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

> **NIH NIH R35** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $185,908

## 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 this grant, we will examine
this hypothesis by addressing three key questions: 1) Does the observed effect of gut dysbiosis on POCD in the
preliminary studies 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 therapeutic ...

## Key facts

- **NIH application ID:** 10388931
- **Project number:** 3R35GM128692-03S1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Shiqian Shen
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $185,908
- **Award type:** 3
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10388931

## Citation

> US National Institutes of Health, RePORTER application 10388931, Administrative Supplement: Gut Microbiota Influences Postoperative Cognitive Dysfunction through Indole-3-Propionic Acid (3R35GM128692-03S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10388931. Licensed CC0.

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