Gut Microbiota Underlies the Heterogeneity of Aging Brain's Susceptibility to Postoperative Delirium

肠道微生物群是衰老大脑对术后谵妄易感性异质性的基础

• 批准号: 10297433
• 负责人: Shiqian Shen
• 金额: $ 173.9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10297433
• 关键词: Address; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Anesthesia procedures; Applications Grants; Area; Attention; Bacteria; Behavior; Behavioral Assay; Binding; Biogenesis; Biological; Brain; Clinical; Clostridium; Cognitive deficits; Data; Delirium; Dementia; Development; Disease susceptibility; Dose; Effectiveness; Elderly; Exhibits; Face; Feces; Gastrointestinal tract structure; Germ-Free; Grant; Heterogeneity; Hippocampus (Brain); Incidence; Individual; Indoles; Interneuron function; Interneurons; Kinetics; Label; Mediating; Mental Health; Metagenomics; Microbe; Mitochondria; Mus; Mutant Strains Mice; Neurodegenerative Disorders; Neurologic; Neurons; Newly Diagnosed; Operative Surgical Procedures; Orthopedic Surgery; Outcome; Parkinson Disease; Pathogenesis; Patients; Play; Positron-Emission Tomography; Postoperative Complications; Predisposition; Prevention; Propionic Acids; Reaction Time; Research; Resistance; Risk; Role; Serum; Supplementation; Testing; Therapeutic Effect; Time; Variant; X-Ray Computed Tomography; age group; aged; aging brain; clinically significant; cognitive function; designer receptors exclusively activated by designer drugs; gut microbiota; healthy aging; high risk; individual patient; innovation; insight; metabolomics; microbiota metabolites; mortality; multiple omics; mutant; novel; older patient; physical conditioning; postoperative delirium; prevent; prospective; protective effect; radiotracer; side effect; therapeutic target; tool; transcriptomics

Postoperative delirium (POD) occurs in 9-50% patients undergoing surgery and anesthesia, which is associated with increased risk of developing Alzheimer’s disease (AD), and poor clinical outcomes. Advanced age and preexisting cognitive deficits are associated with increased risk of developing POD. In patients with advanced age, however, the development of POD is not ubiquitous. Instead, there is marked variation in POD susceptibility for individual patients in the same age group. To date, little research effort has been devoted to unraveling the biological underpinning of the heterogeneity of aging brain’s susceptibility, that is, why some aging brains are resilient while others are susceptible to POD development? Gut microbiota, a consortium of microbes residing in the gastrointestinal tract, is critical for the pathogenesis of many neurological conditions. In preliminary studies, we observed a striking heterogeneity of cognitive function after surgery and anesthesia in mice aged 20 months. These mice were subsequently categorized into two groups, POD group and POD-resistance (POD-R) group. Feces from the POD group and POD-R group rendered germ-free mice susceptible and resistant to POD development, respectively. Metabolomic studies revealed that indole-3-propionic acid (IPA) exhibited the most striking difference between the two groups. The relative abundance of Clostridium sporogenes (C. spo), a key bacterium that produces IPA, was 20 times higher in the POD-R group than the POD group. Using a mutant C. spo strain (fldC) that does not produce IPA to mono-colonize germ-free mice, we found POD was significantly worse in mice received fldC mutant strain than mice received wildtype C. spo. Thus, gut microbiota C. spo and its metabolite IPA played a major role in determining the susceptibility to POD. Congruent with this, patients with POD had significantly lower levels of serum IPA than those without POD. Exogenous supplementation of C. spo and IPA to aged mice significantly increased their levels. Mechanistically, IPA dose dependently increased PGC- 1 in hippocampal HT-22 neurons. PGC-1 is critical for mitochondria biogenesis and interneuron function. Notably, targeted inhibition of hippocampal interneurons with a chemogenetic tool led to severe POD development. As such, we hypothesize the gut microbiota C. spo and its metabolite IPA underlie the heterogeneity of aging brain’s susceptibility to POD. We plan to carry out three Specific Aims to test this hypothesis: 1) to examine the role of C. spo and IPA in the heterogeneity of POD in aged mice; 2) to investigate interneuron-associated mechanisms through which C. spo and IPA influence the development of POD; and 3) to prevent / treat POD, PNCD, and AD with IPA. This proposal aims at examining the biological underpinnings of heterogeneity of aging brain’s susceptibility to POD, an area of great clinical significance. This grant is innovative as it combines multi-omics, chemogenetics, and PET-CT to examine a key role for C. spo and IPA in POD heterogeneity. Successful execution of this grant will provide novel mechanistic insights into heterogeneity of POD susceptibility in aging brain, and potential therapeutic targets to prevent/treat POD, PNCD, and AD.

术后妄想(POD)发生在手术和麻醉的9-50%的患者中，这与 罹患阿尔茨海默病(AD)的风险增加，临床结果不佳。高龄和高龄 先前存在的认知缺陷与患POD的风险增加有关。在晚期患者中 然而，POD的发展并不是无处不在的。相反，POD的易感性有显著的变化 适用于同一年龄段的个别患者。到目前为止，很少有研究致力于解开 老化大脑易感性异质性的生物学基础，也就是为什么一些老化的大脑 当其他人容易受到POD发展的影响时，他们是否具有弹性？肠道微生物区系，一种由微生物组成的联盟 在胃肠道中，对许多神经系统疾病的发病是至关重要的。在初步研究中， 在20个月大的小鼠中，我们观察到手术和麻醉后认知功能的显著异质性。 这些小鼠随后被分为两组，POD组和POD抗性(POD-R)组。 POD组和POD-R组的粪便使无菌小鼠对POD易感和抗药性 分别是发展。代谢组学研究表明，吲哚-3-丙酸(IPA)表现出最大的 两组间有显著差异。生孢梭菌(C.SPO)的相对丰度 产生IPA的细菌在POD-R组是POD组的20倍。使用突变的C. 不产生IPA的SPO菌株(FldC)对无菌小鼠的单次定植，我们发现POD显著 在接受fldC突变株的小鼠中比接受野生型C.spo的小鼠更糟糕。因此，肠道微生物群C.spo和 其代谢产物IPA在决定对POD的敏感性中起主要作用。与此相一致的是，患有 POD患者血清IPA水平显著低于非POD患者。外源补充剂对肉鸡的影响 而IPA能显著提高衰老小鼠的免疫球蛋白水平。从机理上讲，IPA剂量依赖地增加了PGC- 1海马HT-22神经元表达。PGC-1对线粒体的生物发生和神经元间功能起关键作用。 值得注意的是，使用化学发生工具定向抑制海马区中间神经元导致严重的POD 发展。因此，我们假设肠道微生物群C.SPO及其代谢物IPA是 脑老化对POD易感性的异质性。我们计划执行三个具体目标来测试这一点 假设：1)研究C.SPO和IPA在老年小鼠POD异质性中的作用；2)研究 C.SPO和IPA影响POD发生的中间神经元相关机制； 使用IPA预防/治疗POD、PNCD和AD。这项提议旨在研究生物基础。 脑老化对POD易感性的异质性是一个具有重要临床意义的领域。这笔赠款是 具有创新性，因为它结合了多组学、化学遗传学和PET-CT来检查C.SPO和IPA在 豆荚异质性。这笔赠款的成功执行将为异构性提供新的机械性见解 研究POD在脑老化中的易感性，以及预防/治疗POD、PNCD和AD的潜在治疗靶点。