AUTHOR=Forsyth Christopher B. , Shaikh Maliha , Engen Phillip A. , Preuss Fabian , Naqib Ankur , Palmen Breanna A. , Green Stefan J. , Zhang Lijuan , Bogin Zlata R. , Lawrence Kristi , Sharma Deepak , Swanson Garth R. , Bishehsari Faraz , Voigt Robin M. , Keshavarzian Ali 

TITLE=Evidence that the loss of colonic anti-microbial peptides may promote dysbiotic Gram-negative inflammaging-associated bacteria in aging mice

JOURNAL=Frontiers in Aging

VOLUME=5

YEAR=2024

URL=https://www.frontiersin.org/journals/aging/articles/10.3389/fragi.2024.1352299

DOI=10.3389/fragi.2024.1352299

ISSN=2673-6217

ABSTRACT=<p><bold>Introduction:</bold> Aging studies in humans and mice have played a key role in understanding the intestinal microbiome and an increased abundance of “inflammaging” Gram-negative (Gn) bacteria. The mechanisms underlying this inflammatory profile in the aging microbiome are unknown. We tested the hypothesis that an aging-related decrease in colonic crypt epithelial cell anti-microbial peptide (AMP) gene expression could promote colonic microbiome inflammatory Gn dysbiosis and inflammaging.</p><p><bold>Methods:</bold> As a model of aging, C57BL/6J mice fecal (colonic) microbiota (16S) and isolated colonic crypt epithelial cell gene expression (RNA-seq) were assessed at 2 months (mth) (human: 18 years old; yo), 15 mth (human: 50 yo), and 25 mth (human: 84 yo). Informatics examined aging-related microbial compositions, differential colonic crypt epithelial cell gene expressions, and correlations between colonic bacteria and colonic crypt epithelial cell gene expressions.</p><p><bold>Results:</bold> Fecal microbiota exhibited significantly increased relative abundances of pro-inflammatory Gn bacteria with aging. Colonic crypt epithelial cell gene expression analysis showed significant age-related downregulation of key AMP genes that repress the growth of Gn bacteria. The aging-related decrease in AMP gene expressions is significantly correlated with an increased abundance in Gn bacteria (dysbiosis), loss of colonic barrier gene expression, and senescence- and inflammation-related gene expression.</p><p><bold>Conclusion:</bold> This study supports the proposed model that aging-related loss of colonic crypt epithelial cell AMP gene expression promotes increased relative abundances of Gn inflammaging-associated bacteria and gene expression markers of colonic inflammaging. These data may support new targets for aging-related therapies based on intestinal genes and microbiomes.</p>