Abstract Background The role of the gut microbiome in Inflammatory Bowel Disease (IBD) is unclear, particularly how it is influenced by IBD phenotype, and how it may influence disease severity or predict response to treatment. IBD-RESPONSE is a multi-centre observational study of medical therapy, collecting clinical data and stool metagenomes at baseline and during the first year of treatment in 1325 patients 1. Here, we report the first microbiome analysis of baseline (prior to initiation of the study treatment) data from the first 201 IBD-RESPONSE patients, aiming to identify the clinical, demographic and technical drivers of microbiome variation. Methods The baseline stools were sequenced using untargeted metagenomics. We analysed 25 baseline covariates, including clinical factors (diagnosis, surgeries, past and concurrent treatments), disease phenotype, PRO-2 symptom scores, demographics (age, sex, ethnicity) and technical variables (sequencing depth, batch). Reads underwent quality control, host-read removal, and taxonomic profiling using custom BioBakery pipelines 2. Common taxa (≥0.1% abundance in ≥ 10% of samples) were retained. Beta diversity (species level Bray–Curtis) associations with covariates were tested by PERMANOVA 3. Differential abundance was assessed by DESeq2 and ALDEx2; overlapping significant associations (FDR 0.05) were considered robust. All analyses were adjusted for age and sex. Results The 201 participants had a mean age of 43.5 years (range: 17.1–82.5); with slightly more females (52%) and a majority identifying as White (87%). Overall, 59% had Ulcerative Colitis (UC) and 41% had Crohn’s Disease (CD). Among 25 covariates assessed, disease diagnosis (R² = 0.024, adj. p = 0.0009), prior surgeries (R² = 0.032, adj. p = 0.0009), and mesalazine use (R² = 0.021, adj. p = 0.001) were the strongest drivers of overall microbiome variation (PERMANOVA). We identified six unique, robust species–covariate associations. Disease diagnosis (CD vs UC) showed four differentially abundant species: Ruminococcus gnavus and Faecalimonas umbilicata were enriched in CD, while two unclassified species within the Firmicutes phylum and class Clostridia were enriched in UC. Faecalibacterium prausnitzii and Romboutsia timonensis were both enriched in patients with ≥1 surgery. No other covariates showed robust species associations. Conclusion Disease phenotype (diagnosis and location) and clinical history (past surgeries and maintenance therapy) were the strongest drivers of microbiome variation. These are also known predictors of treatment response 4. Controlling for these covariates will be important to avoid confounding when testing for microbiome predictors of treatment response. Reference: Code availability: Analysis pipelines are available from https://github.com/OxfordCMS/ References: 1Wyatt, Nicola J et al. “Defining predictors of responsiveness to advanced therapies in Crohn’s disease and ulcerative colitis: protocol for the IBD-RESPONSE and nested CD-metaRESPONSE prospective, multicentre, observational cohort study in precision medicine.” BMJ open vol. 14,4 e073639. 17 Apr. 2024, doi:10.1136/bmjopen-2023-073639 2Beghini, Francesco et al. “Integrating taxonomic, functional, and strain-level profiling of diverse microbial communities with bioBakery 3.” eLife vol. 10 e65088. 4 May. 2021, doi:10.7554/eLife.65088 3Anderson et al. “A new method for non-parametric multivariate analysis of variance”. Austral Ecology, 26: 32–46. 