Effects of Therapy on Host-Microbe Interactions in Pediatric Inflammatory Bowel Diseases

Abstract

Introduction By 2030, 1/100 Canadians are predicted to be diagnosed with inflammatory bowel diseases (IBD); approximately 25% of cases are diagnosed in children. IBD include Crohn disease (CD) and ulcerative colitis (UC), and manifest with chronic gastrointestinal inflammation. Pathogenesis remains poorly understood but IBD are associated with alterations in microbial recognition and clearance, an altered intestinal microbiome, and certain dietary exposures. Treatments include immune suppression and dietary therapy. Delineating how the intestinal microbiome is associated with treatment outcomes is critical in understanding disease pathogenesis. Methods Multi-centre, prospective IFX studies in 33 paediatric Crohn disease (pCD) and 32 pediatric ulcerative colitis (pUC) patients were conducted with bio-specimen collection before and after treatment. Stool was analyzed for short chain fatty acids (SCFA), fecal calprotectin (FCP), and microbial composition; urine metabolomics was performed. In addition, a cohort of 103 prospectively followed pCD patients initiating dietary therapy completed food frequency questionnaires (FFQs) at the time of diagnosis that were analyzed for dietary patterns using principal component analysis. Results IFX treatment was associated with increased SCFA (p=0.01), altered tryptophan and Clostridia-associated metabolites (p<0.05), and increased SCFA producing bacteria, such as Pseudobutyrivibrio (p=0.07), Akkermansia (p=0.004), and Ruminococcus (p=0.07). FCP and disease severity decreased with treatment (p<0.0001 and <0.001, respectively), while microbial diversity and richness increased (p<0.022). In pUC, SCFA decreased in males but showed an average increase in females (p=0.0095), with similar sex-dependent associations and changes with microbial diversity and richness (p<0.05). Disease severity and location in pCD were also associated with changes in SCFA, metabolites, and microbiota. The top four dietary patterns named after foods with high factor loadings were: “Vegetarian”, “Meat”, “Pre-packaged”, and “Mature”. The patterns characterized 28.9% of dietary variability in the pCD EEN-FFQ cohort, and varied with age, sex, and disease location. Conclusion Increases in SCFA, tryptophan and Clostridia metabolites, as well as SCFA-producing bacteria with therapy may suggest beneficial alterations in the microbiome as an important part of treatment response. Differential responses between males and females suggest sex-specific mechanisms may be present. Sex-specific variations in the dietary therapy cohort may identify a potential mechanism. Further investigation is required to examine the causal associations between microbial metabolites and host health in pediatric IBD. These findings may contribute to understanding disease etiology and development of novel biomarkers, microbial therapeutic targets, or dietary guidelines.