P1314 Multi-omics analysis of Crohn’s Disease trajectory from active to remission reveals that the altered ileal anti-bacterial epithelial signals and pathogenic microbial composition and metabolomics persist despite normalizing ileal immune signals during remission
Authors: Haberman Ziv Y , Braun T , Levhar N , Efroni G , Hadar R , Jessula Levy D , Talan Asher A , Unger B , Picard O , Yablecovitch D , Kopylov U , Denson L , Eliakim R , Ben-Horin S , Amir A ,   The Leona M & Harry B. Helmsley Charitable Trust Israeli IBD Research Nucleus (IIRN)
Published: January 2025

Abstract

Background
Characterizing gut factors that improve or persist during Crohn’s disease (CD) trajectory from active to remission to healthy-normal states is crucial for defining treatment targets and CD cure.

Methods
Using multi-omics (ileal transcriptomics, microbiome, and metabolomics), we aimed to compare active, mostly treatment naïve newly diagnosed CD to patients in remission, using controls as a reference

Results
193 subjects were included (median age 32 years, 60% male); 78 CD in remission, 38 active and mostly (80%) treatment naïve newly diagnosed CD patients, and 77 non-IBD controls (Table 1). Controls and CD remission groups had significantly lower and mostly normal CRP, with significantly lower fecal calprotectin in the remission than in the active group (Table 1). Most patients (79%) in remission were on biologics (58% on anti-TNF and 21% on vedolizumab/Stelara). Ileal transcriptomics (Fig. 1A-B) highlighted a significant reduction of genes and pathways related to adaptive T cell activation in treated patients in remission compared to active treatment naïve patients. This decrease was significantly lower than in controls, suggesting some immune compromise likely secondary to CD therapy. There were no differences between the levels of S1008/9 genes encoding for fecal calprotectin and OSM and TREM1 genes related to the anti-TNF response in patients in remission on treatment, compared to controls. Despite that, patients in remission still showed persistent signals of elevated expression of epithelial antimicrobial pathways and genes, including DUOX2, CEACAM5/6, REG4, and DMBT1, and more novel increased goblet cells and mucin glycosylated genes and signals (Fig. 1A-B). Interestingly, these epithelial antimicrobial signals during remission were coupled with persistent pathogenic gut microbial composition, as indicated by several microbial measurements, including the published Gevers et al index (PMID:24629344), our general health and specific IBD indexes (PMID:35197084), and alpha diversity (Fig. 1C), with significant enrichment of oral bacteria that dislocated to the gut in the CD groups. Similarly, 39 of 43 (91%) of the gut metabolites (Fig. 1D) that were significantly different between CD in remission vs. controls showed similar altered directionally in active treatment naïve CD patients vs. controls, suggesting persistent metabolic alterations during remission

Conclusion
Multi-omics analysis shows that despite normalizing ileal immune signals and genes encoding calprotectin during remission, the altered anti-bacterial epithelial signal and pathogenic microbiome and metabolome signatures persist. This highlights the need to directly target the epithelia-microbes axis, in addition to immune suppression, to improve CD outcomes.