The Role of the Gut Microbiome and Short Chain Fatty Acids in the Regulation of Inflammation and Neuropsychological Symptoms in Patients with Head and Neck Cancer

摘要： 这项研究的目的是了解肠道微生物组在神经心理学发展中的作用。 通过短链脂肪酸在头颈癌（HNC）患者中的潜在作用， 接受放化疗的头颈癌（HNC）患者中的酸和炎症。 患有HNC的患者经历显著的不适，如疲劳、抑郁症状、认知功能障碍， 和睡眠问题。这些症状通常呈簇状发生，影响治疗反应，预测更糟 HNC患者的生存率，对患者结局和生存率的负面影响比 个别症状。我们的早期工作，沿着与其他人，已经显示了一个强大的联系之间的周边 炎症和这些炎症。然而，导致炎症的生物学因素仍然没有完全 但是，这一问题已经得到理解，而且对难民署的管理仍然具有挑战性。一个新兴的欣赏肠脑 这种联系表明肠道微生物组参与了腹泻。微生物群落失调一直是 与包括疲劳、抑郁、认知、睡眠和疼痛在内的复杂症状有关。我们的初步 数据表明与高度炎症相关的分类群与高度炎症相关。此外，肠道 微生物组被认为具有免疫调节作用，部分由短链脂肪酸（SCFA）介导， 肠道中最丰富的膳食纤维细菌发酵代谢产物。SCFA不仅是关键 在肠道和外周发挥抗炎和免疫调节作用，但也可穿过血脑 屏障，从而减少神经炎症和改善脑内稳态。我们初步的直觉 微生物群系数据表明，在高血糖患者中产生SCFA的类群丰度较低。我们的试点数据 通过显示较低的循环丁酸（肠道产生的主要SCFA）， 细菌，与高致病性相关。这些新的令人兴奋的数据表明， 细菌或其代谢物具有逆转生态失调相关表型的潜力。所以我们 建议对350例接受积极治疗的HNC患者进行纵向研究，以检查 治疗前后肠道微生物组和大肠杆菌之间的关系。HNC患者也有高风险， 由于严重的副作用导致的生态失调（即，粘膜炎、口干和张口困难） 治疗这些使人衰弱和持久的副作用降低了患者的食物摄入能力， 导致肠道微生物组和随后的SCFA的显著变化。综合考虑，我们假设 癌症治疗引起的肠道微生物群的改变和导致的SCFAs减少有助于高 外周炎症，然后是炎症。我们的研究结果可能导致靶向治疗的发展。 肠道微生物组和SCFAs的产生。这也可能有助于除其他外， 癌症患者，鉴于在各种癌症丘疹中的高患病率。

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 the high prevalence of NPS in a variety of cancer papulations.