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。最近，肠道微生物群已被认为是一个新的因素，积极参与能量代谢和肥胖及相关疾病的发展。胃肠道微生物群的组成在很大程度上受到饮食的影响，高脂肪饮食被认为会诱导肠道微生物群增加能量收获的能力，尽管肠道微生物群如何影响肥胖发展的机制仍然难以捉摸。在这里，我们将集中在短链脂肪酸（SCFA：主要是乙酸酯，丙酸酯和丁酸酯）的作用，这是由细菌发酵的膳食纤维。我们的目标是澄清一个明显的悖论，即纤维和SCFA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，我们想要测试以下假设：（i）纤维对饮食诱导的肥胖的影响随时间而变化（有益的短期影响vs.肥胖促进长期影响）。(ii)通过发酵产生的SCFA组合物影响宿主能量代谢（乙酸盐作为促进肥胖的SCFA而丙酸盐作为预防肥胖的SCFA）。(iii)膳食脂肪和纤维类型之间的相互作用导致建立具有不同致肥胖潜力的肠道微生物群（促进肥胖与预防肥胖）。为此，我们将使用补充有不同类型的纤维和具有不同乙酸酯：丙酸酯比率的SCFA混合物的高脂肪饮食对小鼠进行喂养研究，喂养不同的时间段。我们将研究微生物发酵（盲肠，门静脉和外周血中的SCFA浓度），微生物群组成和宿主能量代谢（饮食消化率，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）。为了阐明机制，我们将进一步分析肠通透性、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GLP 1）的表达，以及肠粘膜、肝脏和脂肪组织中SCFA受体FFA 3和FFA 3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.