P1320 Longitudinal metagenomic profiling reveals early microbial changes during infliximab response in IBD.

Abstract Background Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is a multifactorial chronic inflammatory disorder driven by dysregulated immune-microbiota interactions. Response to targeted therapies such as anti-TNF varies widely, with nearly one-third of patients failing to achieve remission. This variability not only affects patient outcomes but also leads to high costs and risks due to unnecessary drug exposure. Therefore, it is critical to identify early factors or biomarkers that can predict treatment response at an early stage. While early blood-based predictors have been studied, the role of the gut microbiome in early therapeutic outcomes remains unclear. In this work, we aim to identify early taxonomic and metabolic functions as potential biomarkers of remission in UC and CD patients treated with infliximab. Methods Metagenomic sequencing was performed on stool samples collected from 85 IBD patients (47 UC, 38 CD) enrolled in the GUIDE-IBD Clinical trial cohort at weeks 0, 2, and 14 of anti-TNF (infliximab) treatment. First, we characterized longitudinal microbial diversity and community composition. Then, a differential abundance analysis using mixed-effect linear models allowed us to identify taxa associated with different remission calls at week 14 (Clinical, Endoscopic, and Biochemical remission). Results At baseline, UC patients who achieved remission at week 14 showed lower microbial diversity compared to non-remitters, but alpha diversity increased by week 2, approaching the profiles of healthy-like microbiota by week 14 (Shannon index p 0.05). This trend in alpha diversity was not observed in CD individuals. In addition, beta-diversity analysis confirmed distinct compositional trajectories between remitters and non-remitters (PERMANOVA F = 5.18, p = 0.00009) in both CD and UC. Overall, early enrichment of butyrate-producing taxa, including Faecalibacterium group (F. prausnitzii, F. duncaniae, F. intestinalis), Blautia sp., and Odoribacter splanchnicus, characterized remitters at baseline, whereas non-remitters showed dominance of proteobacteria taxa such as Mesosutterella massiliensis. This was reflected by the enrichment of metabolic functions in relation to SCFA synthesis and branched-chain amino acids, which are known to support intestinal homeostasis. Conclusion Our longitudinal metagenomic analysis shows that the early increase of short-chain fatty acid-producing bacteria during anti-TNF is a hallmark of successful therapy. These microbial changes precede clinical improvement, highlighting their potential as early, non-invasive biomarkers to guide therapeutic decision-making in IBD. Conflict of interest: Dr. Lopez Agudelo, Victor Alonso: No conflicts 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 Florea, Marina: Takeda Pharma Vertrieb GmbH, Abbvie, Dr. Falk Pharma, Galapagos Biopharma Germany GmbH/Alfasigma, Janssen Pharmaceutica Wiestler, Miriam: Financial compensation for lectures, advisory boards, other medical-scientific services by: AbbVie, Alfasigma, CED Service, Dr. Falk Pharma, FomF Forum für medizinische Fortbildung, FORUM Institut für Management GmbH, Johnson & Johnson, Lilly Deutschland GmbH, Pfizer, Takeda Pharma. Rühlemann, Malte: No conflicts Moitinho E Silva, Lucas: No conflicts Groussin, Mathieu: No conflicts Waschina, Silvio: No conflicts Wacker, Eike Matthias: No conflicts Meneses, Rui: No conflicts Verspecht, Chloë: No conflicts Reniers, Iris: No conflicts Ekhlas, Daniel: No conflicts Raes, Jeroen: JR has received grants from Beneo, Cargill, Colruyt group, Danone, DSM, J&J, MRM/Prodigest, Nestle, Pfizer, Takeda and VectivBio and has received consulting and/or speaking fees from Aphea, Biofortis, DSM-Firmenich, Ferring, GSK, Janssen Pharmaceuticals, Metagenics, MSD, MRM/Prodigest, Nutricia, Takeda, Tsumura Huber, Samuel: SH received personal compensation and fees for lectures and consultations as well as travel costs from Janssen Cilag, AbbVie, Ferring, Falk Foundation, Galapagos, Lilly, Bristol-Myers Squibb, and Ardeypharm GmbH Seidler, Ursula: No conflict of interest 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