# Gut Microbiota Influences Postoperative Cognitive Dysfunction through Indole-3-Propionic Acid

> **NIH NIH R35** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $400,203

## Abstract

In up to 26% surgical patients, subtle yet persistent deficits in learning and memory occur postoperatively,
referred to as postoperative cognitive dysfunction (POCD). POCD has become a serious public health concern
as it is associated with worse clinical outcomes including increased mortality. The pathogenesis underlying
POCD remains unclear. Both modifiable and non-modifiable factors may contribute to POCD. To date, studies
on POCD have primarily focused on direct influences of surgery and anesthesia on the central nervous system,
which have identified age and genetics as major risk factors in POCD. Unfortunately, these are non-modifiable
factors and difficult to be translated into clinical treatment. As such, there is an urgent need to identify
modifiable factors underlying POCD. Among many modifiable factors, dietary influences and gut microbiota
have been implicated in many neurological diseases with inflammatory features. Whether gut microbiota
influences POCD has yet to be examined. In our preliminary studies, we observed a previously unrecognized
role for gut microbiota in the development of POCD in mice post femoral artery exposure under isoflurane
anesthesia. Specifically, we found: 1) mice with normal gut microbiota did not develop POCD while mice with
gut dysbiosis developed POCD; 2) oral ampicillin treatment led to a status of gut dysbiosis, characterized by
gut microbiota community structure changes and a dramatic decrease of indoles, particularly indoxyl-3-sulfate
(IS) and indole-3-propionic acid (IPA); 3) oral administration of IPA, but not IS, deterred the POCD
development; 4) mice with POCD displayed increased oxidation and impaired mitochondria function in the
hippocampus, suggested by an enhanced production of reactive oxygen species (ROS), decreased production
of NADH, and decreased protein levels of NDUFS4 (a critical mitochondria complex I component), when
compared with mice without POCD; and 5) oral administration of IPA decreased ROS generation, increased
NADH production and NDUFS4 protein levels in the hippocampus of ampicillin-treated mice. Based on these
preliminary findings, we hypothesize that gut microbiota has a key influence on the development of POCD
through IPA. In the research program proposed in this grant, we will examine the hypothesis by addressing
three key questions: 1) Does the observed effect of gut dysbiosis on POCD represent an epiphenomenon or a
‘permissive’ effect? 2) What are the mechanisms underlying the IPA’s protective role in POCD? and 3) Can we
develop a strategy based on gut microbiota and metabolites to prevent and treat POCD? This grant is built on
our novel preliminary findings and our established research platform that combines cutting-edge
metagenomics and metabolomics with immunological and neurobehavioral assays. Successful execution of
this proposal will establish a novel conceptual framework linking modifiable factors such as diet and gut
microbiota with POCD, and lead to new therape...

## Key facts

- **NIH application ID:** 10475064
- **Project number:** 5R35GM128692-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Shiqian Shen
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $400,203
- **Award type:** 5
- **Project period:** 2018-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475064

## Citation

> US National Institutes of Health, RePORTER application 10475064, Gut Microbiota Influences Postoperative Cognitive Dysfunction through Indole-3-Propionic Acid (5R35GM128692-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10475064. Licensed CC0.

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