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

> **NIH NIH RF1** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $1,739,007

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10297433
- **Project number:** 1RF1AG070141-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Shiqian Shen
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,739,007
- **Award type:** 1
- **Project period:** 2021-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10297433

## Citation

> US National Institutes of Health, RePORTER application 10297433, Gut Microbiota Underlies the Heterogeneity of Aging Brain's Susceptibility to Postoperative Delirium (1RF1AG070141-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10297433. Licensed CC0.

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