Introduction
Gut microbiota in Crohn's disease (CD) exhibits considerable variability, with conflicting associations with disease severity and response to therapeutic intervention. We aimed to longitudinally investigate the dynamics of microbial composition in a cohort of patients with newly diagnosed, treatment-naïve Crohn's disease (ndCD) over a one-year period.
Aims & Methods
A prospective real-world study was conducted, enrolling patients with ndCD who were treatment-naïve. Treatment decisions were made by physicians with expertise in CD management. Key one-year clinical outcomes included corticosteroid-free clinical remission (CSFR) and biochemical remission (BR), defined as C-reactive protein levels <1mg/dL and fecal calprotectin levels <150ug/g. Paired stool samples were subjected to 16S rRNA gene sequencing (V4 region) at diagnosis and after one year, followed by analysis for microbial diversity and dysbiosis indices. A linear mixed-effect model was constructed to identify factors associated with microbial alterations and specific taxa driving these alterations, while controlling for confounding variables.
Results
Seventy-five patients completed the one-year follow-up (49.3% female, median age 27 years [IQR 22-38.5]); 45 (60%) received biologics (95.5% anti-tumor necrosis factor [TNF]). Rates of CSFR, BR, and combined CSFR-BR at one-year post-diagnosis were 64%, 56%, and 45.3%, respectively. Analysis of microbial composition revealed significant improvements in microbial indices among patients achieving all desired clinical outcomes, characterized by increased microbial diversity (Shannon index, p=0.004, p=0.002, p=0.004, respectively) and decreased dysbiosis (microbial dysbiosis index [MDI], p=0.003, p=0.04, p=0.01, respectively). Such improvements were not observed in patients failing to achieve CSFR, BR or combined CSFR-BR. Notably, patients treated with biologics, irrespective of outcome achievement, exhibited prominent shifts (improvement) in microbial composition (both indices p<0.001), whereas non-treated patients did not demonstrate significant changes (Shannon index, p=0.53; MDI, p=0.81). Furthermore, microbial composition at baseline was more disrupted among patients treated with biologics compared to non-treated patients (Shannon index, p=0.04; MDI, p=0.03). The linear mixed model analysis confirmed a positive association between biologics and favorable changes in microbial indices (Shannon index, p=0.02; MDI, p=0.04), identifying an increase in 20 gut commensal taxa (considered beneficial) and a decrease in Escherichia coli among the biologics-treated subgroup. Conversely, no taxa exhibited significant alterations in the non-biologics treated subgroup.
Conclusion
In a real-world cohort of patients with treatment-naïve ndCD, clinical improvement over one year was associated with improvement in microbial composition. Treatment with anti-TNF agents was associated with improvement in microbial composition irrespective of clinical outcomes. These findings suggest that microbial composition reflects inflammatory activity and may be positively and independently modified by anti-TNF treatment.