Understanding the effect of a ketogenic diet in colitis

生酮饮食（KD）是儿童癫痫的既定治疗方法，其神经保护作用已在先前的研究中进行了探索。在初步实验中，我们可以显示与葡聚糖硫酸钠（DSS）结肠炎小鼠模型中的经典高碳水化合物标准饮食相比，用生酮饮食进行预防性饮食治疗的深刻保护作用。该项目的目的是进一步确定KD是否以及如何保护小鼠免受实验诱导的结肠炎，并减轻和治疗小鼠现有的结肠炎疾病。在实践中，我们将测试（1）不同饮食和KD组合物在两种急性和两种慢性小鼠结肠炎模型中的作用和代谢安全性。为了评估长期KD施用的可行性和代谢安全性，我们还将在结肠炎实验中使用的C57 B16小鼠的自然寿命期间用测试的饮食进行长期研究。为了了解潜在的保护和代谢机制和变化，我们将评估临床和组织病理学结肠炎疾病活动，并且-由于先前的结果表明KD导致线粒体功能增加-我们将阐明KD对结肠中线粒体数量，蛋白质表达和功能的影响。(2)此外，为了评估与纯低碳水化合物高脂肪饮食（LCHFD）相比KD中酮症的重要性，将在小鼠的实验性结肠炎模型中测试这两种饮食方法。我们还将直接评估酮体（以酮酯形式给药）作为营养素在预防和治疗与标准饮食（SD）或LCHFD相关的实验性结肠炎中的作用。(3)还将在线粒体生物发生和/或功能存在差异的小鼠品系中测试生酮饮食干预的效果。

The ketogenic diet (KD) is an established therapeutic approach in childhood epilepsy and its neuroprotective effects have been explored in previous studies. In a preliminary experiment we could show a profound protective effect of prophylactic dietary treatment with a ketogenic diet as compared to a classic high-carbohydrate standard diet in the dextran sodium sulfate (DSS) mouse model of colitis. The aim of this project is to further establish whether and how a KD can protect from experimentally induced colitis in mice, and can alleviate and treat existing colitis disease in mice. In practice we will test (1) the effect and metabolic safety of different diets and KD compositions in two acute and two chronic mouse colitis models. To assess the feasibility and metabolic safety of long-term KD administration we will also perform a long-term study with the tested diets over the natural life span of the C57Bl6 mice used in the colitis experiments. In order to understand underlying protective and metabolic mechanisms and changes we will assess clinically and histopathologically colitis disease activity and - as previous results suggest an increase in mitochondrial function due to KD - we will elucidate the effect of KD on mitochondrial number, protein expression and function in the colon. (2) Furthermore, in order to assess the importance of ketosis in KD as compared to purely low-carbohydrate high-fat diet (LCHFD) these two dietary approaches will be tested in experimental colitis models in mice. We will also directly assess the effect of ketone bodies (administered as ketone esters) as nutrients for prevention and treatment of experimental colitis in association with either standard diet (SD) or LCHFD. (3) The effect of ketogenic diet interventions will also be tested in mouse strains with differences in mitochondrial biogenesis and/or function.