Abstract: The goal of this study is to understand the role of the gut microbiome in the development of neuropsychological symptoms (NPS) among patients with head and neck cancer (HNC) through potential roles of short chain fatty acids and inflammation among patients with head and neck cancer (HNC) receiving chemoradiotherapy. Patients with HNC experience significant NPS, such as fatigue, depressive symptoms, cognitive dysfunction, and sleep problems. These symptoms often occur as a cluster, influence treatment responses, predict worse survival among HNC patients, and have a more negative impact on patient outcomes and survival than individual symptoms. Our earlier work, along with others, have shown a robust link between peripheral inflammation and these NPS. However, the biological factors that contribute to inflammation are still not fully understood and the management of NPS is still challenging. An emerging appreciation of the gut-brain connection has suggested the involvement of the gut microbiome in NPS. Microbiome dysbiosis has been implicated in complex symptoms including fatigue, depression, cognition, sleep, and pain. Our preliminary data indicate that taxa associated with high inflammation were associated with high NPS. Moreover, the gut microbiome is believed to paly immunomudolatory roles, in part mediated by short-chain fatty acids (SCFAs), the most abundant metabolites of bacterial fermentation of dietary fibers in the gut. SCFAs not only play key anti-inflammatory and immunomodulatory roles within the gut and periphery, but also cross the blood-brain barrier leading to decreases in neuroinflammation and improvement in brain homeostasis. Our preliminary gut microbiome data suggest lower abundance in SCFA-producing taxa in patients with high NPS. Our pilot data on plasma SCFAs echo this trend by showing that lower circulating butyrate, a main SCFA produced by the gut bacteria, was associated with high NPS. These new exciting data suggest that a restoration of depleted bacteria or their metabolites has the potential to reverse the dysbiosis-associated phenotypes. Therefore, we propose a longitudinal study of 350 HNC patients receiving active treatment to examine the association between the gut microbiome and NPS before and after treatment. Patients with HNC also have a high risk of dysbiosis due to severe side effects (i.e., mucositis, dry mouth, and difficulty opening mouth) of cancer treatment. These debilitating and long-lasting side effects reduce patients' capability for food intake, and could result in marked changes in gut microbiome and subsequently SCFAs. Taken together, we hypothesize that cancer treatment-induced alterations in the gut microbiota and resulting reductions in SCFAs contribute to high peripheral inflammation and then NPS. Our results may lead to the development of NPS therapies targeting the gut microbiome and production of SCFAs. This may also contribute to NPS management among other cancer patients, given t...