New findings strengthen the link between environmental and microbial factors and Crohn’s disease risk

Crohn’s disease (CD) is a lifelong condition primarily characterized by small intestine and colon inflammation. The exact cause of this disease is unknown, but emerging research has suggested that alterations in the gut microbiome activate the immune system, which is influenced by genetic susceptibility and environmental factors. However, it is still subject to debate whether environmental and microbial factors are the causes or consequences of the disease or whether they are unrelated.

Two large multicenter studies have identified environmental and gut microbiome traits closely associated with Crohn’s disease onset and development risk.

The first study comprehensively explored the link between the environmental exposures of 4289 healthy first-degree relatives of patients with CD from the Crohn’s and Colitis Canada—Genetic, Environmental, Microbial (CCC-GEM) project and CD risk. After following participants for over 5.5 years, the authors discovered that living with a dog (hazard ratio, 0.62) and belonging to a large family in early childhood (hazard ratio, 0.63) was associated with decreased CD risk.

Interestingly, some protective environmental exposures were associated with  biomarkers. For instance, living with a dog was associated with higher gut microbiome diversity and good intestinal barrier function. Similarly, being a large family member was associated with altered gut microbiome composition.

The second study demonstrated for the first time that changes in the gut microbiome composition precede CD onset by up to five years. The authors developed a microbiome risk score using a machine-learning model that integrated gut microbiome composition data and clinical variables of 3483 healthy first-degree relatives of patients with CD.

The microbiome risk score accurately predicted CD up to five years prior to disease onset. Bacterial taxa with the most important contribution to the predictive score were Ruminococcus torques, Blautia, Colidextribacter, an uncultured genus-level group of Oscillospiraceae, and Roseburia. An increase in the abundance of the Faecalibacterium genus (the eighth most important genus involved in the development of the model) was inversely associated with an increased microbiome risk score.

The protective role of Faecalibacterium prausnitzii in preventing gut inflammation in Crohn’s disease has been extensively studied by Harry Sokol and colleagues. This is the first time that decreased levels of Faecalibacterium emerge as a microbiome signature that precedes CD diagnosis several years before. Fecal calprotectin did not influence the performance of the microbiome risk score in predicting CD onset risk.

Through microbial functional imputation, the authors found that metabolic pathways involved in short-chain fatty acid or micronutrient synthesis were negatively correlated with the microbiome risk score. In an independent validation cohort, the authors confirmed that patients with the highest microbiome risk score had more than twice the risk of developing CD.

In summary, these studies demonstrate that environmental factors, such as living with a dog, large family size, and alterations in the gut microbiome community (rather than individuals’ taxa) are potential causes of CD. These findings open the way to predicting individual risk of developing CD, preventing disease onset years before symptoms appear, and developing new microbiome-targeted interventions for children with parents with CD.

References:

Xue M, Leibovitzh H, Jingcheng S, et al. Environmental factors associated with risk of Crohn’s disease development in the Crohn’s and Colitis Canada – Genetic, Environmental, Microbial Project. Clin Gastroenterol Hepatol. 2024. doi: 10.1016/j.cgh.2024.03.049.

Raygoza Garay JA, Turpin W, Lee SH, et al. Gut microbiome composition is associated with future onset of Crohn’s disease in healthy first-degree relatives. Gastroenterology. 2023; 165(3):670-681. doi: 10.1053/j.gastro.2023.05.032.

Sokol H, Pigneur B, Watterlot L, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. PNAS. 2008; 105(43):16731-6. doi: 10.1073/pnas.0804812105.