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

• Authors: Domonica N. Powell, Emory University; Alyson Swimm, Emory University; Robert Sonowal, Emory University; Alexis Bretin, Georgia State University; Andrew Gewirtz, Emory University; Rheinallt Jones, Emory University; Daniel Kalman, Emory University
• Journal Title: Proceedings of the National Academy of Sciences of the United States of America
• Volume: Volume 117, Number 35
• Publisher: National Academy of Sciences | 2020-09-01, Pages 21519-21526
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1073/pnas.2003004117
• Subjects: Biology, Cell; Physics, Molecular; Engineering, Biomedical; Health Sciences, Pathology
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; aging; intestinal homeostasis; goblet cell; mucus; Aryl hydrocarbon receptor; Intestinal inflammation; Systemic inflammation; Mice; Mucus; Cells; Interleukin-10; Homeostasis; Dysfunction; Dysbiosis

Abstract

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.