Impact of non-digestible carbohydrates on biomarkers of GI health: a human intervention study

我们吃的东西会影响身体各部分的健康，包括肠道。症状，紊乱和疾病的大肠是焦虑的主要原因，访问全科医生和医疗。特别是，大肠是癌症发展最常见的部位之一。对饮食习惯和相关癌症发病率的大规模观察性研究提供了非常有力的证据，表明饮食选择和营养状况（例如肥胖）影响大肠癌（结直肠癌; CRC）的风险。这些证据非常令人鼓舞，因为它表明，许多肠癌病例可以通过适当的饮食选择和/或通过开发具有抗癌特性的新型食物或饮食制剂来避免。确定有益的饮食制剂需要进行干预研究，即仔细控制实验，其中志愿者被给予已知量的测试制剂。出于实际和伦理方面的原因，在此类实验中使用癌症的发展作为终点很少是合适的，并且需要使用替代结果测量。这类似于在饮食和心脏病风险研究中使用血压或血液胆固醇浓度作为替代结果指标（或生物标志物）。不幸的是，在饮食和肠道健康领域，进展受到缺乏作为替代终点的CRC风险的强大生物标志物的阻碍。为了解决这一差距，我们已经开发了一些新的饮食相关的CRC风险的生物标志物，可以在大肠临床检查期间采集的小样本（活检）中进行测量。我们已经证明，这些生物标志物可以在CRC发展之前检测到，因此可能是识别疾病高风险人群的有用工具。在我们正在进行的工作中，我们正在调查人们吃什么（和生活方式的其他方面）和这些生物标志物之间的关系。下一步是测试最有希望的生物标志物如何对饮食干预做出反应，以确定它们作为肠道健康生物标志物的有用性。我们将通过进行一项精心控制的实验来做到这一点，在这个实验中，志愿者将被给予抗性淀粉（RS）和聚葡萄糖（PD）的食物补充剂-两者都是具有特殊性质的碳水化合物。它们是广泛使用的食品成分，已经有证据表明它们可能有助于降低CRC风险。这两种食品制剂在大肠中显示出生物活性，在大肠中它们似乎对肠道生理学和免疫功能具有有益作用，包括抗炎作用。在我们的人类干预研究中，70名健康志愿者将被给予RS和/或PD或另一种对大肠没有影响的碳水化合物（安慰剂）7周。我们将在干预前后收集肠道内层的微小捏样本（粘膜活检）用于生物标志物测量。这些生物标志物研究将包括测量已知参与癌症发展早期阶段的基因，这些基因可以通过改变饮食来改变。RS和PD等饮食成分可能会通过影响DNA上的调控标记（称为DNA甲基化）来影响基因的开启和关闭，因此我们将量化一组关键癌症相关基因的DNA甲基化。我们还将测量细胞在肠内膜中产生（细胞增殖）的速率，因为更快的细胞增殖似乎表明更高的CRC风险。此外，我们将收集血液和粪便用于测量炎症标志物。越来越多的证据表明，不良饮食和肥胖可导致慢性炎症状态的发展，这可能易患CRC。通过大肠中细菌的发酵，RS和PD可能有助于减少炎症，从而保护肠道健康。

What we eat affects the health of all parts of the body including the gut. Symptoms, disorders and diseases of the large bowel are major causes of anxiety, visits to general practitioners and medical treatment. In particular, the large bowel is one of the commonest sites for cancer development. Large scale observational studies of dietary practices and associated incidence of cancer provide very strong evidence that dietary choices and nutritional status (e.g. obesity) influence risk of cancer in the large bowel (colorectal cancer; CRC). Such evidence is very encouraging because it suggests that many cases of bowel cancer could be avoided by appropriate dietary choices and/or by the development of novel foods or dietary agents with anti-cancer properties. Identification of beneficial dietary agents requires intervention studies i.e. carefully controlled experiments in which volunteers are given known amounts of the test agent. For both practical and ethical reasons, it is seldom appropriate to use the development of cancer as the endpoint in such experiments and there is a need to use surrogate outcome measures. This is analogous to using blood pressure or blood cholesterol concentration as surrogate outcome measures (or biomarkers) in studies of diet and heart disease risk. Unfortunately, in the area of diet and gut health, progress is hampered by the lack of robust biomarkers of CRC risk for use as surrogate endpoints. To address this gap, we have developed a number of novel biomarkers of diet-related CRC risk which can be measured in small samples (biopsies) taken during clinical examination of the large bowel. We have shown that these biomarkers can be detected BEFORE the development of CRC and so may be a useful tool to identify those at higher risk of the disease. In our on-going work, we are investigating relationships between what people eat (and other aspects of lifestyle) and these biomarkers in a cross-sectional study. The next logical step is to test how the most promising biomarkers respond to dietary intervention to determine how useful they will be as biomarkers of gut health. We will do this by carrying out a carefully controlled experiment in which volunteers will be given food supplements of resistant starch (RS) and polydextrose (PD) - both are carbohydrates with special properties. They are widely used food ingredients for which there is already evidence that they may help reduce CRC risk. Both food agents show bioactivity in the large bowel where they appear to have beneficial effects on gut physiology and immune function including anti-inflammatory effects. In our human intervention study, 70 healthy volunteers will be given RS and/or PD or another carbohydrate with no effects on the large bowel (a placebo) for 7 weeks. We will collect tiny pinch samples of the lining of the gut (mucosal biopsies) before and after the intervention for biomarker measurement. These biomarker studies will include measurement of genes which are known to be involved in the early stages of the development of cancer and which may be modifiable by changing diet. Dietary components such as RS and PD may influence how genes are switched on and off by affecting regulatory marks on DNA known as DNA methylation so we will quantify DNA methylation for a panel of key cancer-related genes. We will also measure the rates at which cells are been produced (cell proliferation) in the gut lining because faster cell proliferation appears to indicate higher CRC risk. In addition we will collect blood and stool for measurements of markers of inflammation. There is growing evidence that poor diet and obesity can lead to the development of a chronic inflammatory state and that this may predispose to CRC. Through their fermentation by bacteria in the large bowel, RS and PD may help reduce inflammation and so protect gut health.