Novel therapeutic approaches to malnutrition enteropathy

严重急性营养不良（SAM）通常因感染和代谢紊乱而复杂化，在这种情况下，它成为具有可观死亡率的医疗紧急情况（一个月内死亡率高达35%，取决于并发症的性质）。尽管在社区进行早期的、基于协议的管理可以将死亡率降低到4%，但对于一种影响全世界数十万儿童的良性疾病来说，这仍然是不可接受的。最困难的管理问题之一是SAM合并持续腹泻，表明肠道紊乱，我们称之为营养不良肠病。从以前和现在的工作中我们知道，营养不良性肠病是肠道屏障功能的失败——它吸收营养的能力，同时排除了从出生那一刻起就栖息在肠道中的细菌。在显微镜下，这种屏障失效表现为上皮细胞（肠的内衬细胞层）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，我们就有可能中断营养不良肠病的根本混乱，并挽救成千上万的生命，特别是在非洲和南亚。我们建议测试五种新的治疗方法，试图治愈营养不良的肠病。如果这些成功地扭转了我们在SAM儿童中发现的实验室异常，我们将继续开展一项大规模的多中心临床试验，以衡量几个国家死亡率的降低情况。我们还将展示修复屏障衰竭的新策略的有用性，屏障衰竭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。我们将通过在赞比亚和津巴布韦随机分配患有急性急性腹泻和持续性腹泻的合适儿童，来测试前四种干预措施——牛初乳、n -乙酰氨基葡萄糖、特杜葡肽和布地奈德——与标准治疗的对照。其中最有希望的治疗方法将在一项更深入的研究中进行评估，我们已经知道对这种情况有一定影响的治疗方法-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，我们希望有一种候选治疗方法进行进一步的测试，以及有关其活动的详细信息，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。我们还将生成大量的科学数据，以帮助我们更好地了解破坏的途径，如果干预措施的效果不如我们希望的那样好，这一点至关重要。我们组建的团队借鉴了多年来营养不良肠病的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。非洲的能力建设是我们战略的一个组成部分，我们在这两个国家都有丰富的经验。我们也完全熟悉这项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。在草拟本建议时，已充分考虑道德问题，并详列。

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.