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Individualized Dynamics in the Gut Microbiota Precede Crohn's Disease Flares

Braun, Tzipi MS1; Di Segni, Ayelet PhD1; BenShoshan, Marina MS1,2; Neuman, Sandra RN3; Levhar, Nina MS3; Bubis, Michael BS3; Picard, Orit PhD3; Sosnovski, Katya MS1,2; Efroni, Gilat PhD1; Farage Barhom, Sarit PhD1; Glick Saar, Efrat PhD1; Lahad, Avishay MD2,4; Weiss, Batia MD2,4; Yablecovitch, Doron MD2,3; Lahat, Adi MD2,3; Eliakim, Rami MD2,3; Kopylov, Uri MD2,3; Ben-Horin, Shomron MD2,3; Haberman, Yael MD, PhD2,4,5

American Journal of Gastroenterology: July 2019 - Volume 114 - Issue 7 - p 1142–1151
doi: 10.14309/ajg.0000000000000136

OBJECTIVES: Crohn's disease (CD) is a chronic relapsing-remitting gut inflammatory disorder with a heterogeneous unpredictable course. Dysbiosis occurs in CD; however, whether microbial dynamics in quiescent CD are instrumental in increasing the risk of a subsequent flare remains undefined.

METHODS: We analyzed the long-term dynamics of microbial composition in a prospective observational cohort of patients with quiescent CD (45 cases, 217 samples) over 2 years or until clinical flare occurred, aiming to identify whether changes in the microbiome precede and predict clinical relapse. Machine learning was used to prioritize microbial and clinical factors that discriminate between relapsers and nonrelapsers in the quiescent phase.

RESULTS: Patients with CD in clinical, biomarker, and mucosal remission showed significantly reduced microbial richness and increased dysbiosis index compared with healthy controls. Of the 45 patients with quiescent CD, 12 (27%) flared during follow-up. Samples in quiescent patients preceding flare showed significantly reduced abundance of Christensenellaceae and S24.7, and increased abundance of Gemellaceae compared with those in remission throughout. A composite flare index was associated with a subsequent flare. Notably, higher individualized microbial instability in the quiescent phase was associated with a higher risk of a subsequent flare (hazard ratio 11.32, 95% confidence interval 3–42, P = 0.0035) using two preflare samples. Importantly, machine learning prioritized the flare index and the intrapersonal instability over clinical factors to best discriminate between relapsers and nonrelapsers.

DISCUSSION: Individualized microbial variations in quiescent CD significantly increase the risk of future exacerbation and may provide a model to guide personalized preemptive therapy intensification.

1Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel;

2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;

3Department of Gastroenterology, Sheba Medical Center, Tel-Hashomer, Israel;

4The Pediatric Gastroenterology Unit, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel;

5Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio.

Correspondence: Yael Haberman, MD, PhD. E-mail:

SUPPLEMENTARY MATERIAL accompanies this paper at

Received July 31, 2018

Accepted December 10, 2018

© The American College of Gastroenterology 2019. All Rights Reserved.
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