Microbial Shift over One Year among Patients with Newly Diagnosed Crohn's Disease Reflects Clinical Trajectory and Exposure to Biologic Treatment: A Prospective Real-World Inception Cohort.

The gut microbiome in Crohn's disease (CD) shows variability and conflicting associations with disease activity. We aimed to assess microbial and clinical trajectories in newly diagnosed CD (ndCD) over one year. This prospective longitudinal inception cohort study followed treatment-naïve ndCD patients for one year. The primary outcome was sustained corticosteroid-free clinical remission (CSFR) after one year. Paired fecal samples were collected at diagnosis and one year later, analyzed using bacterial 16S rRNA gene high-throughput sequencing. Microbial composition changes were compared between baseline and one-year follow-up and between biologics-treated and conservatively managed patients. Fecal samples from healthy volunteers served as controls. Seventy-three patients participated; 64.4% achieved sustained CSFR after one year. During follow-up, 60.3% had moderate to severe disease activity and received biologics (95.5% anti-TNF), while 39.7% were managed conservatively. Significant microbial improvements, including increased Shannon diversity and decreased microbial dysbiosis index (MDI), were observed only in patients achieving sustained CSFR (both p<0.001). Biologic-treated patients had more disrupted baseline microbiome composition than conservatively managed ones (Shannon, p=0.04; MDI, p=0.03); they showed significant microbial improvement regardless of clinical success, shifting toward a healthier microbiome profile. Changes in clinical outcomes over one year correlated with microbial alterations. Over one year, treatment-naïve ndCD patients showed microbial improvements paralleling clinical outcomes, with shifts toward a healthier state. Biologic therapy enhanced microbial profiles, likely due to greater baseline disruption in these patients. These findings suggest that the microbiome is a marker of inflammation and a modifiable factor in CD management.