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

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...

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Published in:Immunity (Cambridge, Mass.) Mass.), 2018-12, Vol.49 (6), p.1103-1115.e6
Main Authors: Grizotte-Lake, Mayara, Zhong, Guo, Duncan, Kellyanne, Kirkwood, Jay, Iyer, Namrata, Smolenski, Irina, Isoherranen, Nina, Vaishnava, Shipra
Format: Article
Language:English
Subjects:
Alcohol Oxidoreductases - genetics
Alcohol Oxidoreductases - metabolism
Animal tissues
Animals
antimicrobials
Bacteria
Bacteria - classification
Bacteria - genetics
Clonal deletion
Colonization
colonization resistance
commensal
Commensals
Cytokines
Deoxyribonucleic acid
Digestive system
Digestive tract
DNA
Dysbacteriosis
dysbiosis
Dysbiosis - metabolism
Dysbiosis - microbiology
Epithelial cells
Epithelial Cells - metabolism
Epithelial Cells - microbiology
Genes
Genomics
Germfree
Host Microbial Interactions
IECs
IL-22
Immune response
Immune system
Interleukin 22
Interleukins - metabolism
Intestinal Mucosa - cytology
Intestinal Mucosa - metabolism
Intestinal Mucosa - microbiology
Intestine
Liver
Lymphocytes
Lymphocytes - metabolism
Lymphocytes - microbiology
Metabolism
Metabolites
Mice
Mice, Inbred C57BL
Mice, Knockout
Microbial activity
Microbiota - genetics
Microbiota - physiology
Microorganisms
Oxidation
Physiology
RA-signaling
Rdh7
Retinoic acid
Retinol dehydrogenase
RNA, Ribosomal, 16S - genetics
Salmonella
Salmonella typhimurium - genetics
Salmonella typhimurium - physiology
Small intestine
Software
Symbiosis
Synthesis
Transcription
Tretinoin - metabolism
Variance analysis
Vitamin A
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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. [Display omitted] •Gut commensals curb retinoic acid production by suppressing expression of Rdh7 in IECs•IEC-specific Rdh7 expression is required for IL-22 production by gut lymphocytes•Rdh7ΔIEC mice have diminished IL-22-induced antimicrobial response•Rdh7ΔIEC mice are protected from pathogen colonization and microbial dysbiosis Grizotte-Lake et al. define a mechanism that regulates production of the vitamin A metabolite retinoic acid (RA), a key immunomodulator in the gut. Commensal bacteria suppress RA synthesis by the intestinal epithelium, which in turn results in the control of IL-22 activity and the prevention of microbial dysbiosis during pathogen colonization.
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2018.11.018