Ageing, metabolism and the intestine

Abstract

The intestinal epithelium serves as a dynamic barrier to the environment and integrates a variety of signals, including those from metabolites, commensal microbiota, immune responses and stressors upon ageing. The intestine is constantly challenged and requires a high renewal rate to replace damaged cells in order to maintain its barrier function. Essential for its renewal capacity are intestinal stem cells, which constantly give rise to progenitor cells that differentiate into the multiple cell types present in the epithelium. Here, we review the current state of research of how metabolism and ageing control intestinal stem cell function and epithelial homeostasis. We focus on recent insights gained from model organisms that indicate how changes in metabolic signalling during ageing are a major driver for the loss of stem cell plasticity and epithelial homeostasis, ultimately affecting the resilience of an organism and limiting its lifespan. We compare findings made in mouse and Drosophila and discuss differences and commonalities in the underlying signalling pathways and mechanisms in the context of ageing.

Keywords: ageing; epithelial barriers; intestinal homeostasis; metabolism; stem cells.

Figure 1. The gut functions as a dynamic barrier to the environment with signal integration properties

The gut functions as a chemical and physical barrier to the environment and serves as an integration site to respond to diverse intrinsic as well as extrinsic stimuli. These stimuli display a wide range of metabolites, age‐related changes, microbiota as well as inflammation‐associated processes. The resulting functional consequences include adaption in stem cell and proliferation, immune responses, reinforcement of the barrier function, cellular senescence as well as stem cell exhaustion. Functional consequences constantly affect the epithelial homeostasis and subsequently the barrier function of the intestine, eventually leading to epithelial barrier defects.

Figure 2. Schematic representation of the anatomy of Drosophila and mouse intestine

(A) The Drosophila digestive tract is composed of foregut, midgut and hindgut. The cell types in the adult intestine include: stem cells (SC), enteroblasts (EB), enterocytes (EC) and enteroendocrine cells (EE). The intestinal epithelium is surrounded by visceral muscles and peritrophic membrane that separates the intestinal cells from bacteria presented in the lumen. (B) The epithelium of the mouse small intestine is structured into the crypt region, the transit amplifying (TA) region and the villus region. Stem cells (SC) of the intestine are located in the crypts and are surrounded by Paneth cells (PC), which provide essential growth factors to the SC and are part of the stem cell niche. Transit amplifying cells that have left the crypt region are pushed upwards to the villi and driven towards differentiation in the different cell types of the intestinal epithelium, including goblet cells (GC), enteroendocrine cells (EE), tuft cells, M cells and enterocytes (EC). The intestinal epithelium is underlined by a muscle layer and mesenchyme.

Figure 3. The interplay between metabolism, homeostasis and ageing in Drosophila intestine

(A) Intestinal local signals control stem cell division and metabolism to maintain tissue homeostasis. Specifically, metabolic and signalling influxes influence downstream pathways in various cell types to regulate stem cell activity. (B) The pathways involved in autophagy, growth and metabolism improve intestinal function during ageing and extends animal lifespan. (C) The effects of diet restriction on intestinal barrier function and ageing. Blue arrows indicate an upregulation, and red arrows indicate a downregulation.

Figure 4. The interplay between metabolism, homeostasis and ageing in the mouse intestine

(A) Extrinsic metabolic changes, such as dietary interventions, and intrinsic metabolic states influence the epithelial homeostasis of the intestine. The response of the epithelium to metabolic changes includes stem cell function and renewal capacity, progenitor differentiation and fate determination as well as increased cancer risk. (B) Effects of ageing on the epithelial homeostasis in the mouse intestine include diminished stem cell function and renewal capacity as well as impaired epithelial turnover rate and homeostasis. (C) The effects of metabolites and metabolic changes on ageing‐related phenotypes include induced cellular stress, stem cell rejuvenation, improved epithelial turnover rate and stem cell function as well as impaired villus and stem cell function. Blue arrows indicate an upregulation, red arrows indicate a downregulation, dashed lines indicate suggested biological function, and solid lines indicate shown biological function.

Figure 5. Ageing‐associated intestinal barrier failure

(A) Under normal homeostasis, the intact and healthy intestinal barrier maintains epithelial function and prevents bacterial translocation. (B) Ageing causes septate junctions loss, intestinal barrier dysfunction, microbial dysbiosis, systemic infection and animal death.