The human gut microbiome as the key link between childhood malnutrition and risk of metabolic disorders in later life in south India

我们的研究旨在了解婴儿肠道微生物群如何影响印度南部儿童和年轻人的营养不良、生长轨迹以及随后发生代谢紊乱（如2型糖尿病和心血管疾病）的风险。印度是世界上人口第二多的国家，虽然有巨大的营养不良负担，但现在也面临着迅速增长的肥胖和非传染性疾病问题，特别是代谢紊乱问题。印度在全球糖尿病发病率中排名第二。饮食西化、日益富裕和城市化被认为是糖尿病和心血管疾病发病率上升的主要原因。然而，这一负担也在向年轻人、不太富裕的人群和农村人口转移。研究表明，生命最初的1000天是决定发育迟缓和肥胖的关键。这个早期阶段也与婴儿肠道微生物群的发育相吻合。我们的研究表明，肠道微生物群可能是早期营养与成年期代谢健康之间的机制联系。有一些强有力的证据支持这一假设。研究表明，与健康个体相比，营养不良个体的肠道微生物群组成存在显著差异。短链脂肪酸是主要的能量来源，它是由细菌发酵从饮食中不可消化的糖中产生的。最近的研究表明，与肥胖儿童相比，营养不良儿童的微生物群特征不同，2岁儿童的肠道微生物群组成有可能识别出那些有肥胖风险的儿童。肠道中的一些细菌负责炎症反应，这与糖尿病等代谢紊乱的风险有关，肠道微生物群的改变与2型糖尿病的胰岛素抵抗有关。肠道微生物还能够产生与心血管疾病有关的化学物质。我们的研究提出了以下问题：(1)印度儿童的生长轨迹与他们的微生物群谱有关吗？(2)我们能否确定与正常和发育不良生长状态变化相对应的微生物群特征的关键变化？(3)肠道感染对微生物群特征和慢性炎症的作用是什么，作为晚年代谢疾病风险的标志？(4)我们能否确定微生物组概况的关键方面，这些方面可以转化为疾病风险代谢标志物的变化，从而找到干预途径？为了进行这项研究，我们将利用从印度南部Vellore出生时招募的300名儿童中收集的广泛临床样本和数据，并随访到青春期。我们将使用储存的粪便样本来定义肠道微生物群随时间的变化，使用储存的血液来测量代谢性疾病的风险标记物，并根据它们的生长轨迹研究结果的差异。我们将继续对该队列进行随访，直至成年，以收集额外的信息和测量，以评估肥胖和代谢紊乱的发病或风险。我们的工作旨在提供证据，证明营养不良和相关的代谢紊乱从很小的时候就与肠道微生物群有关。通过调节肠道菌群，营养不良可能得到控制，或其影响得到改善，从而导致有效治疗干预措施的发展。寻找解决营养不良问题的办法将产生深远影响；预防或纠正营养不良可改善认知发展，从而有助于打破营养不良与贫困之间的循环，对低收入和中等收入国家产生深远的社会和经济影响。

Our research aims to understand how the infant intestinal microbiome affects malnutrition, growth trajectories and the subsequent risk of developing metabolic disorders such as type 2 diabetes and cardiovascular disease, among children and young adults in southern India. India is the second most populous country in the world, and whilst having a huge burden of malnutrition is now also facing a rapidly growing problem of obesity and non-communicable diseases, in particular metabolic disorders. India ranks second in the global diabetes epidemic. Westernisation of diet, increasing affluence and urbanisation are believed to be major causes for this increase in rates of diabetes and cardiovascular diseases. However, this burden is also shifting towards younger people, those less affluent and rural populations. Studies have shown that the first 1000 days of life are key to determining both stunting and obesity. This early period also coincides with development of the infant's intestinal microbiome. Our research puts the gut microbiome as the likely mechanistic link between nutrition in early life and metabolic health in adulthood. There is some strong evidence for this hypothesis. Studies have shown marked differences in the intestinal microbiota composition in malnourished individuals compared to healthy ones. Short chain fatty acids, which are produced by bacterial fermentation from non-digestible sugars in the diet, are major energy sources. Recent studies have shown distinct microbiota profiles in undernourished compared to obese children and that the gut microbiome composition of children at 2 years of age has the potential to identify those that are at risk of obesity. Some of the bacteria that inhabit the intestine are responsible for inflammatory responses, which are linked to risk of metabolic disorders such as diabetes, and gut microbiome alterations are associated with insulin resistance in type 2 diabetes. Gut microbes are also able to produce chemical substances linked to the development of cardiovascular diseases. Our research proposes to investigate the following questions: (1) Are growth trajectories in Indian children linked to their microbiome profiles? (2) Can we identify key changes in the microbiota profiles that correspond with changes between normal and stunted growth states? (3) What is the role of enteric infection on microbiome profiles and on chronic inflammation as a marker of risk of metabolic disease in later life? (4) Can we identify key aspects of the microbiome profiles that translate into changes in metabolic markers of risk of disease leading to a pathway for intervention?To conduct this research, we will make use of an extensive collection of clinical samples and data already collected from a cohort of 300 children recruited at birth in Vellore, Southern India, and followed up into adolescence. We will define the gut microbiome profiles over time using stored stool samples, measure markers of risk of metabolic disease using stored blood, and investigate how the results differ according to their growth trajectories. We will continue to follow up this cohort into adulthood to gather additional information and measurements to assess the onset or risk of obesity and metabolic disorders. Our work aims to provide evidence that malnutrition and associated metabolic disorders are linked to gut microbiome profiles from a very early age. Malnutrition may then be controlled, or its effects modified, by modulating the gut microbiota, and therefore lead to the development of effective therapeutic interventions. Finding solutions to tackle malnutrition will have far-reaching impact; Prevention or correction of malnutrition can lead to improving cognitive development and therefore contribute to breaking the cycle between malnutrition and poverty with far-reaching societal and economic impact in low and middle-income countries.