• Xue Zhou, Xinbo Wu, Yan Wu, Liuyue Yang, Eleanor Shi, Weihua Ding, Liang Chen, Xu Shi, Xia Feng, Chienwen Su, Zerong You, Jianguo Xia, Cynthia Chen, Vladimir Yeliseyev, Lynn Bry, Suyun Xia, Peigen Huang, Jiawei Meng, Timothy Houle, Oluwaseun Akeju, Jianren Mao, Robert Gerszten, Qian Chen, Zhongcong Xie, and Shiqian Shen.
• Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
• Ann. Surg. 2023 Dec 1; 278 (6): e1164e1174e1164-e1174.

ObjectiveThe aim was to determine preoperative gut microbiota metabolites that may be associated with postoperative delirium (POD) development in patients and further study in rodents.Summary Background DataPOD 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.MethodsWe 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.ResultsIndole-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.ConclusionsGut microbiota-derived IPA is an important molecule implicated in the pathogenesis of POD, which could potentially be harnessed for POD prevention.Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.

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