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.
Highlights
Aging is symbolized by chronic low-grade inflammation, the term inflammaging has been created [1]
We previously showed that the effects of ghrelin on growth hormone release and food intake are mediated through growth hormone secretagogue receptor (GHS-R) [28], but the role of GHS-R in aging-associated microbiome change and intestinal inflammation is unknown
To decipher the controversial effects of ghrelin signaling on intestinal inflammation and to determine whether GHS-R regulates microbiome-host interaction, in the current study we investigated the role of GHS-R on gut dysbiosis and intestinal inflammation in aging using GHS-R global knockout mice (KO, Ghsr−/− ) with GHS-R ablated in all cell types
Summary
Aging is symbolized by chronic low-grade inflammation, the term inflammaging has been created [1]. Inflamm-aging is linked to many age-associated diseases such as obesity, type 2 diabetes, cardiovascular disease, and various inflammatory diseases. Gut microbiome interacts with the host to modulate intestinal immunity and the host’s disease susceptibility. The microbiota profile is shaped by multifaceted factors, including diet, age, host genetics, environmental factors, and lifestyles; there is huge variation in microbiome signatures among individuals [2,3,4]. Emerging evidence shows that gut microbiome plays an immense role in the biology of aging [5,6].
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