Commensals Suppress Intestinal Epithelial Cell Retinoic Acid Synthesis to Regulate Interleukin-22 Activity and Prevent Microbial Dysbiosis

Abstract

Summary Retinoic acid (RA), a vitamin A metabolite, regulates transcriptional programs that drive protective or pathogenic immune responses in the intestine, in a manner dependent on RA concentration. Vitamin A is obtained from diet and is metabolized by intestinal epithelial cells (IECs), which operate in intimate association with microbes and immune cells. Here we found that commensal bacteria belonging to class Clostridia modulate RA concentration in the gut by suppressing the expression of retinol dehydrogenase 7 (Rdh7) in IECs. Rdh7 expression and associated RA amounts were lower in the intestinal tissue of conventional mice, as compared to germ-free mice. Deletion of Rdh7 in IECs diminished RA signaling in immune cells, reduced the IL-22-dependent antimicrobial response, and enhanced resistance to colonization by Salmonella Typhimurium. Our findings define a regulatory circuit wherein bacterial regulation of IEC-intrinsic RA synthesis protects microbial communities in the gut from excessive immune activity, achieving a balance that prevents colonization by enteric pathogens.

The interaction of intestinal microbiota and innate lymphoid cells in health and disease throughout life

“…Interestingly, microbiota is directly regulating the availability of RA . Specifically, Clostridia species influence epithelial RA synthesis . A similar population of RORyt + ILC3s is required to induce cryptopatches and intestinal lymphoid follicles (ILFs) after birth .…”

“…IFN‐y is key to fight the infection, and its expression has been reported to be shared by conventional NK cells as well as ILC3s during Salmonella infection in mice with T‐bet + CCR6 − RORγt + ILC3s being the strongest IFN‐y producers . In addition, intestinal IL‐22 expression triggered by intestinal epithelial cell‐derived RA affects antimicrobial peptide expression and bacterial load in S. typhimurium infection …”

“…21 Specifically, Clostridia species influence epithelial RA synthesis. 22 [23][24][25][26] Lin À IL-7Ra + Flt3 À a 4 b 7 + progenitors present in the fetal liver can give rise to ILC3s that can be found in the intestinal lamina propria at the time of birth. 27,28 The population of RORyt-expressing ILCs in the lamina propria shortly after birth consists of mainly CCR6 + c-kit hi LTi cells, which seed the intestinal lamina propria during fetal development, and low numbers of CCR6 À c-kit lo ILC3s that expand strongly within the first 2-4 weeks of birth and that can acquire NK cell markers.…”

Metabolism at the centre of the host–microbe relationship

“…However, IL-22 can promote colonization by other pathogens such as S. typhimurium by controlling growth of its niche competitor E. coli [112]. In a study by Grizotte-Lake et al [113] they found that commensal microbes suppress small intestinal epithelial expression of Rdh7, an enzyme required for retinoic acid (RA) production, resulting in reduced RA in SPF mice compared to germ-free mice. This effect was due to sporeforming Clostridia sp.…”

Influence of maternal microbiota during pregnancy on infant immunity

“…Similarly, maternal retinoic acid (RA) induces fetal type 3 innate lymphoid cells and therefore secondary lymphoid organ development [91]. in the gut can modulate RA concentration by suppressing the expression of retinol dehydrogenase 7 (Rdh7) in intestinal epithelial cells [92]. in the gut can modulate RA concentration by suppressing the expression of retinol dehydrogenase 7 (Rdh7) in intestinal epithelial cells [92].…”