The role of enteropathy in the pathogenesis of severe acute malnutrition in HIV-infected African children

在全球范围内，营养不良是5岁以下儿童死亡的常见原因。在非洲，许多因严重营养不良(称为SAM)而入院的儿童存在潜在的艾滋病毒感染。与因食物短缺而患上SAM的儿童相比，同时感染艾滋病毒和SAM的儿童(称为HIV-SAM)死亡或发生严重感染的风险更高，如血液中毒(败血症)、肺炎或迁延性腹泻。艾滋病毒-SAM的结果比SAM本身糟糕得多的原因尚不清楚。我们认为一个重要的因素可能是肠道衬里的严重损伤。SAM和HIV都是针对肠道的，肠道会发炎并“渗漏”。通常情况下，生活在肠道中的无害细菌能够穿过受损的肠壁进入血液中(所谓的微生物易位)。因此，肠道中的细菌可能会导致败血症和肺炎等感染，或者可能会持续刺激免疫系统(这一过程称为炎症)，这对营养不良的儿童可能特别危险。我们认为，艾滋病毒和SAM的“双重打击”共同导致更严重的肠道损伤(称为肠病)，导致更高的死亡机会，更低的营养不良恢复机会，以及更大的感染和炎症风险。我们计划从南部非洲的三家医院(一家在赞比亚，两家在津巴布韦)招募100名SAM儿童和100名HIV-SAM儿童，以比较肠道损伤、微生物易位和炎症的数量。这些儿童将与200名营养良好的儿童进行比较，其中一半是艾滋病毒阳性，一半是艾滋病毒阴性。我们将通过对血液、尿液和粪便样本进行测试，调查每组儿童的肠道损伤、炎症和渗漏情况。在患有SAM和HIV-SAM的儿童中，我们将看到胃内容物的酸性程度。胃酸是阻止有害细菌进入肠道的一种非常重要的屏障，我们认为与SAM儿童相比，HIV-SAM儿童的胃酸可能较弱。一些患有SAM和HIV-SAM的儿童腹泻持续时间很长，死亡的几率很高，尽管我们不清楚到底是什么导致了腹泻。通过使用小型望远镜观察肠道内部并采集活检样本，我们可以看到小肠(位于胃之外的那部分)的衬里受损程度，并试图准确地找出肠壁的哪些组成部分受到了损害。我们将通过寻找血液中细菌或细菌碎片的证据来比较不同组之间的微生物易位。我们还可以观察感染HIV-SAM的儿童的免疫系统是否比SAM儿童对细菌的反应更强烈。如果我们在血液中发现细菌，即使是非常低的水平，我们也可以通过分析胃液样本来判断它们是否来自肠道。我们将从胃液中提取任何细菌的DNA，并放大数量，以便能够‘读取’DNA序列(就像条形码)，以准确地查看存在哪些细菌。我们将测量每组儿童的免疫系统被刺激的程度，并试图找出当儿童营养不良时，更高水平的炎症是否会损害身体的新陈代谢。由于目前有最好的治疗方法，大约三分之一的艾滋病毒-SAM儿童死亡，迫切需要找到降低这一高死亡率的方法。如果我们证明肠病是一个重要的因素，并且它确实会导致微生物移位和炎症，我们可以在治疗艾滋病毒-SAM儿童时使用额外的药物，试图修复肠壁，阻止细菌进入血液，或者关闭炎症，这可能会提高儿童的存活率。

Globally, malnutrition is a common cause of death in children less than 5 years of age. In Africa, many children who are admitted to hospital with severe malnutrition (termed SAM) have underlying HIV infection. Compared to children who develop SAM because of food shortage, children with HIV and SAM together (termed HIV-SAM) have a higher risk of dying or developing severe infections like blood poisoning (septicaemia), pneumonia or protracted diarrhoea. The reason why the outcome of HIV-SAM is so much worse than SAM alone is not clear. We believe that one important factor may be severe damage to the lining of the gut. Both SAM and HIV target the gut, which becomes inflamed and 'leaky'. Usually harmless bacteria living in the gut are then able to pass across the damaged gut wall into the bloodstream (so-called microbial translocation). Bugs from the gut may therefore cause infections like septicaemia and pneumonia, or may continually stimulate the immune system (a process called inflammation), which may be particularly dangerous in children with malnutrition. We believe that the 'double hit' of HIV and SAM together causes more severe gut damage (termed enteropathy), leading to a higher chance of dying, a lower chance of recovering from malnutrition and a greater risk of infections and inflammation. We plan to recruit 100 children with SAM and 100 children with HIV-SAM from three hospitals in southern Africa (one in Zambia and two in Zimbabwe), to compare the amount of gut damage, microbial translocation and inflammation. These children will be compared to 200 well-nourished children, half of whom are HIV-positive, and half of whom are HIV-negative. We will investigate how damaged, inflamed and leaky the gut is in each group of children, by doing tests on blood, urine and stool samples. In children with SAM and HIV-SAM we will see how acidic the stomach contents are. Stomach acid is a very important barrier against harmful bugs getting into the intestines, and we think the acid may be weaker in children with HIV-SAM, compared to children with SAM. Some children with SAM and HIV-SAM have very protracted diarrhoea and have a high chance of dying, although we do not understand exactly what causes the diarrhoea. By using a small telescope to look inside the gut and take biopsy samples, we can see how damaged the lining of the small intestine (the part of the intestine just beyond the stomach) is, and try to work out exactly what components of the gut wall have been damaged. We will compare microbial translocation between groups by looking for evidence of bacteria, or bits of bacteria, in the bloodstream. We can also look to see if the immune system is being triggered to respond to bugs more in children with HIV-SAM than children with SAM. If we find bacteria in the bloodstream, even at very low levels, we can see whether they have come from the gut by analyzing a sample of stomach juice. We will extract the DNA of any bacteria from the stomach juice, and amplify up the amount to be able to 'read' the sequence of the DNA (like a barcode) to see exactly which bugs are present. We will measure how much the immune system is being stimulated in each group of children, and try to work out if a higher level of inflammation is damaging to the body's metabolism when a child is malnourished. With the very best treatment available at the moment, around 1 in 3 children with HIV-SAM die, and there is an urgent need to find ways of reducing this high mortality. If we show that enteropathy is an important factor, and that it does lead to microbial translocation and inflammation, we could use extra medicines when treating children with HIV-SAM to try to repair the gut wall, stop bugs crossing into the bloodstream, or switch off inflammation, which may improve children's survival.