Intestinal mcirobiota and the development of diet induced obesity: the role of fiber and short chain fatty acids

许多环境和遗传因素被认为是导致世界范围内肥胖发展增加的原因。近年来，肠道微生物群被认为是一个积极参与能量代谢和肥胖及相关疾病发展的新因素。胃肠道微生物群的组成在很大程度上受饮食的影响，高脂肪饮食被认为可以诱导肠道微生物群增加能量收集能力，尽管肠道微生物群影响肥胖发展的机制仍然难以捉摸。在这里，我们将重点介绍短链脂肪酸（SCFA：主要是醋酸酯、丙酸酯和丁酸酯）的作用，它们是通过细菌发酵从膳食纤维中产生的。我们的目的是澄清一个明显的悖论，即纤维和短链脂肪酸一方面被认为可以预防肥胖和相关疾病的发展，但另一方面可能为宿主提供额外的能量，从而促进肥胖的发展。为了解决这个矛盾，我们想测试以下假设：(i)纤维对饮食引起的肥胖的影响随着时间的推移而变化（有益的短期影响vs.促进肥胖的长期影响）。（ii）发酵产生的短链脂肪酸组成影响宿主的能量代谢（醋酸酯是促进肥胖的短链脂肪酸，而丙酸是防止肥胖的短链脂肪酸）。（iii）膳食脂肪和纤维类型之间的相互作用导致肠道微生物群的建立具有不同的致肥潜力（促进肥胖与预防肥胖）。为此，我们将对小鼠进行喂养研究，使用高脂肪饲料补充不同类型的纤维和具有不同醋酸：丙酸比例的短链脂肪酸混合物，饲喂不同的时间。我们将研究微生物发酵（盲肠、门脉和外周血中的SCFA浓度）、微生物群组成和宿主能量代谢（日粮消化率、能量摄入和消耗、底物氧化、肝脏和脂肪组织脂质和葡萄糖代谢）。为了明确其机制，我们将进一步分析肠道通透性、炎症标志物和代谢性内毒素血症，以及肠源性饱腹激素（PYY和GLP1）的表达，以及肠黏膜、肝脏和脂肪组织中SCFA受体FFA3和FFA3的表达。

Numerous environmental and genetic factors are thought to contribute to the world wide increase in obesity development. Recently, the gut microbiota has been suggested as a new factor to be actively involved in energy metabolism and development of obesity and associated disorders. Composition of the gastrointestinal microbiota is largely influenced by the diet and high fat diets are thought to induce gut microbiota with an increased capacity of energy harvest, although the mechanisms how gut microbiota affects obesity development are still elusive. Here we will focus on the role of short chain fatty acids (SCFA: mainly acetate, propionate and butyrate) which are produced from dietary fibers by bacterial fermentation. We aim to clarify the apparent paradox that fiber and SCFA are on one hand considered to prevent the development of obesity and associated disorders but on the other might provide additional energy to the host which could promote the development of obesity. In order to resolve this paradox we want to test the following hypotheses: (i) Fiber effects on diet induced obesity vary over time (beneficial short term effects vs. obesity promoting long term effects). (ii) The SCFA composition produced by fermentation affects host energy metabolism (acetate as rather obesity promoting SCFA vs. propionate as obesity preventing SCFA). (iii) Interactions between dietary fat and fiber type lead to the establishment of gut microbiota with different obesogenic potential (obesity promoting vs. obesity preventing). To this end we will perform feeding studies with mice using high fat diets supplemented with different types of fiber and SCFA mixtures with different acetate:propionate ratios, fed for different time periods. We will investigate microbial fermentation (SCFA concentrations in caecum, portal and peripheral blood), microbiota composition, and host energy metabolism (diet digestibility, energy intake and expenditure, substrate oxidation, liver and adipose tissue lipid and glucose metabolism). For clarification of mechanisms we will further analyze gut permeability, inflammation markers and metabolic endotoxemia, as well as expression of gut derived satiety hormones (PYY and GLP1), and expression of SCFA receptors FFA3 and FFA3 in intestinal mucosa, liver and adipose tissue.