OP19 Corticosteroid response rectal gene signature and associated microbial variation in treatment naïve ulcerative colitis
Y. Haberman*1,2, R. Karns2, P. Dexheimer2, M. Schirmer3, T. Braun1, M. Collins2, A. Mo4, M. Rosen2, N. Gotman5, PROTECT Study group, S. Kugathasan6, T. D. Walters7, G. Gibson4, S. Davis Thomas5, C. Huttenhower8, R. J. Xavier9, J. S. Hyams10, L. A. Denson2
1Sheba Medical Center, Tel Hashomer, Israel, 2Cincinnati Children Hospital Medical Center, Cincinnati, USA, 3Broad Institute of MIT and Harvard University, Cambridge, USA, 4Georgia Institute of Technology, Atlanta, USA, 5University of North Carolina, Chapel Hill, USA, 6Emory University, Atlanta, USA, 7Hospital For Sick Children, Toronto, Canada, 8Harvard School of Public Health, Boston, USA, 9Broad Institute of MIT and Harvard University, Boston, USA, 10Connecticut Children’s Medical Center, Hartford, USA
Molecular mechanisms driving disease course and response to initial therapy in ulcerative colitis (UC) are poorly understood. In the full PROTECT cohort, the strongest predictor of corticosteroids (CS)-free remission by Weeks 12 or 52 was Week 4 (WK4) remission. We used pre-treatment rectal biopsies in new-onset UC, and defined key pathways linked to WK4 response to standardised induction with CS in the largest prospective paediatric UC cohort to date.
PROTECT enrolled 428 newly diagnosed paediatric UC patients at 29 North American sites. mRNA-Seq and 16S rRNA defined pre-treatment rectal gene expression and microbial communities in 206 participants. Independent group of 50 participants were used to validate the CS response gene signature. WK4 remission was defined as PUCAI < 10 without additional therapy/colectomy.
Moderate–severe UC patients (152/206) from the discovery cohort and all 50 from the validation cohort received standardised induction therapy with CS. WK4 remission was achieved in 75/152 (49%) and 21/50 (42%) of the discovery and validation groups respectively. 115 genes were differentially expressed (FDR<0.05 and FC ≥1.5) between moderate–severe UC patients who did or did not achieve WK4 remission in the discovery cohort. The corticosteroid response gene signature is highly associated with CXCR chemokines (
We identified a gene signature linked to WK4 CS response, which was validated in independent UC patients, and showed associations with response to anti-TNFα and anti-α4β7 integrin in adults, and with specific microbial taxa. Our data may prioritise future therapies for non-responders to current approaches.