Indole-3-Propionic acid, A Gut Microbiota Metabolite, Protects Against the Development of Postoperative Delirium

Abstract

Objective: 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. Summary Background Data: 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. Methods: 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. Results: 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. Conclusions: Gut microbiota-derived IPA is an important molecule implicated in the pathogenesis of POD, which could potentially be harnessed for POD prevention.

Shotgun metagenomics and systemic targeted metabolomics highlight indole-3-propionic acid as a protective gut microbial metabolite against influenza infection

“…These antibiotics have been shown to target IPA-producing bacteria. 34 , 35 As expected, antibiotic treatment profoundly altered the gut microbiota’s composition as revealed by LEfSe analysis (Supplementary Figure S7). In line with the above findings, 34 , 35 targeted LC-MS/MS revealed that the systemic concentration of IPA was dramatically reduced upon antibiotic treatment ( Figure 7(a) , middle panel).…”

“… 34 , 35 As expected, antibiotic treatment profoundly altered the gut microbiota’s composition as revealed by LEfSe analysis (Supplementary Figure S7). In line with the above findings, 34 , 35 targeted LC-MS/MS revealed that the systemic concentration of IPA was dramatically reduced upon antibiotic treatment ( Figure 7(a) , middle panel). In contrast, there was no change in IAA levels ( Figure 7(a) , right panel for the metabolic pathway).…”

“…Depletion of IPA-producing bacteria was performed as described. 34 , 35 Vancomycin (0.2 mg/ml) and ampicillin (0.5 mg/ml) were administered in drinking water five days prior to the onset of infection until D2. To study the impact of IPA treatment, mice were supplemented daily with IPA (40 mg/kg/day in 0.5% methyl cellulose) or vehicle by oral gavage one day before infection with IAV and until D3.…”