28. February 2001, doi:10.1111/j.1442-9993.2001.01070.pp.x 4Julien Kirchgesner, Bram Verstockt, Michel Adamina, Kristine H Allin, Mariangela Allocca, Arno R Bourgonje, Johan Burisch, Glen Doherty, Parambir S Dulai, Alaa El-Hussuna, Ravi Misra, Nurulamin Noor, Valérie Pittet, Nick Powell, Iago Rodríguez-Lago, Sophie Restellini, ECCO Topical Review on Predictive Models on Inflammatory Bowel Disease Disease Course and Treatment Response, Journal of Crohn’s and Colitis, Volume 19, Issue 6, June 2025, jjaf073, https://doi.org/10.1093/ecco-jcc/jjaf073 Conflict of interest: Dr. Khan, Uzma: No conflict of interest Young, Greg: No conflict of interest Beck, Lauren: No conflict of interest Wyatt, Nicola: No conflict of interest Ahmad, Tariq: Tariq Ahmad reports grants, personal fees and non-financial support from F. Hoffmann-La Roche AG, Biogen Inc, Abbvie, Janssen, Celltrion Healthcare, Galapagos NV, Immundiagnostik, Takeda, ARENA, Gilead, Adcock Ingram Healthcare, Pfizer, Genentech, Tillotts. Allerton, Dean: No conflict of interest Bates, Georgia: No conflict of interest Buckley, Amy: No conflicts of interest Collins, Sonya: No conflict of interest Doyle, Jennifer: No conflict of interest Fachal, Laura: I have no conflicts of interest Frith, Katherine: No conflict of interest Gibson, Rachel: No conflict of interest Harris, Bradley: Personal Fees: I have received honoraria for a presentation at a BridgeBio board meeting. Hart, Ailsa: Grant: Takeda Personal Fees: Abbvie, Amgen, Arena, AZ, Falk, Celltrion, Eli Lilly, Ferring, Genentech/ Roche, GSK, Pfizer, Takeda, Napp, Pharmacosmos, Janssen (J & J), Bristol-Myers Squibb, Gilead, Galapagos, Alfasigma Hildreth, Victoria: No conflict of interest Irving, Peter Miles: Grant: MSD, Pfizer, Takeda, Celltrion, Galapagos Personal Fees: AbbVie, Arena, BMS, Boomerang Medical, Celgene, Celltrion, Falk Pharma, Ferring, Galapagos, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Sapphire Medical, Sandoz, Shire, Takeda, Tillotts, Topivert, VH2, Vifor Pharma, Warner Chilcott Kennedy, Nicholas Alexander: Grant: Dr Kennedy’s department has received research funding from AbbVie, Biogen, Celgene, Celtrion, Galapagos, MSD, Napp, Pfizer, Pharmacosmos, Roche and Takeda Personal Fees: Dr Kennedy has served as a speaker and/or advisory board member for AbbVie, Amgen, BMS, Falk, Ferring, Galapagos, Janssen, Mylan, Pharmacosmos, Sandoz, Takeda and Tillotts Non-financial Support: Dr Kennedy has had support to attend meetings from AbbVie, Falk, Janssen and Tillotts Lawrence, Sarah: No conflict of interest Lees, Charlie: Consultancy and lecture fees: Abbvie, Oshi Health, Gilead, Pfizer, Takeda, Janssen, Shire, Samsung Bioepis, Dr Falk, GSK, Galapagos, Trellus Health, Iterative Scopes, Fresnius Kabi Lindsay, James: Investigator Initiated Research Grant: Takeda, Abbvie, Gilead Personal Fees: I have received fees for speaking and may have received support to attend academic conferences from: Abbvie UK/Global, Bristol Myers Squib, Cornerstones US, Gilead, Galapagos, Lilly, MSD UK, Ferring UK, Ferring Intl., Celltrion, Takeda, Pfizer, Janssen, Tillotts, Other: I serve of the advisory board of Abbvie UK/Global, Alpini, Astra Zeneca, Engytix, Galapagos, Gilead, GSK, Lily, MSD, Ferring UK, Ferring Intl., Celltrion, Takeda, Pfizer, Janssen, Shattucks Laboratory, Marchesi, Julian: No conflict of interest Martin, Cristina Cotobal: No conflict of interest McGregor, Naomi: No conflict of interest Prescott, Natalie: No conflict of interest Powell, Nick: Grant: Takeda, BMS, Pfizer, Astra-Zeneca Personal Fees: Abbvie, Abivax, Allergan, Astra-Zeneca, Bristol-Myers Squibb, Celgene, Celltrion, Dr Falk Pharma UK Ltd, Ferring, Galapagos, GSK, Janssen, MSD, Roche, Pfizer, Sobi, Takeda, Tillotts Raine, Timothy: Grant: Abbvie, Takeda Personal Fees: TR has received research/educational grants and/or speaker/consultation fees from Abbvie, Alfasigma, Arena, Aslan, AstraZeneca, Boehringer-Ingelheim, BMS, Celgene, Domain Therapeutics, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Heptares, LabGenius, Janssen, MonteRosa, Mylan, MSD, Novartis, Numab, Pfizer, Roche, Sandoz, Scientia, Takeda, UCB and XAP therapeutics Speight, Ally: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, Lilly, Dr Falk Pharma Janssen Support for attending meetings and/or travel: AbbVie, Dr Falk Pharma Janssen, Tillott’
Khan et al. (Thu,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: