Aging gut microbiome profile and ghrelin signaling in microbiome homeostasis

Abstract

The aging process is characterized by a progressive decline of metabolic functions, increased chronic low‐grade inflammation (inflamm‐aging) and leaky gut syndrome. While gut microbiota is known to be involved in host physiology, its role and regulatory mechanism in aging is not clear. Here, we assessed metabolic profile and gut microbiome changes in sets of young, middle‐aged, and old mice, ranging from 4, 12, to 18 and 28 months of age, respectively. As expected, old mice exhibited reduced total energy expenditure and resting metabolic rate, as well as reduced cold tolerance and thermogenic impairment. We have evidence that pro‐inflammatory cytokine expression in colons increases with age. To determine whether there is a correlation between gut microbiome community and host aging metabolism, we analyzed fecal samples of these mice by sequencing V4 region of microbial 16S rDNA. At the phylum level, Bacteroidetes was reduced and Firmicutes was increased during aging. At the genus level, Alloprevotella was the highest at middle age, which dramatically decreased at old and very old age. At the species level, Eubacterium siraeum and Bacteroides xylanisolvens were significantly increased in old age. Surprisingly, microbiome composition appeared to show an overall increased diversity with age. Overall the microbiome compositions of older mice support an unhealthy microbiome state, in line with age‐associated metabolic impairment and enhanced inflammation.Gut hormone ghrelin serves as energy and nutrient sensor, which is primarily produced in the gut. Ghrelin's biological relevant receptor is Growth Hormone Secretagogue Receptor (GHS‐R), which is primarily expressed in the brain and macrophages. Pharmacological treatment of ghrelin has been shown to have anti‐inflammatory effect. To determine whether nutrient sensing ghrelin and GHS‐R signal plays a role in microbiome regulation contributing to inflamm‐aging, we assessed fecal samples of ghrelin and GHS‐R null mice. Young ghrelin KO mice showed higher Firmicutes/Bacteroidetes ratio and increased Proteobacteria at the phylum level, and higher Helicobacter but lower Allobactulum at the genus level. In comparison, young GHS‐R KO mice showed no difference in the Bacteroidetes and Firmicutes at the phylum level, but increased Eubacterium siraeum and Bacteroides xylanisolvens at the species level. When challenged with DSS to induce experimental colitis, GHS‐R KO mice exhibited exaggerated disease activity score and colonic inflammation. These data revealed a novel role of ghrelin signaling in microbiota‐gut homeostasis.In summary, the gut microbiome profile may serve as biosignature of functional state of meta‐inflammation in aging. Ghrelin signaling is required for microbiome‐gut homeostasis and gut health maintenance, and it may present a novel target for prevention and treatment of leaky gut syndrome in aging.Support or Funding InformationAmerican Diabetes Association Award #1‐15‐BS‐177, National Institutes of Health R56DK118334, and Oklahoma Nathan Shock Center of Excellence for the Biology of Aging.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.