Loss of Anti-Microbial Peptides as a Mechanism for Age-Related Changes in Gut Microbiome Composition

The balance of microbial populations making up the gut microbiome changes with age in ways that are damaging to long-term health. Firstly the proportion of pro-inflammatory microbes grows, provoking the immune system into greater degrees of unresolved inflammation. This state of inflammaging observed in older individuals is disruptive to tissue structure and function throughout the body, and contributes meaningfully to the onset and progression of many age-related conditions. Secondly, the proportion of microbes generating beneficial metabolites decreases, leading to other forms of dysfunction. For example, butyrate production leads to BDNF expression, regulating important mechanisms such as neurogenesis in the brain. This production of butyrate by the gut microbiome diminishes with age.

Why does the population of the gut microbiome shift with aging? It is widely thought that immune system aging is important, in that (a) the immune system is responsible for gardening the gut microbiome, suppressing problem species, and (b) the immune system becomes less effective with age. In today's open access paper, researchers explore one of the less frequently considered aspects of innate immunity, the production of antimicrobial peptides, small molecules that can kill many types of microbe. Working in mice, the researchers show that decreased production of these peptides in intestinal tissues correlates directly with the increase of harmful bacterial species in the gut microbiome. This points the way to novel classes of therapy that might beneficially adjust the gut microbiome, restoring it to a more youthful balance of microbial populations.

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

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.

As a model of aging, C57BL/6J mice fecal (colonic) microbiota and isolated colonic crypt epithelial cell gene expression were assessed at 2 months, 15 months, and 25 months. 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.

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.

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