Age-related changes in intestinal immunity and the microbiome

Abstract

The gastrointestinal (GI) tract is a vitally important site for the adsorption of nutrients as well as the education of immune cells. Homeostasis of the gut is maintained by the interplay of the intestinal epithelium, immune cells, luminal Ags, and the intestinal microbiota. The well-being of the gut is intrinsically linked to the overall health of the host, and perturbations to this homeostasis can have severe impacts on local and systemic health. One factor that causes disruptions in gut homeostasis is age, and recent research has elucidated how critical systems within the gut are altered during the aging process. Intestinal stem cell proliferation, epithelial barrier function, the gut microbiota, and the composition of innate and adaptive immune responses are all altered in advanced age. The aging population continues to expand worldwide, a phenomenon referred to as the "Silver Tsunami," and every effort must be made to understand how best to prevent and treat age-related maladies. Here, recent research about changes observed in the intestinal epithelium, the intestinal immune system, the microbiota, and how the aging gut interacts with and influences other organs such as the liver, lung, and brain are reviewed. Better understanding of these age-related changes and their impact on multi-organ interactions will aid the development of therapies to increase the quality of life for all aged individuals.

Keywords: epithelium; inflammaging; inflammation; liver; lung; microbiome.

Figure 1.. Alterations in the intestinal epithelium and immune cells with advanced age.

The intestinal epithelium is arranged into crypts and villi. Crypt base columnar stem cells reside at the base of the crypt and asymmetrically divide to give rise to stem cells and rapidly dividing cells that make up the transit amplifying region, which differentiate as they move up the crypt. The +4 label retaining, or “reserve,” stem cells reside at the boundary between the crypt base columnar stem cells and the transit amplifying region and can repopulate the crypt base columnar stem cells if they are lost. As the host enters advanced age, a multitude of changes occur, leading to overall increased inflammation. GIP: Glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide ILC : Innate lymphoid cell IgA : Immunoglobulin A

Figure 2.. The ‘leaky gut’ model of aging and inflammation.

Age-related intestinal microbial dysbiosis leads to reductions in commensal bacteria-derived short-chain fatty acids (SCFAs), increases in lipopolysaccharide (LPS) production, and decreased secondary bile acid production. Loss of SCFAs results in degradation of the intestinal barrier, leakage of bacterial products and other pro-inflammatory luminal and mucosal debris, leading to inflammation and further dysbiosis in a feed-forward cycle. TNFα: tumor necrosis factor alpha CRP: C-reactive protein IL-6, IL-1β, IL-18: Interleukin-1, Interleukin-1 beta, Interleukin-18