In Crohn'S Disease, An Aggressive Disease Course Is Related To An Increased Abundancy Of Proteobacteria; A Seven Year Follow Up Study

Background: Many studies have found an imbalance of the gut microbiota – termed dysbiosis – in inflammatory bowel disease (IBD) patients, with an overall loss of diversity, a depletion of Firmicutes and an increase of Proteobacteria. Differences in abundance seem to depend on disease activity and are found significantly lower in IBD patients with active disease compared to patients with inactive disease. However, studies have emerged from tertiary centers and selected cohorts. The aim of this study was to investigate the microbiota in 139 IBD patients from an unselected inception cohort of patients diagnosed in Copenhagen, Denmark year 2003–04 after 7 years of disease duration. Methods: Sixty Crohn's disease (CD) and 79 ulcerative colitis (UC) patients were included. Disease activity was assessed by the Harvey-Bradshaw Index for CD and Simple Clinical Colitis Activity Index for UC and fecal samples were collected at a follow-up (FU) visit after 7 years of disease duration. The diversity of the fecal microbiome was assessed by 16S rDNA MiSeq sequencing. Medical and surgical data was registered retrospectively at the follow-up visit. An aggressive disease course was defined as ≥3 courses of ≥50mg/day systemic steroids and/or biological therapy (any dose) and/or surgical resection (CD) or colectomy (UC) during the 7 years of FU. Results: The diversity of microbiota measured both as OTUs and Shannon index was significantly lower for active compared to inactive IBD (p=0.005 and p=0.038 respectively). The abundance of Firmicutes (p=0.001) decreased and the abundance of Proteobacteria (p=0.004) increased in patients with active IBD. For CD, a significant decrease was observed in the number of OTUs in patients with aggressive disease compared to patients with non-aggressive disease (p=0.007), but not in Shannon index (p=0.13). There was no change in diversity or the number of OTUs or Shannon index observed between non-aggressive and aggressive disease for UC (p>0.20). Only Proteobacteria was significantly more abundant in CD patients with aggressive disease compared to non-aggressive (p=0.049). There were no significant phyla-level differences in abundance for UC. Conclusions: In this unselected cohort of patients with 7 years of follow-up, we found a lower microbial diversity in IBD patients with active disease. The abundance changed with loss of Firmicutes and an increase in Proteobacteria. The abundance of Proteobacteria was also found to be increased in CD patients with aggressive disease. These results are in accordance with former studies, suggesting that dysbiosis of the gut in CD patients is not only related to activity but also to severity of disease.