DDW 2018: Predicting who will get IBD

To have a chance of preventing IBD clinicians need to be able to predict who is at risk, based on sensitive and selective risk factors. In a translational symposium at DDW 2018, speakers discussed the role of genetics, diet and environment in IBD aetiology.

Interview by Hannah Chatfield

Dr Charles Bernstein (Canada) discusses the risk factors associated with IBD, and how this relates to predicting who will get IBD in the future.

Professor Steven Brant from the Rutgers Robert Wood Johnson Medical School explained that while gastroenterologists can use genetics in gross estimates of IBD risk based on family history of IBD with or without Jewish ancestry, the role of molecular genetics as a predictor of sporadic IBD is limited. Only in Very Early Onset (VEO) IBD, a syndrome where children develop IBD before the age of six which has been shown to be associated with multiple Mendelian genetic disorders, are molecular genetics highly predictive:¹ loss-of-function mutations in IL10 receptor subunits and the IL10 cytokine have been shown to cause severe, autosomal-recessive, fully penetrant CD in the first year of life.² Genetic analysis with whole exome sequencing is now standard of care in VEO-IBD and influences the choice of treatment. In non-syndromic IBD, the results of twin studies indicate that given the level of monozygotic concordance (approximately 30% in CD and 15% in UC), genetic risk factors alone will not be able to predict the majority of IBD cases. A population-based cohort study in a single centre in Manitoba, Canada, showed that NOD2 mutations were an independent risk factor for CD with a three-fold increase in heterozygous individuals and 35 times higher risk in homozygous individuals; however, the estimated penetrance rate of CD in homozygous individuals was 4.9% which means the vast majority of patients will not develop CD.³ Among patients with young-onset IBD only approximately 10% have sufficiently high genetic risk scores to allow high-confidence predictions, and in only 20% of the general population is the genetic risk score low enough to state that young-onset IBD is highly unlikely.⁴ Similar results have been shown in a general IBD population.⁵ According to Professor Brant, the molecular genetic prediction of IBD risk can be improved by weighing IBD risk scores with true dosage effects of dominant and recessive genes, and by including all independent risk haplotypes for each locus through improved fine mapping and taking into account rare variants.^{6, 7} However, it is likely that a large part of the genetic risk of IBD is due to gene-gene and gene-environment interactions.^{8, 9}

Next, Professor Siew Ng from the Chinese University of Hong Kong presented data on how IBD is increasing in Asia which suggests that the answer to predicting IBD may be in our environment. In the West, the first reports of IBD appeared in the mid-1800s when USA and Europe were undergoing rapid industrialisation and urbanisation, and since then the incidence and prevalence of IBD has soared. An almost identical process can now be seen in many countries in Asia where economic growth and increasing affluence has led to more people living in cities and having a westernised lifestyle and diet.¹⁰ While the incidence of IBD appears to be plateauing in the West it continues to increase in Asia.¹¹ In Professor Ng’s opinion, the most likely cause is environmental factors related to changes in diet, hygiene, and travel habits and migration. In India and China where the IBD incidence is the highest in Asia, urban areas with high population density have significantly higher IBD incidence than rural areas where the population density is low.¹² Urbanisation and a westernised diet affect the diversity of the gut microbiome in ways that may incite IBD in genetically susceptible individuals.¹⁰  Improved sanitation and food hygiene, and use of antibiotics and food additives are surrogate markers for urbanisation that are associated with reduced alpha-diversity and increased beta-diversity in the gut microbiome.¹³ Among migrants, children who arrive in more westernised countries with a higher incidence of IBD at a young age are at greater risk of developing IBD than adults,¹⁴ and second-generation migrants develop IBD at a significantly younger age than first-generation migrants;¹⁵ this highlights the importance of exposure to early life events in IBD aetiology and suggests that the hygiene hypothesis may have the greatest impact soon after birth. An Australian study which compared migrants from the Middle East with Australian IBD patients showed that while antibiotic use in childhood was a risk factor in Australian patients, it was in fact protective against IBD among migrants.¹⁵ Similar results were seen in the ACCESS study in which high antibiotic use in childhood was protective against both CD and UC; other protective factors included breast feeding beyond 12 months, daily tea consumption, having access to hot water and a flush toilet, and growing up with dogs.¹⁶

Diet is a hugely important part of the IBD exposome which is likely to have a key role to play in prevention but is also a major challenge in terms of studies. A nested case-control study in the Yunan province in China showed that fried and/or salty foods, frozen dinners, and eating at irregular hours doubled the risk of developing IBD, whereas eating fruit or drinking tea halved the risk.¹⁷ Professor Ng attributed this risk not to the components of fast food as such but rather to specific food additives which are widely used in western diets and that affect the gut microbiome. One example is dietary emulsifiers such as carboxymethyl cellulose and polysorbate-80, that are used in eg mayonnaise and which have been shown to trigger low-grade inflammation in the gut in mice.¹⁸ The ENIGMA study which is currently in progress at centres in China and Australia will use integrated clinical, microbial and dietary datasets to determine how microbial and environmental factors interact in the development of IBD. Another ongoing study, the MECONIUM study, will compare pregnant women with and without IBD to determine whether children born to mothers with IBD have a different environmental exposure. Work is also underway to evaluate tooth matrix components as biomarkers of prenatal exposure to environmental IBD risk factors.

Dr James Lewis from University of Pennsylvania next reiterated the importance of diet in IBD aetiology by emphasising the finding that while faecal diversion has been shown to heal ileal mucosa, exposure to ileal contents will trigger post-operative recurrence in patients with ileocolonic anastomoses¹⁹. The influence of diet on the risk of developing IBD is evident from the very first diet: children who are breast-fed are significantly less likely to develop IBD compared with those who are fed infant formula.²⁰ As children become teenagers the percentage of calories from fast food in the diet almost doubles²¹ which coincides with a dramatic increase in the incidence of IBD.^{22, 23} Microparticle additives which are frequently present in processed food accumulate in macrophages in Peyer’s patches and are known to exacerbate inflammation in CD;^24-26 a study in which CD patients were randomised to either  a low micro particle diet or a control diet for four months showed that the former was associated with a significantly greater reduction in CDAI and a higher remission rate.²⁷ Other studies have shown that exclusive enteral nutrition is superior to partial enteral nutrition for inducing remission²⁸ and reducing FCP levels²⁹ in CD. Dr  Lewis recommended a Mediterranean diet prepared from fresh ingredients as likely to reduce the risk of IBD, in addition to having other health benefits including a reduction of cardiovascular and cancer mortality.³⁰

The PREDICTS study has been designed to gain a better understanding of the asymptomatic preclinical period in IBD during which dysregulated immune pathways are setting the stage for the disease to manifest, with a view to developing predictive algorithms and strategies for preventing IBD.^{31, 32} Professor Jean-Frederic Colombel from Icahn School of Medicine at Mount Sinai in New York presented results from an analysis of the longitudinal evolution and predictive performance of antimicrobial and inflammatory markers in a large population of CD (n=202) and UC (n=200) patients and healthy controls (n=201). Samples tested for ASCA IgA, ASCA IgG, Anti-OmpC, Anti-Cbir1, Anti-FlaX, Anti-Fla2 and pANCA antibodies and protein markers using the Somalogics panel showed that serological markers were significantly elevated many years prior to the IBD diagnosis in CD, and that a simple model which combined serological markers with some of the protein markers had good predictive performance for CD. In UC, no single marker showed acceptable predictive accuracy. The PREDICTS investigators concluded that CD can be predicted with high accuracy at least five years prior to diagnosis.

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