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个部位的健康，包括肠道。大肠的症状、紊乱和疾病是焦虑、看全科医生和就医的主要原因。特别是，大肠是癌症发展最常见的部位之一。关于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（如肥胖）会影响大肠癌（结直肠癌；CRC）的癌症风险。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品或膳食剂来避免。确定有益的膳食制剂需要进行干预研究，即仔细控制实验，在实验中，志愿者被给予已知量的试验制剂。出于实际和伦理的原因，在这样的实验中使用癌症的发展作为终点是不合适的，有必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胆固醇浓度作为替代结果测量（或生物标志物）。不幸的是，在饮食和肠道健康领域，由于缺乏可靠的结直肠癌风险生物标志物作为替代终点，进展受到阻碍。为了解决这一差距，我们开发了许多新的与饮食相关的结直肠癌风险的生物标志物，这些标志物可以在大肠临床检查期间通过小样本（活检）进行测量。我们已经证明，这些生物标志物可以在结直肠癌发展之前检测到，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，我们正在横断面研究中调查人们的饮食（以及生活方式的其他方面）与这些生物标志物之间的关系。下一个合乎逻辑的步骤是测试最有希望的生物标志物对饮食干预的反应，以确定它们作为肠道健康生物标志物的用处。为了做到这一点，我们将进行一项精心控制的实验，志愿者将被给予抗淀粉（RS）和聚葡萄糖（PD）的食物补充剂，这两种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结直肠癌的风险。这两种食物制剂在大肠中都显示出生物活性，它们似乎对肠道生理和免疫功能有有益的影响，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膜的微小捏捏样本（粘膜活检）以进行生物标志物测量。这些生物标记研究将包括测量已知与癌症发展的早期阶段有关的基因，这些基因可能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DNA甲基化调节标记来影响基因的开启和关闭方式，因此我们将量化一组关键癌症相关基因的DNA甲基化。我们还将测量肠壁细胞生成（细胞增殖）的速率，因为细胞增殖速度越快，CRC风险越高。此外，我们将收集血液和粪便来测量炎症标志物。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，这可能易患结直肠癌。通过大肠细菌的发酵，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.