HDHL MICA GENETIC CARBOHYDRATE MALDIGESTION AS A MODEL TO STUDY FOOD HYPERSENSITIVTY MECHANISM AND GUIDE PERSONALISED TREATMENT USING A NON-INVASIVE
Lead Research Organisation:
University of Nottingham
Department Name: School of Medicine
Abstract
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
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
Technical Summary
Food intolerance (including food aversion) accounts for most adverse food responses, affecting 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 "organic" IBS who carry hypomorphic (defective) sucrase-isomaltase (SI) gene variants. This carbohydrate malabsorption is characterized by diarrhea, abdominal pain and bloating, which are also features of IBS. Similarly, to the congenital SI deficiency (CSID), these SI variants (Phe15Val) are characterized by reduced in vitro disaccharidase activity. Expected prevalence of single and double carriers for this variant, in those with the European ancestry, are 40% and 10% respectively. These observations suggest that DNA variation in the SI gene affects the risk of carbohydrate malabsorption in a continuum, 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 hydrogen and/or methane is produced, and a rise detected in the breath, if the tested carbohydrate reaches fermenting bacteria before being digested/absorbed in the small bowel. These tests do not
indicate whether gas production takes place in the small bowel and/or the colon. Nor do they indicate whether other factors like gut distension or intraluminal water content play a role in symptom generation. Members of our team have developed a multiparametric magnetic resonance imaging (MRI) platform which has been successfully utilised to study IBS. We propose a
three-component study to assess: the prevalence of gene variants predisposing to carbohydrate malabsorption in a large number of IBS patients; their in vitro functional characterization; and their in vivo mechanistic consequences using MRI.
indicate whether gas production takes place in the small bowel and/or the colon. Nor do they indicate whether other factors like gut distension or intraluminal water content play a role in symptom generation. Members of our team have developed a multiparametric magnetic resonance imaging (MRI) platform which has been successfully utilised to study IBS. We propose a
three-component study to assess: the prevalence of gene variants predisposing to carbohydrate malabsorption in a large number of IBS patients; their in vitro functional characterization; and their in vivo mechanistic consequences using MRI.
