Novel therapeutic approaches to malnutrition enteropathy

营养不良性肠病的新治疗方法

• 批准号: MR/P024033/1
• 负责人: Paul Kelly
• 金额: $ 77.36万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP024033%2F1
• 关键词: Novel; therapeutic; approaches; malnutrition; enteropathy

Severe acute malnutrition (SAM) is often complicated by infection and metabolic derangements, and in this situation it becomes a medical emergency with appreciable mortality (up to 35%, depending on the nature of the complications, over one month). Although early, protocol-based management in the community can bring the mortality down to 4%, this is still unacceptable for a benign disorder affecting many hundreds of thousands of the world's children. One of the most difficult management problems is SAM complicated by persistent diarrhoea, indicative of an intestinal derangement we refer to as malnutrition enteropathy. We know, from previous and current work, that malnutrition enteropathy is a failure of the barrier function of the intestine - its ability to absorb nutrients while simultaneously excluding the bacteria which inhabit the gut from the moment of birth. Under the microscope this barrier failure appears as gaps in the epithelium - the lining cell layer of the intestine - and it allows microbial components into the bloodstream where they generate an inflammatory response. This process is called microbial translocation and we have evidence that it is one of the critical disturbances leading to deterioration and death in children with SAM. If we can identify treatments to heal this barrier failure we may be able to interrupt the fundamental derangements of malnutrition enteropathy and save many thousand of lives, particularly in Africa and South Asia.We propose to test out five novel treatments in an attempt to heal malnutrition enteropathy. If these are successful in reversing the laboratory abnormalities we have identified in children with SAM, we will go on and carry out a large-scale multi-centre clinical trial to measure any reduction in mortality in several countries. We will also have demonstrated the usefulness of novel strategies for repairing the barrier failure which characterises other disorders common in Europe and North America, such as inflammatory bowel disease and a sort of infectious disorder common in patients in critical care units.We will test the first four interventions - bovine colostrum, N-acetyl glucosamine, teduglutide and budesonide - against standard care by randomising suitable children with SAM and persistent diarrhoea in Zambia and Zimbabwe. The most promising of these will then be evaluated against a treatment which we already know has some impact in this condition - elemental feeding - in a more intensive study designed to provide very detailed confirmation of safety and healing ability in the intestine. Once the two parts of this study are complete, we hope to have a candidate treatment for further testing, as well as detailed information on its activity which will enable us to test it across the world in the most rigorous medical scientific trial format. We will also generate large amounts of scientific data to help us to understand better the pathways of damage, which is essential in case the interventions work less well than we hope.The team we have assembled draws on years of experience of malnutrition enteropathy and the interventions we propose to evaluate, and will establish a scientific consortium in the UK and southern Africa dedicated to reducing the impact of this neglected but important disorder. Capacity development in Africa is an integral part of our strategy, and we have deep experience of this in both countries. We are also fully conversant of the ethical and regulatory requirements of such work, as we are currently engaged in non-therapeutic studies in the same groups of children. Ethical issues have been considered fully in the preparation of this proposal and are set out in detail.

严重急性营养不良（SAM）往往并发感染和代谢紊乱，在这种情况下，它成为一种医疗紧急情况，具有可观的死亡率（高达35%，取决于并发症的性质，超过一个月）。虽然早期，基于协议的管理，在社区可以降低死亡率到4%，这仍然是不可接受的良性疾病影响了世界上成千上万的儿童。最困难的管理问题之一是SAM并发持续腹泻，表明肠道紊乱，我们称之为营养不良肠病。我们知道，从以前和目前的工作，营养不良性肠病是一个失败的屏障功能的肠道-它的能力，吸收营养物质，同时排除细菌居住的肠道从出生的那一刻。在显微镜下，这种屏障失效表现为上皮细胞（肠道的衬里细胞层）中的间隙，它允许微生物成分进入血液，在那里它们产生炎症反应。这个过程被称为微生物易位，我们有证据表明，这是导致SAM儿童恶化和死亡的关键障碍之一。如果我们能够找到治疗这种屏障失效的方法，我们就可以中断营养不良性肠病的根本紊乱，挽救成千上万人的生命，特别是在非洲和南亚。我们建议测试五种新的治疗方法，试图治愈营养不良性肠病。如果这些药物能够成功逆转我们在SAM儿童中发现的实验室异常，我们将继续进行大规模的多中心临床试验，以衡量几个国家的死亡率是否有所降低。我们还将证明修复屏障失效的新策略的有效性，屏障失效是欧洲和北美常见的其他疾病的特征，例如炎症性肠病和重症监护病房患者常见的一种感染性疾病。替度鲁肽和布地奈德-通过随机选择合适的赞比亚和津巴布韦SAM和持续性腹泻儿童进行标准治疗。其中最有希望的将在一项更深入的研究中进行评估，我们已经知道这种治疗对这种情况有一定的影响-元素喂养-旨在提供非常详细的安全性和肠道愈合能力的确认。一旦这项研究的两个部分完成，我们希望有一个候选治疗方法进行进一步的测试，以及关于其活性的详细信息，这将使我们能够在世界各地以最严格的医学科学试验形式进行测试。我们还将产生大量的科学数据，以帮助我们更好地了解损害的途径，这是必要的，以防干预措施的效果不如我们所希望的。我们组建的团队借鉴了营养不良肠病的多年经验和我们建议评估的干预措施，并将在英国和南部非洲建立一个科学联盟，致力于减少这种被忽视但重要的疾病的影响。非洲的能力发展是我们战略的一个组成部分，我们两国在这方面都有丰富的经验。我们也完全熟悉此类工作的伦理和监管要求，因为我们目前正在同一组儿童中进行非治疗性研究。在编写本提案时，已充分考虑到道德问题，并详细列出了这些问题。

项目成果

Colostrum Therapy for Human Gastrointestinal Health and Disease.

• DOI: 10.3390/nu13061956
• 发表时间: 2021-06-07
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Chandwe K;Kelly P
• 通讯作者: Kelly P

TAME trial: a multi-arm phase II randomised trial of four novel interventions for malnutrition enteropathy in Zambia and Zimbabwe - a study protocol

• DOI: 10.1136/bmjopen-2018-027548
• 发表时间: 2019-11-01
• 期刊: BMJ OPEN
• 影响因子: 2.9
• 作者: Kelly, Paul;Bell, Lauren;Prendergast, Andrew
• 通讯作者: Prendergast, Andrew