A Fight Against Gut Dysbiosis: Dendritic‐cell Derived Hepcidin and its Healing Role and Prevention of Neurologic Disease Authors: Barbara Kania, Alexis Sotelo, Darren Ty, Jonathan J. Wisco, PhD

Introduction The human gut microbiome colonizes 70% of total microorganisms in the body and its composition can be impacted by several environmental factors, particularly a high fat and high sugar diet called the Western diet. The Western diet has been extensively studied for its consequential shift towards gut dysbiosis and inflammation in the host and other negative health outcomes including brain disorders such as Alzeihmer’s and Parkinson's disease. This so‐called gut‐brain axis may be mediated by key biomarkers including hepcidin and trimethylamine N‐oxide (TMAO). In the setting of the inflamed gut, hepatocyte‐derived hepcidin levels are increased relative to baseline levels as it could potentially have an anti‐inflammatory effect. Dendritic cell‐derived hepcidin also has an anti‐inflammatory effect, but operates differently than the hepcidin derived by hepatocytes. It could be hypothesized that dendritic cell‐derived hepcidin works through a more localized approach through nutritional immunity versus hepatocyte‐derived hepcidin that functions through a systemic approach. Very few studies have focused on dendritic cell‐derived hepcidin and its effects on gut dysbiosis and neurologic disorder. This literature review aims to offer a thorough analysis of the importance of both dendritic cell and hepatocyte‐derived hepcidin in the fight against gut dysbiosis and neuroinflammation through two separate mechanisms. Methods In order to better understand the role of dendritic cell‐derived hepcidin, a literature review of over 80 papers was conducted using a search for key terms including Western diet, gut dysbiosis, gut microbiome, hepcidin, brain, dendritic cell, hepatocyte, inflammation, vagus nerve, iron, TMAO, and brain disorder. Results Breakthrough studies focused on dendritic‐cell derived hepcidin show evidence of mucosal healing after blunt trauma to the intestines in experimental animal models containing the gene for this specific hepcidin, and signs of persistent weight loss, disruption of epithelial architecture, shorter colon lengths and lower systemic hepatocyte‐derived hepcidin levels in models that lacked the gene. Conclusions This new relationship between dendritic cell hepcidin opens a new conversation regarding the gut‐brain axis. There could be a potential relationship between hepcidin produced by dendritic cells and the repair and maintenance of intestinal mucosa. While hepcidin released from the liver could be sequestering iron systemically, the hepcidin from dendritic cells could potentially be working through a means of nutritional immunity by keeping a tight control on local iron and its availability to pathogenic bacteria to promote intestinal homeostasis by starving them of their food source. Future studies can focus on experimentally determining whether both dendritic cell and hepatocyte‐derived hepcidin upregulation causes downregulation of iron in the brain, or vice versa. It is important for future researchers to account for all of the key players in the complex crosstalk between the gut and brain when considering neurologic diseases including Alzeheimer’s disease, Parkinson’s disease and dementia.