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

Abstract

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.

Defining the Celiac Disease Transcriptome using Clinical Pathology Specimens Reveals Biologic Pathways and Supports Diagnosis

“…TNF and Interferon-γ) regulate intestinal epithelial proliferation at the crypt base 29,30 , inducing or restricting intestinal epithelial proliferation and cell death 31,32 depending on the circumstances. Differences between Crohn disease and celiac disease in this respect may be driven by the role of the gut microbiota that was already linked to Crohn disease pathogenic processes in several large cohorts 33 . The role of microbiota in celiac disease was linked to different metabolic patterns of gluten break down 34 and was shown to be different in infants with an affected first degree relative 35 , but the overall microbial composition has not yet been fully defined in large human cohorts of celiac disease, and is still controversial 36 .…”

Contribution of the Intestinal Microbiome and Gut Barrier to Hepatic Disorders

“…74,91,102,123,152,180,181 Even the associations we have identified might be used as biomarkers and to develop functional assays for more timely disease detection and more accurate risk calculation. 91,182…”

Regional distribution of Christensenellaceae and its associations with metabolic syndrome based on a population-level analysis

“…These studies demonstrated that age, gender, and ethnicity are associated with the abundance of Christensenellaceae . The relative abundance of Christensenellaceae in the intestine was found to be inversely proportional to body mass index (BMI) ( Fu et al, 2015 ; Goodrich et al, 2014 ; Oki et al, 2016 ; Peters et al, 2018b ) and exhibited a negative correlation with obesity and inflammatory bowel disease ( Braun et al, 2019 ; Gevers et al, 2014 ; Imhann et al, 2018 ).…”