Commensal bacteria regulate host TGF-β and retinoic acid metabolism to promote intestinal homeostasis.

Abstract TGF-β signaling and retinoic acid (RA) metabolism are essential to intestinal homeostasis, but the mechanisms by which the microbiota influence these host processes are not clear. We have previously reported a mouse model of cow’s milk allergy (CMA) in which germ-free mice were colonized with the fecal microbiota of healthy infants or infants with CMA. That study revealed that Tgfbr3was part of an ileal transcriptomic signature that distinguished healthy from CMA-colonized mice. Follow-up experiments using RT-qPCR confirmed that Tgfbr3expression was significantly higher in the ileum of healthy-colonized than CMA-colonized mice. Tgfbr3encodes a TGF-β co-receptor, and its expression is reported to be induced by RA; genes in the CMA transcriptomic signature encode enzymes with RA catabolic activity (Cyp2c29, Cyp2b10, Cyp3a59, and Akr1c19). The expression of RA-catabolic enzymes and concurrent downregulation of Tgfbr3led us to hypothesize that these distinct microbiotas differentially modulate host RA metabolism, and consequently influence TGF-β signaling through the induction of Tgfbr3. In support of this hypothesis, we found lower ileal expression of Aldh1a1in CMA-colonized mice, suggesting a lower capacity to produce RA. Furthermore, Tgfbr3expression correlated with the transcript levels of TGF-β pathway mediators, Smad3and Smad7, both of which are increased in the ileum of healthy-colonized mice. Ongoing experiments will use single cell RNA-sequencing to identify the cell populations responsible for the differential expression of Tgfbr3in the ileum and to characterize the microbial mechanisms responsible for modulating host RA metabolism. Supported by NIH R01 AI146099 Supported by NIH R01 AI146099