Gut Microbiota-Derived Short-Chain Fatty Acids Promote Poststroke Recovery in Aged Mice

Authors

Juneyoung Lee
John d'Aigle
Louise Atadja
Victoria Quaicoe
Pedram Honarpisheh
Bhanu P Ganesh
Ahmad Hassan
Joerg Graf
Joseph Petrosino
Nagireddy Putluri
Liang Zhu
David J Durgan
Robert M Bryan
Louise D McCullough
Venugopal Reddy Venna

Publication Date

7-31-2020

Journal

Circulation Research

DOI

10.1161/CIRCRESAHA.119.316448

PMID

32354259

PMCID

PMC7415518

PubMedCentral® Posted Date

7-31-2021

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Age Factors, Animals, Bifidobacterium longum, Brain Chemistry, Clostridium symbiosum, Faecalibacterium prausnitzii, Fatty Acids, Volatile, Fecal Microbiota Transplantation, Feces, Gastrointestinal Microbiome, Infarction, Middle Cerebral Artery, Interleukin-17, Intestines, Intraepithelial Lymphocytes, Ischemic Stroke, Limosilactobacillus fermentum, Male, Mice, Mucin-2, Mucin-4, T-Lymphocytes, Regulatory

Abstract

RATIONALE: The elderly experience profound systemic responses after stroke, which contribute to higher mortality and more severe long-term disability. Recent studies have revealed that stroke outcomes can be influenced by the composition of gut microbiome. However, the potential benefits of manipulating the gut microbiome after injury is unknown.

OBJECTIVE: To determine if restoring youthful gut microbiota after stroke aids in recovery in aged subjects, we altered the gut microbiome through young fecal transplant gavage in aged mice after experimental stroke. Further, the effect of direct enrichment of selective bacteria producing short-chain fatty acids (SCFAs) was tested as a more targeted and refined microbiome therapy.

METHODS AND RESULTS: Aged male mice (18-20 months) were subjected to ischemic stroke by middle cerebral artery occlusion. We performed fecal transplant gavage 3 days after middle cerebral artery occlusion using young donor biome (2-3 months) or aged biome (18-20 months). At day 14 after stroke, aged stroke mice receiving young fecal transplant gavage had less behavioral impairment, and reduced brain and gut inflammation. Based on data from microbial sequencing and metabolomics analysis demonstrating that young fecal transplants contained much higher SCFA levels and related bacterial strains, we selected 4 SCFA-producers (

CONCLUSIONS: This is the first study suggesting that the poor stroke recovery in aged mice can be reversed via poststroke bacteriotherapy following the replenishment of youthful gut microbiome via modulation of immunologic, microbial, and metabolomic profiles in the host.

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