Increased Propionate Production In The Colon Is Associated With Reduced Appetite Body Weight And Improved Insulin Sensitivity

结肠中丙酸产量的增加与食欲体重减轻和胰岛素敏感性提高有关

• 批准号: BB/H004815/1
• 负责人: Douglas Morrison
• 金额: $ 17.06万
• 依托单位: Scottish Universities Environmental Research Centre
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH004815%2F1
• 关键词: Increased; Propionate; Production; Colon; Associated

Obesity is the greatest public health challenge facing most developed and many developing countries. Obesity is directly related to increased mortality, causing 600 premature deaths in the UK per week. In the current obesity epidemic, using therapeutic foodstuff to tackle obesity is potentially a would be economically viable for industrial partners. Recent epidemiological and experimental studies link the decline in consumption of non digestible carbohydrates (NDC) to the rise in obesity. NDCs are not broken down in the small intestine, but can be fermented by bacteria in the colon, part of the large intestine. Previous studies and our own pilot data shows that increasing the NDC in the diet of animals and humans reduces appetite and body weight and increase insulin sensitivity. Unfortunately, the high doses required to produce these effects are unpalatable and result in side effects, limiting the use of NDC supplements as a treatment for obesity or diabetes. Short chain fatty acids (SCFA) are molecules produced by the fermentation of NDC in the colon and are responsible for the biological effects of NDC. Recently, a receptor has been found that binds SCFAs, and in particular the SCFA propionate. This receptor is found on cells in the large bowel where it stimulates the release appetite-inhibiting hormones, and on fat cells where it acts to decrease the release of free fatty acids. Reducing free fatty acid levels within the body increases the sensitivity of the body to insulin and thus reduces the effect of insulin resistance which is present in type 2 diabetes. Until now, controlling the production of propionate in the colon has been impossible. Both the type of NDC ingested and the gut microbiota of an individual dictate the levels and types of SCFA produced in the colon. Recently, we have developed a novel molecule in which propionate is bound to a carrier molecule. The chemical bond that links proprionate to its carrier molecule cannot be broken down in most parts of the gut. However, in the colon, this chemical bond is broken by the bacteria present there, delivering specific amounts of propionate to the colon. We have shown that supplementing the diet of rats with this proprionate carrier molecule reduces their body weight compared to controls, and that in humans it reduces hunger and food intake. This study will determine the effect of 24 weeks diet supplementation with this propionate carrier molecule on appetite, body weight and insulin sensitivity in obese volunteers. We will test the hypothesis that supplementing the diet with propionate carrier molecule will reduce appetite through gut hormone release and improve insulin sensitivity by reducing the concentration of free fatty acids in circulation. Industry will have an important role in developing products which produce propionate in the colon to reduce appetite and improve insulin sensitivity. In collaboration with Leatherhead Food International we will design foods which can be used to supplement the diet of the general population with proprionate carrier. Demonstrating the link between colonic propionate production and appetite regulation has significant implications for public health given current trends in obesity rates. However, if colonic production of propionate increases satiety, then simply adding any NDC may not be sufficient to increase propionate production to a significant level to impact on satiety. This study will determine if colonic propionate leads to a reduction in appetite and body weight and cause beneficial metabolic change, and will demonstrate proof of principle for using NDC esters to deliver SCFAs to the large intestine. These data will therefore provide valuable information for future studies investigating the effects of SCFAs on appetite regulation and insulin sensitivity. Industry will play an important role in developing products which produce propionate in the colon to reduce appetite and improve insulin sensitivity.

