The relationship between mucosal microbiota, colitis and systemic inflammation in Chronic Granulomatous Disorder

Abstract

BackgroundChronic granulomatous disorder (CGD) is a primary immunodeficiency which is frequently complicated by an inflammatory colitis and is associated with systemic inflammation. ObjectiveTo investigate the role of the microbiome in the pathogenesis of colitis and systemic inflammation. MethodsWe performed 16S rDNA sequencing on mucosal biopsy samples from each segment of 10 CGD patients colons, and conducted compositional and functional pathway prediction analyses. ResultsThe microbiota in samples from colitis patients demonstrated reduced taxonomic alpha diversity compared to unaffected patients, even in apparently normal bowel segments. Functional pathway richness was similar between the colitic and non-colitic mucosa, although metabolic pathways involved in butyrate biosynthesis or utilisation were enriched in patients with colitis and correlated positively with faecal calprotectin levels. One patient with very severe colitis was dominated by Enterococcus spp., while among other patients Bacteroides spp. abundance correlated with colitis severity measured by faecal calprotectin and an endoscopic severity score. In contrast, Blautia abundance associated with low severity scores and mucosal health. Several taxa and functional pathways correlated with concentrations of inflammatory cytokines in blood but not with colitis severity. Notably, dividing patients into High and Low systemic inflammation groups demonstrated clearer separation than on the basis of colitis status in beta diversity analyses. ConclusionThe microbiome is abnormal in CGD-associated colitis and altered functional characteristics probably contribute to pathogenesis. Furthermore, the relationship between the mucosal microbiome and systemic inflammation, independent of colitis status, implies that the microbiome in CGD can influence the inflammatory phenotype of the condition. Key MessagesThe colonic mucosal microbiome and bacterial metabolic pathways in patients with CGD colitis differ from patients without colitis, even in macroscopically normal bowel segments. The mucosal microbiome and bacterial metabolic pathways in patients with CGD also differ according to the extent of systemic inflammation, independently from the presence of colitis, suggesting a role for the gut microbiota in the inflammatory phenotype of this condition. Capsule summaryThe pathogenesis of chronic granulomatous disorder (CGD)-associated colitis and other inflammatory complications is unclear. We demonstrate potentially treatable alterations in the mucosa-associated microbiome in CGD colitis and microbial differences which associate with systemic inflammation independently of colitis status.