RESUMEN
BACKGROUND AND AIMS: Crohn's disease (CD) and ulcerative colitis (UC) demonstrate considerable phenotypic heterogeneity and course. Accurate predictors of disease behaviour are lacking. The contribution of genetics and specific polymorphisms is widely appreciated; however, their cumulative effect(s) upon disease behaviour remains poorly understood. Here, we investigate the relationship between genetic burden and disease phenotype in a Canadian inflammatory bowel disease (IBD) Cohort. METHODS: We retrospectively examined a cohort of CD and UC patients recruited from a single tertiary referral center genotyped using a Goldengate Illumina platform. A genetic risk score (GRS) incorporating strength of association (log odds ratio) and allele dose for 151 IBD-risk loci was calculated and evaluated for phenotypic associations. RESULTS: Among CD patients, higher GRS was associated with earlier onset of disease (regression coefficient -2.19, 95% confidence interval [CI] -3.77 to -0.61, P = 0.007), ileal disease (odds ratio [OR] 1.45), stricturing/penetrating disease (OR 1.72), perianal disease (OR 1.57) and bowel resection (OR 1.66). Higher GRS was associated with use of anti-tumor necrosis factor (TNF) (P < 0.05) but not immunomodulators. Interestingly, we could not demonstrate an association between higher GRS and family history of IBD (OR 1.27, P = 0.07). Onset of disease remained statistically significant for never smokers (P = 0.03) but not ever smokers (P = 0.13). For UC, having a higher GRS did not predict the age of diagnosis nor was it predictive of UC disease extent (P = 0.18), the need for surgery (P = 0.74), nor medication use (immunomodulators P = 0.53, anti-TNF P = 0.49). We could not demonstrate an association between increased GRS and having a family history of IBD in the UC group. CONCLUSIONS: Increasing genetic burden is associated with early age of diagnosis in CD and may be useful in predicting disease behaviour in CD but not UC.
RESUMEN
Polymicrobial infections of the gastro-intestinal tract are common in areas with poor sanitation. Disease outcome is the result of complex interactions between the host and pathogens. Such interactions lie at the core of future management strategies of enteric diseases. In developed countries of the world, Giardia duodenalis is a common cause of diarrheal disease. In contrast, giardiasis appears to protect children against diarrhea in countries with poor sanitation, via obscure mechanisms. We hypothesized that Giardia may protect its host from disease induced by a co-infecting pathogen such as attaching and effacing Escherichia coli. This enteropathogen is commonly implicated in pediatric diarrhea in developing countries. The findings indicate that co-infection with Giardia attenuates the severity of disease induced by Citrobacter rodentium, an equivalent of A/E E. coli in mice. Co-infection with Giardia reduced colitis, blood in stools, fecal softening, bacterial invasion, and weight loss; the protective effects were lost when co-infection occurred in Nod-like receptor pyrin-containing 3 knockout mice. In co-infected mice, elevated levels of antimicrobial peptides Murine ß defensin 3 and Trefoil Factor 3, and enhanced bacterial killing, were NLRP3-dependent. Inhibition of the NLRP3 inflammasome in human enterocytes blocked the activation of AMPs and bacterial killing. The findings uncover novel NLRP3-dependent modulatory mechanisms during co-infections with Giardia spp. and A/E enteropathogens, and demonstrate how these interactions may regulate the severity of enteric disease.
