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群在神经心理学发展中的作用。 短链脂肪在头颈癌患者中的潜在作用 接受放化疗的头颈癌患者的酸度和炎症。 HNC患者会出现明显的NPS，如疲劳、抑郁症状、认知功能障碍、 还有睡眠问题。这些症状通常以聚集性形式出现，影响治疗反应，预测病情恶化 HNC患者的存活率，并且对患者预后和存活率的影响比 个别症状。我们早期的工作，以及其他工作，都显示了外围设备之间的强大联系 炎症和这些神经节细胞。然而，导致炎症的生物因素仍然不完全。 我明白，核动力源的管理仍然具有挑战性。对肠脑的新兴欣赏 Connection表明肠道微生物群参与了NPS。微生物群失调一直是 与疲劳、抑郁、认知、睡眠和疼痛等复杂症状有关。我们的预赛 数据表明，与高炎症相关的分类群与高NPS相关。而且，这种胆量 微生物组被认为发挥免疫调节作用，部分是由短链脂肪酸(SCFA)介导的， 肠道中膳食纤维细菌发酵的最丰富的代谢物。SCFA不仅发挥关键作用 抗炎和免疫调节作用在肠道和外周，但也跨越血脑 屏障可减少神经炎症，改善脑内稳态。我们的初步直觉 微生物组数据表明，NPS高的患者产生SCFA的类群丰度较低。我们的试点数据 在血浆中，SCFA与这一趋势相呼应，表明循环中较低的丁酸，一种由肠道产生的主要SCFA 细菌与较高的NPS相关。这些新的令人兴奋的数据表明，枯竭的 细菌或其代谢产物有可能逆转与生物失调相关的表型。因此，我们 建议对350名接受积极治疗的HNC患者进行纵向研究，以检查这种联系 治疗前后肠道微生物群与NPS之间的关系。HNC患者也有很高的风险 由于癌症的严重副作用(如粘膜炎、口干和张口困难)而导致的生物失调 治疗。这些衰弱和持久的副作用降低了患者的食物摄取能力，并可能 导致肠道微生物组和随后的单链脂肪酸发生显著变化。总而言之，我们假设 癌症治疗引起的肠道微生物区系的改变以及由此导致的单链脂肪酸的减少导致高 外周炎症，然后是NPS。我们的结果可能会导致NPS靶向治疗的发展 肠道微生物群与单链脂肪酸的产生。这也可能有助于核动力源的管理等 癌症患者，考虑到NPS在各种癌症溃疡中的高患病率。

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.