Host-microbiome interactions shape the metabolic effects of ketogenic diets

肥胖及其相关的代谢疾病是一场全球健康危机，影响着超过三分之一的美国成年人。人类和动物模型的研究表明，极低碳水化合物，高脂肪生酮饮食（KDs）促进体重减轻，改善葡萄糖耐量，减少胰岛素抵抗和肠道炎症。虽然相关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质，但肝外细胞在介导KDs的全身效应中的作用仍不清楚。这项RO1应用（PA-19-056）的目的是验证一种假设，即饮食诱导的宿主酮体产生的变化选择性地抑制肠道细菌的生长，导致免疫细胞激活减少和代谢表型改善。我们广泛的初步结果，以及该领域越来越多的科学文献，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群的直接影响转移到宿主-微生物群相互作用在介导用于治疗人类疾病的普通饮食效果中的作用。我们相信这些研究在技术上也是创新的，因为我们将利用宿主和肠道微生物组的配对遗传操作，这是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：（目标一）使用一种新的转基因小鼠模型来测试肠道生酮对肠道微生物群的影响；（目标II）利用自然菌株收集和转座子诱变来评估细菌对酮体敏感性的特异性和遗传决定因素；（目的III）使用传统和非生物制剂小鼠来测试kd相关细菌免疫激活在饮食诱导的肥胖中的作用。该研究计划代表了当前肠道微生物组领域对宏量营养素的关注的背离，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生理后果中的重要性。如果成功，这些研究可以显著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，强调有益的相互作用，可能被用来开发未来的益生元和益生菌。

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.