肥胖是大多数发达国家和许多发展中国家面临的最大公共卫生挑战。肥胖与死亡率的增加直接相关，在英国每周导致600人过早死亡。在目前的肥胖流行中，使用治疗性食品来解决肥胖问题对工业合作伙伴来说可能是经济上可行的。最近的流行病学和实验研究将非可消化碳水化合物(NDC)消费量的下降与肥胖症的上升联系起来。NDCs不会在小肠中被分解，但可以被大肠的一部分--结肠中的细菌发酵。先前的研究和我们自己的试点数据表明，在动物和人类的饮食中增加NDC会降低食欲和体重，并增加胰岛素敏感性。不幸的是，产生这些效果所需的高剂量是令人不快的，并导致副作用，限制了NDC补充剂作为肥胖或糖尿病治疗的使用。短链脂肪酸(SCFA)是NDC在结肠中发酵产生的分子，与NDC的生物学效应有关。最近发现了一种受体，可以与SCFA结合，特别是与SCFA丙酸结合。这种受体存在于大肠的细胞上，在那里它刺激抑制食欲的激素的释放，在脂肪细胞上，它的作用是减少游离脂肪酸的释放。减少体内的游离脂肪酸水平会增加身体对胰岛素的敏感性，从而减少2型糖尿病中存在的胰岛素抵抗的影响。到目前为止，控制丙酸在结肠中的产生一直是不可能的。摄入的NDC的类型和个人的肠道微生物区系都决定了结肠中产生的SCFA的水平和类型。最近，我们开发了一种新型的分子，其中丙酸与载体分子结合。连接专有酸与其载体分子的化学键在肠道的大多数部分都无法被破坏。然而，在结肠中，这种化学键被那里存在的细菌打破，将特定数量的丙酸输送到结肠。我们已经证明，与对照组相比，补充这种固有载体分子的大鼠饮食可以减轻它们的体重，而且在人类中，它减少了饥饿和食物摄入量。这项研究将确定24周饮食补充这种丙酸载体分子对肥胖志愿者的食欲、体重和胰岛素敏感性的影响。我们将验证这样一种假设，即补充丙酸载体分子的饮食将通过释放肠道激素来降低食欲，并通过降低循环中游离脂肪酸的浓度来改善胰岛素敏感性。工业将在开发在结肠中产生丙酸以减少食欲和改善胰岛素敏感性的产品方面发挥重要作用。与Leatherhead Food International合作，我们将设计出可用于补充普通人群饮食的食品，并配备适当的载体。鉴于目前肥胖率的趋势，证明结肠丙酸盐的产生和食欲调节之间的联系对公共健康具有重大影响。然而，如果结肠产生的丙酸增加了饱腹感，那么简单地添加任何NDC可能不足以将丙酸的产生增加到显著影响饱腹感的水平。这项研究将确定结肠癌丙酸盐是否导致食欲和体重下降，并导致有益的代谢变化，并将证明使用NDC酯将SCFAs输送到大肠的原理证据。因此，这些数据将为未来研究SCFA对食欲调节和胰岛素敏感性的影响提供有价值的信息。工业将在开发在结肠中产生丙酸以减少食欲和改善胰岛素敏感性的产品方面发挥重要作用。

项目成果

Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism.

肠道微生物群形成短链脂肪酸及其对人代谢的影响。

• DOI: 10.1080/19490976.2015.1134082
• 发表时间: 2016-05-03
• 期刊: Gut microbes
• 影响因子: 12.2
• 作者: Morrison DJ;Preston T
• 通讯作者: Preston T

The role of short chain fatty acids in appetite regulation and energy homeostasis.

• DOI: 10.1038/ijo.2015.84
• 发表时间: 2015-09
• 期刊: International journal of obesity (2005)
• 作者: Byrne CS;Chambers ES;Morrison DJ;Frost G
• 通讯作者: Frost G

Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods.

• DOI: 10.3945/ajcn.115.126706
• 发表时间: 2016-07
• 期刊: The American journal of clinical nutrition
• 作者: Byrne CS;Chambers ES;Alhabeeb H;Chhina N;Morrison DJ;Preston T;Tedford C;Fitzpatrick J;Irani C;Busza A;Garcia-Perez I;Fountana S;Holmes E;Goldstone AP;Frost GS
• 通讯作者: Frost GS

Propionate production from fermentation of selected ß-glucans by gut microbiota in vitro

肠道微生物群体外发酵选定的α-葡聚糖产生丙酸

• DOI: 10.1017/s0029665116000483
• 发表时间: 2016
• 期刊: Proceedings of the Nutrition Society
• 影响因子: 7
• 作者: Harris H

A novel dietary strategy to increase colonic propionate production in humans and improve appetite regulation and bodyweight management

一种增加人类结肠丙酸产量并改善食欲调节和体重管理的新型饮食策略

• DOI: 10.1111/nbu.12157
• 发表时间: 2015
• 期刊: Nutrition Bulletin
• 影响因子: 3.3
• 作者: Chambers E