PUFAs and IBD: Is There a Relationship?

Extract

The exact pathogenesis of inflammatory bowel disease (IBD) is under intense investigation. The most accepted notion for now is that an aberrant host immune system reacts excessively toward the gut mucosa, which results in chronic relentless inflammation that is likely triggered by a variety of environmental factors including microbiota and diet in genetically susceptible hosts. Although it has been established that IBD is in part heritable, numerous genome-wide association studies involving many thousands of patients taught us a simple fact that despite identifying over 200 IBD susceptibility genes, these genes explain only less than 15% heritability in IBD,¹ making the studies of gene–diet–environmental interactions a priority. Genes interacting with diet and gut microbiota resulting in differential gene expression and modulating gut inflammation either as a cause or determining the course of IBD is gaining a lot of traction recently, partly because of the future use of “nutraceuticals” (loosely defined as food with medical benefits), in the management of IBD. For example, high intake of dietary n-3 polyunsaturated fatty acids (n-3 PUFA, also known as omega 3) is shown to be associated with a decreased risk of ulcerative colitis (UC) and Crohn's disease (CD) and even decreased “flares” in patients with established disease.² However, PUFAs such as n-6 PUFA (also known as omega-6), commonly consumed in fast food and processed food increase the risk of IBD.² Modern Western diets typically have ratios of n-6 to n-3 in excess of 10 to 1, some as high as 30 to 1; the average ratio of n-6 to n-3 in the Western diet is 15:1.³ Humans are believed to have evolved with a diet of a 1:1 ratio of n-6 to n-3 (hunters and gatherers ate fish, fresh meat, and nuts), and the optimal ratio is believed to be 4 to 1 or lower. Interestingly, n-3 PUFA and n-6 PUFA metabolisms share a common pathway for metabolism and compete with each other enzymatically (Fig. 1). In this issue, Ananthakrishnan et al² have examined this question of whether genetic variation in 3 genes that control PUFA metabolism has any risk of UC and CD, by elegantly integrating and performing nested case–control studies in 2 well-established prospective cohorts, the Nurses' Health Study (NHS) and NHS 2. Among women providing consent for genotyping (n = 62,437), they confirmed 101 new diagnoses of CD and 139 of UC. Confirmed IBD cases were matched 1:2 to controls in the case–control analyses. They genotyped for several single nucleotide polymorphisms (SNPs) at CYP4F3, FADS1, and FADS2 genes/loci. Conditional logistic regression models examined the interaction between genotype, PUFA intake, and risk of CD and UC. On multivariable analysis, a high n3:n6 ratio of PUFA intake was associated with a reduced risk of UC in individuals with the GG/AG genotype at an SNP in the CYP4F3 gene (odds ratio, 0.57; 95% confidence interval, 0.32–0.99) but not those with the AA genotype (odds ratio, 0.95; 95% confidence interval, 0.47–1.93) (P interaction = 0.049). This is particularly very exciting, as we find further evidence that association between dietary n3:n6 PUFA intake and development of UC risk may be modified by the individual's genetic makeup and providing fuel that personalized dietary approaches/manipulation can be used in the management or even prevention of IBD based on their genotypes.