Influence of Prebiotics on Intestinal Permeability in First Degree Relatives of Crohn's Patients

1. Background:

Crohn's disease (CD) is a chronic intestinal inflammation, affecting approximately 130,000 Canadians. Its incidence and prevalence is rising worldwide. The disease etiology is unknown; however its pathogenesis is thought to be mediated by commensal gut bacteria, affected by environmental factors in a genetically susceptible host. It is well established that susceptibility to CD has a strong genetic component with up to 12% of the patients having family history of inflammatory bowel disease (IBD). Genome-wide association studies (GWAS) have identified more than 230 single nucleotide polymorphisms (SNPs) associated with IBD. However the risk-associated SNPs seems to account for only a portion of the observed IBD heritability, as many healthy individuals and relatives of Crohn's patients who carry these risk alleles never develop disease.

The gut microbiome, which is also implicated in the CD pathogenesis, also has a certain degree of inheritance. Up to a third of the intestinal bacteria are heritable, raising the possibility of specific host genetic variants shaping the individual variability in microbial profiles. A study with 582 healthy individuals found that a high genetic risk for IBD was associated with a decrease in the relative abundance of the butyrate-producing Roseburia. Diet independently can affect the gut microbiome in short- and long term. Population-based studies in IBD indicate strong association of high dietary intakes of total fats, n-6 polyunsaturated fatty acids (PUFAs) and meats with increased risk of IBD, while high intake of fruits and vegetables decrease that risk. Animal studies have described the mechanisms underlying the pathogenesis of high-fat diets in colitis, including decreased Paneth cell area and less production of antimicrobial peptides by Paneth cells in the small intestines; reduced goblet cell number and less secreted mucin by goblet cells in the small intestines; reduced levels of tight junction proteins as occludin in the ileum, further illustrated by increased small intestinal permeability; increased IL-6 secretion in colon; and finally expanded abundance of pathobionts, such as Atopobium and Proteobacteria in stool. This data suggests that a high-fat diet (as an example of Western diet) has significant effect on the intestinal immunity and barrier function together with induction of dysbiosis and pathobiont expansion that can finally predispose to the development of inflammatory bowel disease.

N-6 PUFAs have been identified as a risk factor for IBD. Canadians currently consume 5-10% dietary energy from n-6 PUFA, due to increased consumption of vegetable oils recommended by Canada's Food Guide. Meanwhile consumption of n-3 PUFAs (docosahexaenoic acid and eicosapentaenoic acid) with anti-inflammatory actions, represent only 0.15% dietary energy. Both n-6 and n-3 PUFAs are precursors of eicosanoids that regulate inflammation but in polarizing means. N-6 PUFAs, promote the production of pro-inflammatory series 2 prostaglandins (like prostaglandin E2, PGE2), thromboxanes and series 4 leukotrienes and also exacerbated murine colitis in several models. In contrast, n-3 PUFAs have anti-inflammatory properties that lead to the series 3 PGE, series 5 leukotrienes, and resolvins, which reduce translocation of inflammatory mediators to the site of injury. However clinical studies have shown conflicting results on the use of fish oil as source of n-3 PUFAs in IBD. Previously it was shown that fish oil can cause enrichment with gut pathobionts, and worsened mortality during infectious colitis in mice when added to n-6 PUFA rich diet, but not if combined with other fatty acids, revealing the importance of the background diet. Therefore a diet with reduced n-6 PUFA but higher fibre intake is proposed to be protective in IBD.

Increased small intestinal permeability or so called "leaky gut" has been associated with many chronic conditions as obesity, type 2 diabetes and IBD. Increased intestinal permeability is also one of the potential pathogenetic risk factors for CD identified in up to 20% of our 10 years' longitudinal study population of healthy first-degree relatives (FDR) of Crohn disease patients. Furthermore, certain diets such as high-fat, high-glucose or high-fructose diets can also cause barrier dysfunction and increase the gut permeability, thus increasing the risk of developing metabolic endotoxemia and chronic intestinal inflammation. In contrast, reducing small intestinal permeability attenuates experimental colitis. These findings suggest that reduction of the gut permeability may reduce the risk factors leading to development of CD in FDR of CD patients.