Abstract Background Over the past decade, therapeutic goals in ulcerative colitis (UC) have shifted from mere symptom control towards achieving deeper, multidimensional remission. This has led to a critical re-evaluation of the validity of traditional single endpoints in representing disease activity and therapeutic success 1,2. A Delphi consensus process has proposed a new concept of comprehensive disease control (CDC), combining multiple clinical, endoscopic, and patient-centered endpoints to define a state of disease inactivity 3. We hypothesized that this stringent combined endpoint might identify a molecular signature of minimal residual inflammation. To test this, we analyzed mRNA and mucosa-associated microbiota signatures in a cohort of UC patients across different remission categories. Methods A total of 211 colonic biopsies were collected from 173 UC patients between 2010 and 2020 at Kiel University Hospital. Bulk mRNA sequencing and mucosal 16S rRNA analysis was performed. Patients were categorized according to the following remission criteria: Biochemical: CRP 5mg/dL and leukocytes 2.5–9/nL; Clinical: pMayo 0–1; Histological: Nancy Index 0–1; Endoscopic: eMayo 0. Patients fulfilling all the above remission criteria were defined as achieving CDC. A random forest approach (80% training/20% testing) was iteratively applied to identify molecular features predictive of CDC. Results Microbial and transcriptomic data reflected gradients of inflammation. Comparative analyses revealed overlapping yet distinct molecular and microbial signatures across individual and combined remission categories. None of the 31 CDC patients required IBD-related hospitalization or surgery during 2-year follow-up, supporting its relevance as a state of deep disease inactivity. Linear mixed model analysis identified IBD-related Lachnoclostridium and Lachnospiraceae FC020 as differentially abundant in CDC. Transcriptomic profiling identified a molecular gradient between CDC and non-CDC patients, enriched for pathways related to fatty acid metabolism and downregulated immune responses. The random forest model identified 19 transcriptomic features predictive of CDC (AUC 0.856), including CXCL1, KRT7, SLC6A14, ESRRA, FGFR3, ITPKA, which were previously linked with IBD and regulated in line with existing literature. Conclusion CDC represents a biologically, deeply inactive state of UC that extends to the molecular and microbial level of the intestinal mucosa. The molecular gradient signature points to a continuum of mucosal healing and supports the development of objective biomarkers capable of quantifying minimal residual disease activity. Validation of this molecular signature in external cohorts will clarify its prognostic relevance for long-term disease outcomes. References: 1. Schreiber, S., et al., Rise of precision medicine: can it deliver on its promise in IBD? Gut, 2025 2. Argmann, C., et al., Molecular Characterization of Limited Ulcerative Colitis Reveals Novel Biology and Predictors of Disease Extension. Gastroenterology, 2021. 161(6): p. 1953-1968 e15. 3. Schreiber, S., et al., Defining Comprehensive Disease Control for Use as a Treatment Target for Ulcerative Colitis in Clinical Practice: International Delphi Consensus Recommendations. J Crohns Colitis, 2024. 18(1): p. 91-105. Conflict of interest: Hinrichsen, Finn: Received travel support from Pfizer. Holds shares in 10x Genomics Received research material from CatalYm P. Bernardes, Joana: I have no conflict of interest to declare Lopez Agudelo, Victor Alonso: No conflicts Mishra, Neha: none Welz, Lina: Received support from Celltrion for independent reporting from scientific congresses. Tran, Florian: Grant: Sanofi/Regeneron Personal Fees: Speaker’s fees: Abbvie, Bristol-Myers-Squibb, Celltrion Healthcare, Dr Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, J & J, Sanofi, Takeda Consulting honoraria: AbbVie, J & J, Takeda Non-financial Support: Sanofi for statistical analysis Aden, Konrad: Personal Fees: Lecture fee: Takeda, Janssen, Lilly, Abbvie Consulting fee: Takeda, Jannsen, Lilly, Guidepoint Schreiber, Stefan Wolfgang: Personal Fees: AbbVie, Alfasigma, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol Meyers Squibb, Celgene, Celltrion, Falk, Ferring, Fresenius Kabi, Galapagos, Gilead, IMAB, Janssen, Lilly, MSD, Mylan, Novartis, Pfizer, Protagonist, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance Rosenstiel, Philip: stock ownership Gerion
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