Faculty, Staff and Student Publications
Publication Date
7-13-2022
Journal
Cell Host & Microbe
Abstract
The intestinal microbiome releases a plethora of small molecules. Here, we show that the Ruminococcaceae metabolite isoamylamine (IAA) is enriched in aged mice and elderly people, whereas Ruminococcaceae phages, belonging to the Myoviridae family, are reduced. Young mice orally administered IAA show cognitive decline, whereas Myoviridae phage administration reduces IAA levels. Mechanistically, IAA promotes apoptosis of microglial cells by recruiting the transcriptional regulator p53 to the S100A8 promoter region. Specifically, IAA recognizes and binds the S100A8 promoter region to facilitate the unwinding of its self-complementary hairpin structure, thereby subsequently enabling p53 to access the S100A8 promoter and enhance S100A8 expression. Thus, our findings provide evidence that small molecules released from the gut microbiome can directly bind genomic DNA and act as transcriptional coregulators by recruiting transcription factors. These findings further unveil a molecular mechanism that connects gut metabolism to gene expression in the brain with implications for disease development.
Keywords
Amines, Animals, Bacteria, Bacteriophages, Cognitive Dysfunction, Gastrointestinal Microbiome, Humans, Mice, Microglia, Tumor Suppressor Protein p53, DNA unwinding, aged brain, binding promoter, cognitive dysfunction, gut bacterial metabolite, gut bacteriophages, isoamylamine, microglial, sensome gene S100A8, transcription factor p53
DOI
10.1016/j.chom.2022.05.005
PMID
35654045
PMCID
PMC9283381
PubMedCentral® Posted Date
7-13-2023
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons