Abstract Background Immune suppression with advanced biologics or small-molecule therapies is the recommended treatment for Crohn’s Disease (CD). However, biologics do not cure CD, and a significant portion of patients experience flares of disease despite treatment, for reasons that are still largely elusive. We aimed to identify dietary and gut signals during Crohn’s disease (CD) remission that differ from the healthy state to highlight targets that may improve disease control and clearance. Methods We analyzed diet, ileal transcriptomics, microbiomics, and metabolomics across patients with CD in remission, patients with active CD, and non-IBD controls as the reference for healthy signals. Results 191 subjects were included; 77 CD patients in remission in stable clinical remission for at least three months, with the majority (81%) receiving biologic therapy (Fig. 1A). Non-IBD controls (n = 77) were used as a reference for normal signals. We also compared these groups to data from 37 active, mostly treatment-naïve CD patients at diagnosis, before any IBD-related therapies or dietary guidance. Ileal transcriptomics revealed a significant decrease in genes and pathways associated with adaptive T-cells and innate granulocytes during remission, which was notably deeper than the levels seen in control subjects, impairing host mucosal immune response (Fig. 1B-E). Despite this observed mucosal ileal immune suppression, patients in remission showed an increase in the expression of epithelial antimicrobial pathways and related genes, including DUOX2, along with a rise in genes associated with goblet cells and mucin glycosylation. These signals during remission coincided with a persistent pathogenic gut microbial composition, metabolic alterations, and less healthy dietary habits (Fig. 2), which were characterized by a higher intake of ultra-processed foods and lower consumption of fiber, folate, vitamin C, and vegetables. Greater exposure to ultra-processed foods was significantly associated with more dysbiotic gut signals and negatively correlated with genes enriched for mucin glycosylation, which is essential for maintaining gut barrier homeostasis. Conclusion Perturbations in dietary, ileal, microbial, and metabolic signatures persist during CD remission despite advanced, effective immune treatments. These findings likely underline the remitting-relapsing nature of CD and suggest that interventions targeting diet, epithelial health, microbial, and metabolic functions may promote deeper, longer-lasting remission states. Conflict of interest: Braun, Tzipi: No conflict of interest Levhar, Nina: No conflict of interest Efroni, Gilat: No conflict of interest Hadar, Rotem: No conflict of interest Jessula Levy, David: No conflict of interest Talan Asher, Adi: No conflict of interest Ungar, Bella: No conflict of interest Picard, Orit: No conflict of interest Yablecovitch, Doron: No conflict of interest Kopylov, Uri: Grant: Takeda, Janssen,Abbvie, Medtronic, Ely Lilly Other: Takeda, Janssen, Ely Lilly, Roche, Celtrion, Abbvie, Medtronic, CTS, Pfizer, BMS- speaker and advisory fees Eliakim, Rami: No conflict of interest Ben-Horin, Shomron: Grant: Abbvie, Takeda, Janssen, Celltrion, Pfizer, Medtronic, Galmed, OutSense Personal Fees: Advisory board and/or consulting and/or Speaker fees from Abbvie, Takeda, Janssen, Celltrion, Pfizer, GSK, Ferring, Novartis, Roche, Gilead, NeoPharm, EviNature, Galmed, Medial Earlysign, BMS, Pfizer, Falk, Medtronic and Eli Lilly. Options/stocks in Predicta Med, Evinature, Galmed, Alma Therpeautics. Amir, Amnon: No conflict of interest Prof. Haberman Ziv, Yael: Grant: ECCO, CCF, ISF, I-Core, Helmsley, ERC, NIH.
Braun et al. (Thu,) studied this question.