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

肠道微生物组和短链脂肪酸在调节头颈癌患者炎症和神经心理症状中的作用

• 批准号: 10344486
• 负责人: Veronika Fedirko
• 金额: $ 79.76万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-09 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10344486
• 关键词: 16S ribosomal RNA sequencing; Aftercare; Anti-Inflammatory Agents; Bacteria; Biological Factors; Biological Markers; Blood - brain barrier anatomy; Brain; Butyrates; Cancer Patient; Cancer Survivor; Clinical; Cognition; Complex; Data; Development; Dietary Fiber; Distress; Eating; Fatigue; Fermentation; Food; Goals; Head and Neck Cancer; High Prevalence; Homeostasis; Human; Human papilloma virus infection; Impaired cognition; Incidence; Individual; Inflammation; Inflammatory; Lead; Link; Longitudinal Studies; Malignant Neoplasms; Mass Fragmentography; Mediating; Mental Depression; Mucositis; Neuropsychology; Oral cavity; Outcome; Pain; Pathway interactions; Patient-Focused Outcomes; Patients; Peripheral; Phase; Phenotype; Plasma; Play; Production; Proteins; Radiation therapy; Regulation; Research; Role; Signal Pathway; Sleep; Sleep Disorders; Symptoms; Time; Transcriptional Regulation; Validation; Volatile Fatty Acids; Work; Xerostomia; active method; cancer therapy; chemoradiation; commensal bacteria; depressive symptoms; dysbiosis; experience; fecal microbiome; gut bacteria; gut microbiome; gut microbiota; gut-brain axis; head and neck cancer patient; high risk; immunoregulation; malignant mouth neoplasm; metagenomic sequencing; microbial; microbiome; neuroinflammation; new therapeutic target; prognostic; protein biomarkers; restoration; side effect; symptom management; targeted treatment; therapeutic target; transcriptome; treatment response; trend

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.

抽象的： 本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 通过短链脂肪的潜在作用，头颈癌 (HNC) 患者的症状 (NPS) 接受放化疗的头颈癌（HNC）患者的酸和炎症。 HNC 患者会经历显着的 NPS，例如疲劳、抑郁症状、认知功能障碍、 和睡眠问题。这些症状通常成群出现，影响治疗反应，预测更糟的情况 HNC 患者的生存率，对患者预后和生存率的负面影响比 个别症状。我们早期的工作以及其他人的工作已经表明外围设备之间存在牢固的联系 炎症和这些NPS。然而，导致炎症的生物学因素尚未完全阐明。 理解，但 NPS 的管理仍然具有挑战性。对肠脑的新兴认识 这种联系表明肠道微生物组参与了 NPS。微生物群失调 与疲劳、抑郁、认知、睡眠和疼痛等复杂症状有关。我们的初步 数据表明，与高炎症相关的类群与高 NPS 相关。此外，肠道 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最丰富的代谢物。 SCFA 不仅发挥关键作用 在肠道和外周内具有抗炎和免疫调节作用，而且还可以穿过血脑 屏障导致神经炎症减少和大脑稳态改善。我们初步的直觉 微生物组数据表明，高 NPS 患者中产生 SCFA 的类群丰度较低。我们的试点数据 血浆 SCFA 的变化反映了这一趋势，表明循环丁酸盐（肠道产生的主要 SCFA）较低 细菌，与高 NPS 相关。这些令人兴奋的新数据表明，枯竭的经济正在恢复 细菌或其代谢物有可能逆转与菌群失调相关的表型。因此，我们 提议对 350 名接受积极治疗的 HNC 患者进行一项纵向研究，以检验这种关联 治疗前后肠道微生物组和 NPS 之间的差异。 HNC 患者也有很高的风险 由于癌症的严重副作用（即粘膜炎、口干和张口困难）而导致菌群失调 治疗。这些使人衰弱且持久的副作用会降低患者的食物摄入能力，并可能 导致肠道微生物组以及随后的 SCFA 发生显着变化。综合起来，我们假设 癌症治疗引起的肠道微生物群变化以及由此导致的短链脂肪酸 SCFA 的减少导致高 周围炎症，然后是 NPS。我们的结果可能会导致 NPS 疗法的开发 肠道微生物组和 SCFA 的产生。这也可能有助于 NPS 管理等 鉴于 NPS 在各种癌症患者中的患病率很高，因此癌症患者需要考虑。