Exclusive enteral nutrition and infliximab combination therapy are superior to monotherapy in inducing endoscopic response in active adult Crohn’s disease

Background: Anti-tumor necrosis factor alpha (anti-TNFα) agents assume a significant role in the management of Crohn’s disease (CD). Exclusive enteral nutrition (EEN) is as effective as corticosteroids for inducing remission in children with active CD, but less effective in adults. Few studies have compared the relative effectiveness of these strategies in achieving endoscopic improvement and symptom relief. Objectives: We aimed to compare the efficacy of EEN, infliximab (IFX), and combination therapy in adult patients with CD. Design: Retrospective cohort study. Methods: Between March 2021 and June 2024, 270 adult patients with active CD were recruited and received EEN, IFX, or combination treatment for 14 weeks. Propensity-score (PS) matching was conducted to balance the baseline characteristics across the three groups. The fecal 16S rRNA sequencing and metabolomics analyses were applied to further analyze the underlying mechanism involved in combination and monotherapy. Results: Of the 270 reviewed patients, a total of 146 PS-matched adult CD patients who received EEN ( n = 29), IFX ( n = 56), and combination therapy ( n = 61), respectively, were analyzed. The combination therapy of EEN plus IFX demonstrated greater improvement in endoscopic response at week 14 compared to both the EEN group ( p = 0.021) and the IFX group ( p = 0.032), but not in endoscopic remission. Combination therapy also exhibited a significantly higher clinical response rate compared with EEN ( p = 0.027) and IFX ( p = 0.038) monotherapy, but no significant difference in clinical remission. Furthermore, compared with IFX monotherapy, combination therapy increased the IFX trough level at week 14 ( p < 0.001). Fecal 16S rRNA sequencing revealed that combination therapy successfully restored the abundance of Bacteroidetes and related genera. Targeted metabolomics further confirmed a significant increase in short-chain fatty acids (SCFA) and key metabolites (e.g., indolelactic acid) in fecal samples 14 weeks after combination therapy. Conclusion: Combination therapy is more effective than EEN or IFX monotherapy for short-term endoscopic and clinical response. Mechanistically, combination therapy reshapes the gut microbiota, restores levels of SCFAs, and increases key protective fecal metabolites, offering a promising strategy for the management of CD.