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

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.

Deletion of ghrelin alters tryptophan metabolism and exacerbates experimental ulcerative colitis in aged mice

“…Consistent with a role for endogenous ghrelin in intestinal homeostasis, we recently showed that deletion of its receptor growth hormone secretagogue receptor (GHS-R) led to gut dysbiosis in an age-dependent manner, and also showed increased susceptibility to DSS-induced colitis. 62 At the phylum level, the ratio of Firmicutes and Bacteroidetes (F/B ratio) was similar in young but increased in older GHS-R KO mice. At the family level, young GHS-R KO mice showed lower Lachnospiraceae and Prevotellaceae , but higher Erysipelotrichaceae .…”

“…63 In addition, DSS-induced colitis was exacerbated in both young and older GHS-R KO mice, with older GHS-R KO showing more severe disease activity than young GHS-R KO mice. 62 Collectively, these data suggested that endogenous ghrelin signaling has an important role in maintaining intestinal homeostasis.…”

Berberine Depresses Inflammation and Adjusts Smooth Muscle to Ameliorate Ulcerative Colitis of Cats by Regulating Gut Microbiota

“…For instance, with the highest relative abundance of microbiota, Bacteroidetes was increased and Firmicutes was decreased by DSS. The increase of Bacteroidetes and the ratio of Bacteroidetes / Firmicutes are the indicators of IBD ( 17 , 46 , 47 ). Our results showed that BBR can decrease Bacteroidetes and increase Firmicutes in DSS-induced cats.…”

Potential role of ghrelin in the regulation of inflammation

“…Similarly, an in vitro study expounded that exogenous ghrelin prevents gastric mucosal inflammatory responses to Helicobacter pylori by controlling p38 phosphorylation and Src/Akt‐dependent up‐regulation of constitutive nitric oxide synthase 98 . Additionally, the lack of GHSR exacerbates dextran sulfate sodium (DSS)‐induced acute colitis in GHSR knockout mice by increasing the levels of inflammatory cytokines and reducing gap junction proteins, consistent with colonic inflammation and intestinal permeability 81 . Moreover, other previous studies have shown that the administration of ghrelin decreases inflammation‐induced colorectal carcinogenesis in mice 99 …”