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

HDHL 云母遗传碳水化合物消化不良作为研究食物过敏机制并指导使用非侵入性个体化治疗的模型

• 批准号: MR/W031213/1
• 负责人: Maura Corsetti
• 金额: $ 32.02万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW031213%2F1
• 关键词: HDHL; MICA; GENETIC; CARBOHYDRATE; MALDIGESTION

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

食物不耐受影响了大约20%的人口。在肠易激综合征（IBS）中，每10人中就有1人受到影响，据报道，食物不耐受的患病率高达80%。小组成员已经确定了一个IBS的子集，他们携带蔗糖酶-异麦芽糖酶（SI）的亚型（缺陷）基因变体，这种酶通常分解碳水化合物，蔗糖和淀粉。这种碳水化合物消化不良（一个人的小肠酶分解复合碳水化合物）的特点是腹泻，腹痛和腹胀，这也是IBS的特征。类似地，对于先天性SI缺陷（CSID），这些SI变体的特征在于SI酶的实验室测试活性的降低。在具有欧洲血统的人群中，该变体的单（一个基因改变）和双（两个基因改变）携带者的预期患病率分别为40%和10%。这些观察结果表明，SI基因中DNA的这种遗传改变可以确定碳水化合物消化不良，症状范围从轻度IBS样形式到完全爆发的严重CSID。直到最近，研究碳水化合物消化不良机制的唯一技术是呼吸试验。其原理是气体（氢气和/或甲烷）产生，并在呼吸中检测到上升，如果测试的碳水化合物在小肠消化和吸收之前到达发酵细菌。这些测试并不表明是否气体生产发生在小肠和/或结肠。此外，他们也没有表明是否其他因素，如肠道扩张（扩张的肠壁产生的增加量的气体和/或水）在症状的产生中发挥作用。我们的团队成员已经开发出一种磁共振成像（MRI）测试，已成功地用于研究肠道反应的食物在IBS。与健康受试者相比，肠道对碳水化合物的反应在小肠含水量，产气量，结肠气体和膨胀量方面没有差异，而IBS患者参与者的队列报告了更强烈的症状。虽然这表明对正常功能性食物反应的感知改变可能导致IBS，但参与者没有遗传变异的特征，因此本项目的目的是评估：1）在一个大的IBS患者群体中，这种遗传变异易诱发碳水化合物消化不良的患者数量; 2）在对人类细胞的实验室测试中确认这些遗传改变对应于酶的功能障碍; 3）通过MRI比较健康受试者和遗传改变携带者对蔗糖摄入的反应，了解症状的机制