HDHL MICA GENETIC CARBOHYDRATE MALDIGESTION AS A MODEL TO STUDY FOOD HYPERSENSITIVTY MECHANISM AND GUIDE PERSONALISED TREATMENT USING A NON-INVASIVE

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Food intolerance affects an estimated 20% of the population. In irritable bowel syndrome (IBS), which affects 1 in 10 people, the reported prevalence of food intolerance is as high as 80%. Team members have identified a subset of IBS who carry hypomorphic (defective) gene variant of the sucrase-isomaltase (SI), the enzyme that normally digests carbohydrates, sucrose and starch. This carbohydrate maldigestion (the breakdown of complex carbohydrates by a person's small bowel enzymes) is characterized by diarrohea, abdominal pain and bloating, which are also features of IBS. Similarly, to the congenital SI deficiency (CSID), these SI variants are characterized by reductions in lab testing activity of the SI enzyme. Expected prevalence of single (one gene altered) and double (two genes altered) carriers for this variant, in those subject of the population with the European ancestry, are 40% and 10% respectively. These observations suggest that this genetic alteration of the DNA in the SI gene can determine carbohydrate maldigestion with symptoms ranging from mild IBS-like forms to fully blown severe CSID. Until recently the only technique available for mechanistic carbohydrate maldigestion studies was the breath test. The principle is that gas (hydrogen and/or methane) is produced, and a rise detected in the breath, if the tested carbohydrate reaches fermenting bacteria before being digested and absorbed in the small bowel. These tests do not indicate whether gas production takes place in the small bowel and/or the colon. Further, nor do they indicate whether other factors like gut distension (dilatation of the gut wall generated by increase quantity of gas and/or water) play a role in symptom generation.Members of our team have developed a magnetic resonance imaging (MRI) test which has been successfully utilised to study the gut response to food in IBS. No difference was seen in gut response to carbohydrate, in terms of small bowel water content, gas production, colon gas and volume of distention compared with healthy subjects, whilst the cohort of patient participants with IBS reported more intense symptoms. Although this suggests that altered perception of normal functional food responses may contribute to IBS, participants were not characterised for genetic variants.Aim of the present project is therefore to assess: 1) the number of patients with this genetic alteration liable predisposing to carbohydrate maldigestion in a large group of IBS patients; 2) confirm these genetic alteration correspond to dysfunction of the enzyme in lab testing on human cells; 3) understand the mechanism of symptoms comparing the response to sucrose ingestion of healthy subjects and carriers of the genetic alterations with MRI