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

术后谵妄（POD）发生在9-50%接受手术和麻醉的患者中， 患阿尔茨海默病（AD）的风险增加，临床结果不佳。高龄和 预先存在的认知缺陷与发展POD的风险增加有关。治疗晚期 年龄，然而，POD的发展并不普遍。相反，POD敏感性存在显著差异 同一年龄组的个别患者。到目前为止，很少有研究工作致力于解开 衰老大脑易感性异质性的生物学基础，也就是为什么一些衰老的大脑 有弹性，而其他人容易受到POD的发展？肠道微生物群，一个居住在 在胃肠道中，对于许多神经系统疾病的发病机制是至关重要的。在初步研究中， 我们观察到20个月大的小鼠在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敏感和抵抗 发展，分别。代谢组学研究表明，吲哚-3-丙酸（IPA）表现出最 两组之间的显著差异。产孢梭菌（C. spo），一个键 POD-R组中产生IPA的细菌比POD组高20倍。使用一种变异的C. spo菌株（fldC）对单菌落无菌小鼠的过氧化物酶（POD）活性显著降低， 接受fldC突变株的小鼠比接受野生型C的小鼠更差。spo.因此，肠道微生物群C. spo和 其代谢产物IPA在决定POD敏感性方面起主要作用。与此同时，患者 POD组血清IPA水平显著低于非POD组。外源补充C. spo 和IPA对老年小鼠的水平显着增加。机械地，IPA剂量依赖性地增加PGC- 海马HT-22神经元中1 μ g/ml。PGC-1 β对线粒体生物发生和中间神经元功能至关重要。 值得注意的是，用化学发生工具靶向抑制海马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及其代谢产物IPA是 衰老大脑对POD敏感性的异质性。我们计划进行三个具体目标来测试这一点 假设：1）探讨C. spo和IPA在老年小鼠POD异质性中的作用 神经元间的相关机制，通过C. spo和IPA影响POD的发育; 用IPA防治POD、PNCD和AD。这项建议旨在研究生物学基础， 衰老大脑对POD的易感性的异质性，这是一个具有重要临床意义的领域。这笔赠款是 创新，因为它结合了多组学，化学遗传学和PET-CT来研究C的关键作用。Spo和IPA在 POD异质性这项资助的成功实施将为异质性提供新的机制见解 POD易感性在衰老脑中的作用，以及预防/治疗POD、PNCD和AD的潜在治疗靶点。

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.