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，这是相关的

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.