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

• Published in: International journal of molecular sciences 2022-02, Vol.23 (4), p.2219
• Main Authors: Noh, Ji Yeon, Wu, Chia-Shan, DeLuca, Jennifer A A, Devaraj, Sridevi, Jayaraman, Arul, Alaniz, Robert C, Tan, Xiao-Di, Allred, Clinton D, Sun, Yuxiang
• Format: Article
• Language: English
• Subjects: Ablation; Age; Aging; Aging (artificial); Aging - metabolism; Animals; Bacteroidetes; Cardiovascular diseases; Colitis; Colitis - metabolism; Colon; Cytokines; Cytokines - metabolism; Dextran; Dextran sulfate; Dextrans; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - metabolism; Digestive system; Disease; Dysbacteriosis; Dysbiosis - metabolism; Energy metabolism; Energy Metabolism - physiology; Feces; Firmicutes; Gastrointestinal Microbiome - physiology; Genotype & phenotype; Ghrelin; growth hormone secretagogue receptor (GHS-R); Growth hormones; gut permeability; Homeostasis; Inflammation; Inflammation - metabolism; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory Bowel Diseases - metabolism; Insulin Resistance - physiology; Intestinal microflora; Intestine; Male; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Mice, Knockout; microbiome; Microbiomes; Microbiota; Microbiota - physiology; Obesity - metabolism; Pathogenesis; Receptors, Ghrelin - metabolism; Rodents; ulcerative colitis
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23042219

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.