Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
Seeds Scientific Research & Performance, Spire Institute, Geneva, OH 44041, USA.
Oxid Med Cell Longev. 2020 Sep 9;2020:6401341. doi: 10.1155/2020/6401341. eCollection 2020.
Human SARS-CoV-2 infection is characterized by a high mortality rate due to some patients developing a large innate immune response associated with a cytokine storm and acute respiratory distress syndrome (ARDS). This is characterized at the molecular level by decreased energy metabolism, altered redox state, oxidative damage, and cell death. Therapies that increase levels of (R)-beta-hydroxybutyrate (R-BHB), such as the ketogenic diet or consuming exogenous ketones, should restore altered energy metabolism and redox state. R-BHB activates anti-inflammatory GPR109A signaling and inhibits the NLRP3 inflammasome and histone deacetylases, while a ketogenic diet has been shown to protect mice from influenza virus infection through a protective T cell response and by increasing electron transport chain gene expression to restore energy metabolism. During a virus-induced cytokine storm, metabolic flexibility is compromised due to increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that damage, downregulate, or inactivate many enzymes of central metabolism including the pyruvate dehydrogenase complex (PDC). This leads to an energy and redox crisis that decreases B and T cell proliferation and results in increased cytokine production and cell death. It is hypothesized that a moderately high-fat diet together with exogenous ketone supplementation at the first signs of respiratory distress will increase mitochondrial metabolism by bypassing the block at PDC. R-BHB-mediated restoration of nucleotide coenzyme ratios and redox state should decrease ROS and RNS to blunt the innate immune response and the associated cytokine storm, allowing the proliferation of cells responsible for adaptive immunity. Limitations of the proposed therapy include the following: it is unknown if human immune and lung cell functions are enhanced by ketosis, the risk of ketoacidosis must be assessed prior to initiating treatment, and permissive dietary fat and carbohydrate levels for exogenous ketones to boost immune function are not yet established. The third limitation could be addressed by studies with influenza-infected mice. A clinical study is warranted where COVID-19 patients consume a permissive diet combined with ketone ester to raise blood ketone levels to 1 to 2 mM with measured outcomes of symptom severity, length of infection, and case fatality rate.
人类感染 SARS-CoV-2 的死亡率很高，这是由于一些患者产生了与细胞因子风暴和急性呼吸窘迫综合征（ARDS）相关的强烈固有免疫反应。从分子水平上看，这种反应的特征是能量代谢降低、氧化还原状态改变、氧化损伤和细胞死亡。通过增加（R）-β-羟基丁酸（R-BHB）水平的疗法，如生酮饮食或摄入外源性酮体，应该可以恢复改变的能量代谢和氧化还原状态。R-BHB 激活抗炎 GPR109A 信号，并抑制 NLRP3 炎性小体和组蛋白去乙酰化酶，而生酮饮食已被证明可以通过保护性 T 细胞反应和增加电子传递链基因表达来恢复能量代谢，从而保护小鼠免受流感病毒感染。在病毒引起的细胞因子风暴期间，由于活性氧（ROS）和活性氮（RNS）水平升高，代谢灵活性受到损害，这会损害、下调或失活包括丙酮酸脱氢酶复合物（PDC）在内的许多中心代谢酶，从而导致能量和氧化还原危机，降低 B 和 T 细胞增殖，并导致细胞因子产生增加和细胞死亡。据推测，在出现呼吸窘迫的最初迹象时，适度高脂肪饮食加上外源性酮体补充，将通过绕过 PDC 的阻断来增加线粒体代谢。R-BHB 介导的核苷酸辅酶比和氧化还原状态的恢复应该会降低 ROS 和 RNS，从而减轻固有免疫反应和相关的细胞因子风暴，使负责适应性免疫的细胞增殖。拟议疗法的局限性包括以下几点：目前尚不清楚酮症是否会增强人类免疫和肺细胞功能；在开始治疗之前，必须评估酮酸中毒的风险；并且，促进免疫功能的外源性酮体的允许饮食脂肪和碳水化合物水平尚未确定。第三个限制可以通过感染流感的小鼠研究来解决。有必要进行一项临床研究，让 COVID-19 患者摄入允许的饮食并结合酮酯，将血液酮体水平提高到 1 至 2mM，并测量症状严重程度、感染持续时间和病死率等结果。
