Indoles from the commensal microbiota act via the AHR and IL-10 to tune the cellular composition of the colonic epithelium during aging

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 35; pp. 21519 - 21526
• Main Authors: Powell, Domonica N., Swimm, Alyson, Sonowal, Robert, Bretin, Alexis, Gewirtz, Andrew T., Jones, Rheinallt M., Kalman, Daniel
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 01-09-2020
• Subjects: Aging; Aging (artificial); Aging - metabolism; Aldehydes; Animals; Aromatic compounds; Bacteria - metabolism; Biological Sciences; Cell differentiation; Cell Differentiation - drug effects; Cell proliferation; Colon; Colonization; Composition; Cytokines; Differentiation (biology); Epithelial cells; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - microbiology; Epithelium; Female; Goblet cells; Goblet Cells - cytology; Goblet Cells - drug effects; Goblet Cells - metabolism; Goblet Cells - microbiology; Homeostasis; Indoles; Indoles - pharmacology; Interferon; Interleukin 10; Interleukin 22; Interleukin-10 - biosynthesis; Interleukin-10 - metabolism; Interleukins - metabolism; Intestine; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Microbiota; Microbiota - physiology; Mucus - metabolism; Receptors, Aryl Hydrocarbon - metabolism; Signal Transduction; Signaling; intestinal homeostasis; aging; goblet cell; mucus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2003004117

The intestinal epithelium is a highly dynamic structure that rejuvenates in response to acute stressors and can undergo alterations in cellular composition as animals age. The microbiota, acting via secreted factors related to indole, appear to regulate the sensitivity of the epithelium to stressors and promote epithelial repair via IL-22 and type I IFN signaling. As animals age, the cellular composition of the intestinal epithelium changes, resulting in a decreased proportion of goblet cells in the colon. We show that colonization of young or geriatric mice with bacteria that secrete indoles and various derivatives or administration of the indole derivative indole-3 aldehyde increases proliferation of epithelial cells and promotes goblet cell differentiation, reversing an effect of aging. To induce goblet cell differentiation, indole acts via the xenobiotic aryl hydrocarbon receptor to increase expression of the cytokine IL-10. However, the effects of indoles on goblet cells do not depend on type I IFN or on IL-22 signaling, pathways responsible for protection against acute stressors. Thus, indoles derived from the commensal microbiota regulate intestinal homeostasis, especially during aging, via mechanisms distinct from those used during responses to acute stressors. Indoles may have utility as an intervention to limit the decline of barrier integrity and the resulting systemic inflammation that occurs with aging.