Living with IBD: Gut microbiome signatures correlated with clinical response to treat-to-target therapy in IBD.
Background & Rationale
Inflammatory bowel disease (IBD), encompassing Crohn’s disease and ulcerative colitis, is characterised by dysregulated immune responses to the gut microbiota in genetically susceptible individuals. Current therapeutic strategies often rely on a ‘step-up’ approach, which may not optimally address individual patient needs. Treat-to-target (TTT) strategies, aiming for endoscopic remission and mucosal healing, represent a more personalised approach. However, objective biomarkers to guide TTT and predict treatment response remain limited. The gut microbiome is increasingly recognised as a key modulator of IBD pathogenesis, and multi-omics approaches offer the potential to identify microbial signatures associated with disease activity and treatment outcomes. This study investigated the utility of integrated metagenomic, metatranscriptomic, and metabolomic analyses to identify microbiome signatures predictive of response to TTT in IBD patients.
Study Design
This prospective cohort study enrolled patients with IBD initiating or adjusting TTT therapy. Baseline stool samples were collected prior to treatment modification. Patients underwent clinical assessment, including endoscopic evaluation and biomarker measurements (C-reactive protein and faecal calprotectin), at baseline and after 12 weeks of TTT. Multi-omics profiling, including shotgun metagenomics, metatranscriptomics, and untargeted metabolomics, was performed on the baseline stool samples. Data integration was achieved using a Spearman correlation network analysis to identify co-abundance groups (CAGs) of genes, pathways, and metabolites. Statistical modelling was then used to determine associations between microbiome signatures and clinical response, defined as endoscopic remission and normalisation of C-reactive protein.
Patient Population
The study included 120 patients with IBD: 65 with Crohn’s disease and 55 with ulcerative colitis. The mean age of participants was 38.2 years, with 53% identified as male. At baseline, 68 patients were receiving biological therapy, 32 were receiving immunomodulators, and 20 were receiving conventional therapies. Of the cohort, 72 patients achieved clinical response to TTT after 12 weeks, while 48 did not. Disease duration prior to enrolment ranged from 1 to 20 years, with a median of 5.5 years.
Key Findings
Integrated multi-omics analysis revealed distinct microbiome signatures associated with response to TTT. Patients who responded to TTT exhibited a significantly higher relative abundance of Faecalibacterium prausnitzii and Roseburia species compared to non-responders. Metagenomic analysis identified enrichment of genes involved in butyrate synthesis in responders, with an average of 12.5% greater abundance of butyrate kinase genes. Metatranscriptomic data showed increased expression of genes related to short-chain fatty acid (SCFA) metabolism in the responder group, with a 18.7% increase in butyryl-CoA transferase expression. Metabolomic profiling demonstrated elevated levels of butyrate and propionate in responders, measuring 2.8 µmol/g and 1.5 µmol/g respectively, compared to 1.9 µmol/g and 0.8 µmol/g in non-responders. A predictive model incorporating these microbiome features achieved an area under the receiver operating characteristic curve (AUROC) of 0.82 for identifying patients likely to respond to TTT.
Discussion
This study demonstrates the potential of multi-omics analysis to identify gut microbiome signatures associated with response to TTT in IBD. The observed enrichment of butyrate-producing bacteria and increased SCFA levels in responders aligns with the known anti-inflammatory effects of these metabolites. These findings suggest that modulating the gut microbiome to enhance butyrate production could be a therapeutic strategy to improve treatment outcomes in IBD. The predictive model developed in this study offers a potential tool for personalising TTT strategies, allowing clinicians to identify patients who are more likely to benefit from specific interventions. The study reported that all multi-omic analyses were well tolerated, with no adverse events directly attributable to sample collection or analysis.
Authors’ Conclusions
The authors concluded that integrated multi-omics analysis of the gut microbiome can identify signatures associated with clinical response to TTT in IBD. These findings provide a rationale for developing microbiome-targeted therapies to optimise treatment strategies and improve outcomes for patients with IBD, and suggest that microbiome profiling may serve as a valuable biomarker for predicting treatment response.
Reference
Cai X, Yao Y, Zheng Y, Zhao X. Multi-omics gut microbiome signatures for treat-to-target management in inflammatory bowel disease. Microbiological research. 2026;128511. DOI: 10.1016/j.micres.2026.128511.