Indole-3-Propionic Acid, a Gut Microbiota Metabolite, Protects Against the Development of Postoperative Delirium.
Indole-3-Propionic Acid, a Gut Microbiota Metabolite, Protects Against the Development of Postoperative Delirium.
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Indole-3-Propionic Acid 是一种肠道微生物代谢物，可预防术后谵妄的发生。
DOI：
10.1097/sla.0000000000005886
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发表时间：
2023-12-01
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
目的是确定可能与患者术后谵妄（POD）发展相关的术前肠道微生物代谢物，并在啮齿类动物中进行进一步研究。接受麻醉/手术的老年患者中有 9% 至 50% 会发生 POD，但缺乏有效的治疗或预防。使用液相色谱和串联质谱的高通量代谢组学加速了疾病相关生物标志物的发现。我们对人类进行了代谢组学研究，以确定与 POD 相关的潜在代谢物生物标志物，并检查了啮齿类动物的潜在机制。我们进行了一项前瞻性观察队列研究来检查与 POD 发生相关的代谢组变化。然后，通过啮齿动物肠道微生物群的扰动来概括与肠道微生物群相关的代谢组变化。使用一系列行为测试对小鼠进行 POD 评估，包括新颖的客观测试、Y 迷宫测试、旷场测试和埋藏食物测试。使用化学遗传学研究了肠道微生物群相关代谢组变化影响 POD 的机制。 3-吲哚丙酸 (IPA) 是一种肠道微生物代谢物，属于吲哚家族。在 103 名（17 例）人类个体中，IPA 基线血浆水平与 POD 发病呈显着负相关。这种关系在 POD 的临床前小鼠模型中得到了验证：通过肠道微生物群扰动降低 IPA 水平可促进 POD 样行为。更重要的是，IPA 管理阻止了类似 POD 的行为。突变型产孢梭菌在无菌小鼠中定植，但不会产生 IPA 促进的 POD 样行为。化学遗传学研究表明，IPA 对小鼠的保护作用部分是由海马中间神经元中的过氧化物酶体增殖物激活受体 γ 共激活剂 1-α 介导的。肠道微生物群衍生的 IPA 是一种与 POD 发病机制有关的重要分子，可用于预防 POD。
The aim was to determine preoperative gut microbiota metabolites that may be associated with postoperative delirium (POD) development in patients and further study in rodents. POD occurs in 9% to 50% of older patients undergoing anesthesia/surgery but lacks effective treatments or prevention. High-throughput metabolomics using liquid chromatography with tandem mass spectrometry has accelerated disease-related biomarkers discovery. We performed metabolomic studies in humans to identify potential metabolite biomarkers linked to POD and examined potential mechanisms in rodents. We performed a prospective observational cohort study to examine the metabolomic changes that were associated with the development of POD. Then the gut microbiota-related metabolomic changes were recapitulated by gut microbiota perturbation in rodents. POD was assessed in mice using a battery of behavioral tests including novel objective test, Y-maze test, open-field test, and buried food test. The mechanisms through which gut microbiota-related metabolomic changes influenced POD were examined using chemogenetics. Indole-3-propionic acid (IPA) is a gut microbiota metabolite that belongs to the indole family. Baseline plasma levels of IPA were significantly inversely correlated with the onset of POD in 103 (17 cases) human individuals. This relationship was validated in preclinical mouse models for POD: reducing IPA levels through gut microbiota perturbation promoted POD-like behavior. More importantly, IPA administration deterred POD-like behavior. Colonization of germ-free mice with mutant Clostridium sporogenes that did not produce IPA-promoted POD-like behavior. Chemogenetic studies revealed that the protective effect of IPA in mice was mediated, in part, by peroxisome proliferator-activated receptor gamma coactivator 1-alpha in hippocampal interneurons. Gut microbiota-derived IPA is an important molecule implicated in the pathogenesis of POD, which could potentially be harnessed for POD prevention.
影响因子：
3
作者：
Szalardy L;Molnar MF;Zadori D;Cseh EK;Veres G;Kovacs GG;Vecsei L;Klivenyi P
通讯作者：
Klivenyi P
影响因子：
13.8
作者：
Oberhaus J;Wang W;Mickle AM;Becker J;Tedeschi C;Maybrier HR;Upadhyayula RT;Muench MR;Lin N;Schmitt EM;Inouye SK;Avidan MS
通讯作者：
Avidan MS