Novel Role of Ghrelin Receptor in Gut Dysbiosis and Experimental Colitis in Aging

Authors

Ji Yeon Noh
Chia-Shan Wu
Jennifer A A DeLuca
Sridevi Devaraj
Arul Jayaraman
Robert C Alaniz
Xiao-Di Tan
Clinton D Allred
Yuxiang Sun

Publication Date

2-17-2022

Journal

International Journal of Molecular Sciences

DOI

10.3390/ijms23042219

PMID

35216335

PMCID

PMC8875592

PubMedCentral® Posted Date

2-17-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Aging, Animals, Colitis, Cytokines, Diabetes Mellitus, Type 2, Dysbiosis, Energy Metabolism, Gastrointestinal Microbiome, Inflammation, Inflammatory Bowel Diseases, Insulin Resistance, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microbiota, Obesity, Receptors, Ghrelin, ghrelin, growth hormone secretagogue receptor (GHS-R), aging, microbiome, gut permeability, ulcerative colitis, inflammatory bowel disease (IBD)

Abstract

Chronic low-grade inflammation is a hallmark of aging, which is now coined as inflamm-aging. Inflamm-aging contributes to many age-associated diseases such as obesity, type 2 diabetes, cardiovascular disease, and inflammatory bowel disease (IBD). We have shown that gut hormone ghrelin, via its receptor growth hormone secretagogue receptor (GHS-R), regulates energy metabolism and inflammation in aging. Emerging evidence suggests that gut microbiome has a critical role in intestinal immunity of the host. To determine whether microbiome is an integral driving force of GHS-R mediated immune-metabolic homeostasis in aging, we assessed the gut microbiome profiles of young and old GHS-R global knockout (KO) mice. While young GHS-R KO mice showed marginal changes in Bacteroidetes and Firmicutes, aged GHS-R KO mice exhibited reduced Bacteroidetes and increased Firmicutes, featuring a disease-susceptible microbiome profile. To further study the role of GHS-R in intestinal inflammation in aging, we induced acute colitis in young and aged GHS-R KO mice using dextran sulfate sodium (DSS). The GHS-R KO mice showed more severe disease activity scores, higher proinflammatory cytokine expression, and decreased expression of tight junction markers. These results suggest that GHS-R plays an important role in microbiome homeostasis and gut inflammation during aging; GHS-R suppression exacerbates intestinal inflammation in aging and increases vulnerability to colitis. Collectively, our finding reveals for the first time that GHS-R is an important regulator of intestinal health in aging; targeting GHS-R may present a novel therapeutic strategy for prevention/treatment of aging leaky gut and inflammatory bowel disease.