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Investigating the Link Between Gut Dysbiosis and Depression: A Mechanism Review Using the Functional Medicine Matrix
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Objectives: Recent systematic reviews have shown associations between chronic, low-grade inflammation and depression. However, mechanisms driving such inflammatory processes are still under investigation. The aim of this mechanism review was to investigate the links between gut dysbiosis in the pathophysiology of depression. The primary hypothesis was that gut dysbiosis could be a mediator influencing pathophysiological mechanisms involved in depression. This review also investigated the current literature on probiotic and prebiotic supplementation in the treatment of depression.
Methods: The PubMed electronic database was systematically searched for papers up to November 2015, examining the relationship between gut dysbiosis in the pathophysiology of depression. This search was conducted in five phases: review literature, animal mechanism studies, animal intervention studies, human mechanism studies and human intervention studies. Search returns were assessed for relevance with strict inclusion and exclusion criteria. This led to the final inclusion of 120 studies (thirty-two review, forty-six animal studies and forty-two human studies). A mechanism diagram, using the functional medicine matrix, was created upon completion of the review, animal and human searches to summarise findings.
Results: Results demonstrated a convergence of evidence linking gut dysbiosis to the pathophysiology of depression. This was primarily mediated through the effect of gut dysbiosis on intestinal permeability; leading to circulation of lipopolysaccharides, increased toll-like receptor four signalling, activation of NFκB, and subsequent expression of pro-inflammatory cytokines associated with depression. The literature therefore supports the primary hypothesis of this mechanism review. Evidence from animal studies demonstrated that in the presence of gut dysbiosis, probiotic and prebiotic administration could ameliorate certain mechanisms. This included reduction of intestinal permeability, enhanced colonic epithelial stability, decreased blood-brain permeability, and improved Gut Dysbiosis and Depression Student Number 133255 Page 3 microglial cell function. Evidence from human interventions was insufficient to demonstrate safety and efficacy of probiotic or prebiotic supplementation in the treatment of depression. Human intervention studies also contained significant methodological limitations and the potential for author bias.
Conclusion: Results of this mechanism review provide insight into upstream drivers of inflammatory mechanisms associated with depression; of which gut dysbiosis plays a part. High-quality randomised controlled trials and prospective cohort studies are needed to determine the safety and efficacy of probiotic and/or prebiotic interventions in the treatment of depression. The effect of different strains, doses and duration of probiotic and prebiotic supplementation also need to be determined.
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Early-life stress is a determinant of vulnerability to a variety of disorders that include dysfunction of the brain and gut. Here we exploit a model of early-life stress, maternal separation (MS) in mice, to investigate the role of the intestinal microbiota in the development of impaired gut function and altered behaviour later in life. Using germ-free and specific pathogen-free mice, we demonstrate that MS alters the hypothalamic–pituitary– adrenal axis and colonic cholinergic neural regulation in a microbiota-independent fashion. However, microbiota is required for the induction of anxiety-like behaviour and behavioural despair. Colonization of adult germ-free MS and control mice with the same microbiota produces distinct microbial profiles, which are associated with altered behaviour in MS, but not in control mice. These results indicate that MS-induced changes in host physiology lead to intestinal dysbiosis, which is a critical determinant of the abnormal behaviour that characterizes this model of early-life stress.
Animal models of mental disorders should ideally have construct, face, and predictive validity, but current animal models do not always satisfy these validity criteria. Additionally, animal models of depression rely mainly on stress-induced behavioral changes. These stress-induced models have limited validity, because stress is not a risk factor specific to depression, and the models do not recapitulate the recurrent and spontaneous nature of depressive episodes. Although animal models exhibiting recurrent depressive episodes or bipolar depression have not yet been established, several researchers are trying to generate such animals by modeling clinical risk factors as well as by manipulating a specific neural circuit using emerging techniques.
Copyright © 2015. Published by Elsevier Ltd.
Obesity is associated with a high prevalence of mood disorders and cognitive dysfunctions in addition to being a significant risk factor for important health complications such as cardiovascular diseases and type 2 diabetes. Identifying the pathophysiological mechanisms underlying these health issues is a major public health challenge. Based on recent findings, from studies conducted on animal models of obesity, it has been proposed that inflammatory processes may participate in both the peripheral and brain disorders associated with the obesity condition including the development of emotional and cognitive alterations. This is supported by the fact that obesity is characterized by peripheral low-grade inflammation, originating from increased adipose tissue mass and/or dysbiosis (changes in gut microbiota environment), both of which contribute to increased susceptibility to immune-mediated diseases. In this review, we provide converging evidence showing that obesity is associated with exacerbated neuroinflammation leading to dysfunction in vulnerable brain regions associated with mood regulation, learning, and memory such as the hippocampus. These findings give new insights to the pathophysiological mechanisms contributing to the development of brain disorders in the context of obesity and provide valuable data for introducing new therapeutic strategies for the treatment of neuropsychiatric complications often reported in obese patients.
