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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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