Background Obesity is associated with systemic and intestine-specific inflammation as well as alterations in gut microbiota, which in turn impact mucosal immunity. Nonetheless, a specific role of obesity and its interaction with genetics in the progression of Crohn's disease (CD) is unclear. Methods We conduced a cross-sectional study of CD patients enrolled in Prospective Registry in Inflammatory Bowel Disease Study at Massachusetts General Hospital (PRISM). Information on diagnosis of CD and its complications were collected and confirmed through review of medical records. A genetic risk score was calculated using previously reported single nucleotide polymorphisms (SNPs) associated genome-wide with CD susceptibility. We used logistic regression to estimate the effect of body mass index (BMI) and its interaction with genetic risk on risk of CD complications. Results Among 846 CD patients, 350 required surgery, 242 with penetrating disease, 182 with stricturing disease, and 226 with perianal disease. There were no associations between obesity (BMI ≥ 30) and risk of perianal disease, stricturing disease, or surgery. Compared to normal weight individuals with BMI < 25, obesity was associated with lower risk of penetrating disease (OR = 0.56, 95% CI 0.31-0.99). This association persists among a subgroup of participants with available BMI prior to development of penetrating disease (OR = 0.40, 95% CI 0.16-0.88). There were no interactions between BMI and genetic risk score on risk of CD complications (All Pinteraction > 0.28). Conclusion Our data suggest that obesity does not negatively impact long-term progression of CD, even after accounting for genetic predisposition.

BackgroundRecent animal studies have identified that dietary salt intake may modify the risk and progression of autoimmune disorders through modulation of the IL-23/TH17 pathway, which is critical in the pathogenesis of ulcerative colitis (UC) and Crohn’s disease (CD).MethodsWe conducted a prospective study of U.S. women enrolled in the Nurses’ Health Study (NHS) and NHSII who provided detailed and validated information on diet and lifestyle beginning in 1984 in NHS and 1991 in NHSII. We confirmed incident cases of UC and CD reported through 2010 in NHS and 2011 in NHSII. We used Cox proportional hazards models to calculate hazard ratios and 95% confidence intervals. In a case–control study nested within these cohorts, we evaluated the interaction between single nucleotide polymorphisms (SNPs) in genes involved in TH17 pathway and dietary potassium on risk of CD and UC. In a cohort of healthy volunteers, we also assessed the effect of supplemental potassium on development of naïve and memory T cells, differentiated with TGFβ1 or TH17 conditions.ResultsAmong a total of 194,711 women over a follow-up of 3,220,247 person-years, we documented 273 cases of CD and 335 cases of UC. Dietary intake of potassium (Ptrend = 0.005) but not sodium (Ptrend = 0.44) was inversely associated with risk of CD. Although, both dietary potassium and sodium were not significantly associated with risk of UC, there was a suggestion of an inverse association with dietary potassium (Ptrend = 0.08). The association of potassium with risk of CD and UC appeared to be modified by loci involved in the TH17 pathway that have previously been associated with susceptibility to CD, particularly SNP rs7657746 (IL21) (Pinteraction = 0.004 and 0.01, respectively). In vitro, potassium enhanced the expression of Foxp3 in both naïve and memory CD4+ T cells via activating Smad2/3 and inhibiting Smad7 in TH17 cells.ConclusionDietary potassium is inversely associated with risk of CD with both in vitro and gene–environment interaction data suggesting a potential role for potassium in regulating immune tolerance through its effect on Tregs and TH17 pathway.

Introduction Adipose tissue in mesenteric fat plays a key role in systemic and luminal inflammation. However, little is known about the role of visceral adipose tissue (VAT) and its interaction with genetic predisposition in Crohn’s disease (CD) progression. Methods Our study population included CD patients enrolled in Prospective Registry in Inflammatory Bowel Disease Study at Massachusetts General Hospital (PRISM). VAT volume was measured from CT scans using Aquarius 3D. We used logistic regression models to estimate the multivariable-adjusted odds ratio (MV-adjusted OR) and 95% confidence interval (CI). We tested for effect modification by genetic predisposition using the log-likelihood ratio test. Results Among 482 CD patients with available data on VAT, 174 developed penetrating disease, 132 developed stricturing disease, 147 developed perianal disease, and 252 required surgery. Compared to individuals in the lowest quartile of VAT volume, the MV-adjusted OR of surgery among individuals in the highest quartile was 2.02 (95% CI, 1.09 – 3.76; Ptrend = 0.006). Similarly, the risk of penetrating disease appeared to increase with greater VAT volume (Ptrend = 0.022) but not stricturing or perianal disease (all Ptrend > 0.23). The associations between VAT volume and CD complications were not modified by genetic predisposition (all Pinteraction > 0.12). Conclusions Visceral adiposity as measured by VAT volume may be associated with a significant increase in risk of penetrating disease and surgery in CD. Our data suggest that visceral adiposity as measured by VAT may negatively impact long-term progression of CD regardless of genetic predisposition.