Host-microbiome interactions shape the metabolic effects of ketogenic diets

肥胖及其相关代谢性疾病代表着一场全球健康危机，影响着超过三分之一的美国成年人。在人类和动物模型中的研究表明，极低碳水化合物、高脂肪的生酮饮食(KDS)可促进体重减轻、改善糖耐量、降低胰岛素抵抗和肠道炎症。虽然所涉及的主要机制被认为是由于肝脏代谢从碳水化合物转变为脂肪，但肝外细胞在介导KDS全身效应中的作用尚不清楚。此RO1应用程序(PA-19-056)的目标是测试以下假设：饮食诱导的酮体宿主生产的变化选择性地抑制肠道细菌的生长，导致免疫细胞活性下降和代谢表型改善。我们广泛的初步结果，加上这一领域不断增长的科学文献，为我们假设的科学前提提供了强有力的支持。这项工作在概念上是创新的，因为它将重点从饮食对肠道微生物区系的直接影响转移到宿主-微生物区系相互作用在调节用于治疗人类疾病的常见饮食的效果方面的作用。我们相信，这些研究也是技术上的创新，因为我们将利用宿主和肠道微生物组的配对基因操作，这是一个在微生物组领域许多研究领域仍然难以实现的总体目标。我们将追求以下具体目标：(一)利用一种新的转基因小鼠模型来测试肠道中酮类生成对肠道微生物区系的影响；(二)利用天然菌株收集和转座子突变来评估细菌对酮体的敏感性的特异性和遗传决定因素；以及(三)使用常规和诺生小鼠来测试KD相关细菌的免疫激活在饮食诱导的肥胖中的作用。这一研究计划偏离了目前肠道微生物组领域对大量营养素的关注，扩大了微生物组研究的范围，以评估宿主-微生物组相互作用在调节特定饮食的生理后果方面的重要性。如果成功，这些研究可以极大地推进我们开发基于微生物组的策略来治疗代谢性疾病的长期目标，重点放在可能被利用来开发未来的益生菌和益生菌的有益相互作用上。

Obesity and its associated metabolic diseases represent a global health crisis, affecting more than one third of US adults. Studies in humans and animal models indicate that very low-carbohydrate, high-fat ketogenic diets (KDs) promote weight loss, improve glucose tolerance, and decrease insulin resistance and intestinal inflammation. While the primary mechanisms involved are thought to be due to a shift in hepatic metabolism from carbohydrates to lipids, the role of extrahepatic cells in mediating the systemic effects of KDs remains unclear. The goal of this RO1 application (PA-19-056) is to test the hypothesis that diet-induced shifts in the host production of ketone bodies selectively inhibit the growth of gut bacteria leading to a decrease in immune cell activation and improved metabolic phenotypes. Our extensive Preliminary Results, together with the growing body of scientific literature in this area, provide strong support for the scientific premise of our hypothesis. This work is conceptually innovative as it shifts the focus from the direct impact of diet on the gut microbiota to the role of host-microbiota interactions in mediating the effects of common diets used to treat human disease. We believe that these studies are also technically innovative as we will leverage the paired genetic manipulation of the host and the gut microbiome, a general goal that remains elusive in the microbiome field for many areas of study. We will pursue the following Specific Aims: (Aim I) the use of a new transgenic mouse model to test the impact of enteric ketogenesis on the gut microbiota; (Aim II) the use of natural strain collections and transposon mutagenesis to evaluate the specificity and genetic determinants of bacterial sensitivity to ketone bodies; and (Aim III) the use of conventional and gnotobiotic mice to test the role of KD-associated bacterial immune activation in diet-induced obesity. This research plan represents a departure from the current focus of the gut microbiome field on macronutrients, expanding the scope of microbiome studies to assess the importance of host-microbiome interactions in modulating the physiological consequences of a given diet. If successful, these studies could significantly advance our long-term goal of developing microbiome-based strategies to treat metabolic disease, with an emphasis on beneficial interactions that might be harnessed to develop the prebiotics and probiotics of the future.