The acquisition of intestinal microbiota in the immediate postnatal period has a defining impact on the development and function of many immune and metabolic systems integral to health and well-being. Recent research has shown that the presence of gut microbiota regulates the set point for hypothalamic-pituitary-adrenal (HPA) axis activity.1 Accordingly, we sought to investigate if there were other changes of brain function such as behavioral alterations in germ free (GF) mice, and if so, to compare these to behavior of mice with normal gut microbiota. Our recent paper showed reduced anxiety-like behavior in the elevated-plus maze (EPM) in adult GF mice when compared to conventionally reared specific pathogen-free (SPF) mice.2 Here, we present data collected when we next colonized the adult GF mice with SPF feces thereby introducing normal gut microbiota, and then reassessed anxiety-like behavior. Interestingly, the anxiolytic behavioral phenotype observed in GF mice persisted after colonization with SPF intestinal microbiota. These data show that gut-brain interactions are important to CNS development of stress systems and that a critical window may exist after which reconstitution of microbiota and the immune system does not normalize the behavioral phenotype
The field of microbial endocrinology is expressly devoted to understanding the mechanisms by which the microbiota (bacteria within the microbiome) interact with the host (“us”). This interaction is a two-way street and the driving force that governs these interactions are the neuroendocrine products of both the host and the microbiota. Chapters include neuroendocrine hormone-induced changes in gene expression and microbial endocrinology and probiotics. This is the first in a series of books dedicated to understanding how bi-directional communication between host and bacteria represents the cutting edge of translational medical research, and hopefully identifies new ways to understand the mechanisms that determine health and disease.
Purpose of review: With depressive disorders the leading source of disability globally, the identification of new targets for prevention and management is imperative. A rapidly emerging field of research suggests that the microbiome-gut-brain axis is of substantial relevance to mood and behaviour. Similarly, unhealthy diet has recently emerged as a significant correlate of and risk factor for depression. This review provides evidence for the gut microbiota as a key factor mediating the link between diet and depressive illness.
Background:
Accumulating evidence supports health benefits of dietary fibre, such as improving lipid profiles, lowering blood pressure and improving insulin sensitivity, but evidence from comprehensive investigation of dietary fibre intake and mortality from cardiovascular disease (CVD) and all cancers is limited.
Aims:
To quantitatively assess the association between dietary fibre intake and mortality from CVD and all cancers.
Methods:
We performed a meta-analysis of prospective cohort studies. Eligible studies were identified by searching PubMed and Embase databases for all articles published up to September 2014 and via hand searching. Study-specific estimates adjusting for potential confounders were combined to calculate pooled relative risks (RRs) with 95% confidence intervals (CIs), using a random-effects model.
Results:
We found 15 studies that examined the association between dietary fibre and mortality from CVD, coronary heart disease (CHD) and all cancers. The pooled RRs of CVD, CHD and all-cancer mortality for the highest versus lowest category of dietary fibre were 0.77 (95% CI: 0.71-0.84), 0.76 (95% CI: 0.67-0.87) and 0.86 (95% CI: 0.79-0.93), respectively. In a dose-response meta-analysis, the pooled RRs for an increment of 10g/day in dietary fibre intake were 0.91 (95% CI: 0.88-0.94) for CVD, 0.89 (95% CI: 0.85-0.93) for CHD and 0.94 (95% CI: 0.91-0.97) for all cancers.
Conclusions:
Our findings suggest that high dietary fibre intake is associated with a reduced risk of mortality from CVD and all cancers. These results support the current recommendation that high dietary fibre intake should be part of a healthy diet.
The human gut microbiota encompasses a densely populated ecosystem that provides essential functions for host development, immune maturation, and metabolism. Alterations to the gut microbiota have been observed in numerous diseases, including human metabolic diseases such as obesity, type 2 diabetes (T2D), and irritable bowel syndrome, and some animal experiments have suggested causality. However, few studies have validated causality in humans and the underlying mechanisms remain largely to be elucidated. We discuss how systems biology approaches combined with new experimental technologies may disentangle some of the mechanistic details in the complex interactions of diet, microbiota, and host metabolism and may provide testable hypotheses for advancing our current understanding of human-microbiota interaction.