M. Viladomiu1, M. Metz1, S. Lima1, C.J. Guo1, K. Simpson2, E. Scherl1, R. Longman1
1Weill Cornell Medicine, Medicine, New York, USA, 2Cornell University, Veterinary Medicine, Ithaca, USA
Background
Our lab has recently shown that adherent-invasive E. coli (AIEC), which is enriched in patients with Crohn’s disease, is sufficient to induce intestinal Th17 cell inflammation. Although AIEC lack pathogenic factors including type III secretion systems, virulence-associated metabolic enzymes, including propanediol dehydratase (PduC), enable AIEC to use fucose-derived propanediol as an alternate carbon source in the gut. We hypothesised that this propanediol utilisation pathway functionally modulates AIEC contribution to intestinal tissue immunity and inflammation.
Methods
We generated pduC-deficient (ΔpduC) and catalytically inactive pduC (pduC*) mutants of a patient-derived, AIEC isolate. Gnotobiotic and genetic mouse models were used to evaluate the cellular and metabolic contribution of pduC to mucosal Th17-cell inflammation.
Results
We found that pduC is enriched in the microbiome and within E. coli genomes in Crohn’s disease patients compared with healthy controls. Mono-colonisation of mice with pduC-deficient AIEC resulted in reduced, inflammatory Th17 cells and attenuated weight loss using a T-cell transfer colitis model. Using mouse models for inducible deletion of CX3CR1+mononuclear phagocytes (MNPs) or IL10-deficiency, we found that MNPs are required for AIEC-mediated induction of Th17 cells and that IL-10 is required to restrain pduC-dependent colitis. Using a catalytically inactive mutant in mono-colonised mice, we determined that PduC metabolic activity was required for this immune phenotype. Cell-free supernatants from WT AIEC (but not pduC-deficient AIEC) promoted ex vivo Th17 cell polarisation and LC-MS of these supernatants defined PduC-dependent metabolites capable of promoting Th17 polarisation.
Conclusion
These data reveal a link between AIEC microbial metabolism and inflammatory Th17 cells with the potential to serve as a therapeutic target for tissue inflammation in the treatment of Crohn’s disease.
