P779 CD patients in deep remission harbor a high dysbiosis index similar to active CD at diagnosis, yet both are higher in comparison to healthy controls
Haberman Y.*1,2, Klein T.1, Di Segni A.1, Neuman S.1, Levhar N.1, Bubis M.1, Picard O.1, BenShoshan M.1, Farage Barhom S.1, Glick Saar E.1, Cesarkas K.1, Lahad A.1, Shouval D.1, Weiss B.1, Eliakim R.1, Ben-Horin S.1, Kopylov U.1
1Sheba Medical Center, Tel Hashomer, Israel 2Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
Altered microbial composition (dysbiosis) is detected in Crohn's disease (CD), but it is questionable if this is a primary process that contributes to pathogenesis or is secondary to a survival advantage in inflammatory environment. Murine studies showed that gut dysbiosis from CD patients augments pro-inflammatory responses in the host, suggesting contribution to pathogenesis. We aimed to test if CD patients under clinical, biomarkers, and capsule-proven deep remission, restore or persist their dysbiosis in comparison to active treatment naïve CD patients (US RISK, n=133), and healthy controls (n=1031 from Israel and US).
The global pattern of microbial composition was determined by 16S sequencing in fecal samples of CD patients (n=38) from the prospective observational Israeli IBD Research Network (IIRN). Clinical corticosteroid-free remission was defined as CDAI≤150. Biomarkers remission included fecal calprotectin ≤100 μg/g (BÜHLMANN Laboratories) and CRP levels ≤5 mg/l. Mucosal healing (MH) was defined by SB-III or PillCam 2 colonic capsules (Given Imaging) with Lewis score (LS) ≤135.
18 (51%) of 35 patients in clinical remission showed clinical and biomarker remission, and only 10 (29%) showed MH with clinical and biomarker remission. Principal Component analyses of the unweighted UniFrac matric to summarize the overall microbial dysregulation showed clear separation between CD in remission and healthy controls. Alpha diversity (richness within sample) showed significant reduction in healthy Israeli population in comparison to healthy US population (p<0.001), but no significant differences were detected between healthy Israeli controls, IIRN CD patients irrespective of their remission state, or active US CD. Remarkably the dysbiosis index of Israeli patients in clinical remission was similar to that of active US CD, but was significantly different from that of healthy Israeli and US individuals (p<0.001). Moreover, no differences were noted between Israeli CD patients with and without biomarkers remission and with and without mucosal healing, while all those groups were significantly different from healthy controls.
CD patients in deep remission and in the absence of mucosal inflammation, show significantly higher dysbiosis index as treatment naïve active CD. These results may suggest that the dysbiosis observed in CD, like genetics, is a primary intrinsic component of the pathogenesis that is not affected by current therapeutic approaches. However, as opposed to genetics that is harder to manipulate, future therapeutic and nutritional interventions should aim to target the microbiota to potentially improve CD natural history.