欧美医界谈断食法防治“新冠”之二（20230113）
一、理论泛说可能防治
Fasting off “The COVID-19” (Missouri Medicine 2021-04-03)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8029627/
(Extract) Intermittent fasting not only provides a cost-effective method of losing weight, it also has long lasting health benefits. Several dietary interventions have shown to improve cardiovascular risk involving limiting calorie intake during a given period. Participants have seen improvements in weight, blood pressure, and insulin sensitivity. Intermittent fasting is similar to caloric restriction, with the subtle caveat that it focuses on the timing of consumption of the meals.
The Circadian Rhythm hypothesis involves timing of fasting allowing for optimization of organ systems. Eating later in the day is associated with higher postprandial glucose levels which have been shown to increase the risk of diabetes mellitus. Fasting regimens that allow eating during the middle of the day had better weight loss with less adipose, better glucose control, lower lipid levels and decreased inflammation. Conversely, time restriction that only allows late afternoon or evening intake (after 4:00 p.m.) saw no improvement and worsening glucose control, blood pressure, and lipid levels.
With obesity rates continuing to rise, and the restrictions placed by the COVID-19 pandemic limiting physical activity, it only makes sense that people are snacking more, showing an increase in the rates of depression, and gaining weight. we recommend finding an at-home body weight exercise routine. we would recommend focusing on a healthier diet at home. These practices along with well-studied intermittent fasting strategies as outlined above are likely to lead to sustained weight loss in a cost-efficient manner; both facets that are currently necessary during the current global pandemic.
《禁食防治“新冠”》（《密苏里医学》2021-04-03）
（摘录）间歇性断食不仅是一种经济有效的减肥方法，而且对健康也有长期持久的益处。数种饮食干预措施（包括在特定时间限制热量摄入）已被证明可改善心血管风险。参与者的体重、血压和胰岛素敏感度均有所改善。间歇性断食与热量限制相似，但需要注意的是，它关注的是进食的时间。
昼夜节律假说涉及禁食时间，以便优化器官系统。一天中较晚进食与较高的餐后血糖水平相关，已被证明会增加糖尿病的风险。允许在中午进食的禁食方案减少脂肪，更好地减轻体重，更好地控制血糖，更低的血脂水平和减少炎症。相反，仅允许下午晚些时候或晚上（下午4:00之后）进食的时间限制没有改善，而且血糖控制、血压和血脂水平恶化。
随着肥胖率继续上升，以及“新冠”疫情对体育活动的限制，人们吃更多的零食，抑郁症发病率增加，体重增加是有道理的。我们建议找到一个在家锻炼的方法，建议在家里注意健康的节制饮食。上述这些做法，以及经过充分研究的间歇性断食策略，可能会以经济有效的方式持续减轻体重。这两个方面在当前全球疫情期间都是必要的。
二、深研可能防治机理
（一）原始论文
Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19 (Nature 2022-07-28)
https://www.nature.com/articles/s41586-022-05128-8
(Abstract) Anorexia and fasting are host adaptations to acute infection, and induce a metabolic switch towards ketogenesis and the production of ketone bodies, including β-hydroxybutyrate (BHB). However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we show that the production of BHB is impaired in individuals with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) but not in those with influenza-induced ARDS. We found that BHB promotes both the survival of and the production of interferon-γ by CD4+ T cells. Applying a metabolic-tracing analysis, we established that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but could be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we show in mice that a ketogenic diet and the delivery of BHB as a ketone ester drink restores CD4+ T cell metabolism and function in severe respiratory infections, ultimately reducing the mortality of mice infected with SARS-CoV-2. Altogether, our data reveal that BHB is an alternative source of carbon that promotes T cell responses in pulmonary viral infections, and highlight impaired ketogenesis as a potential confounding factor in severe COVID-19.
(Extract) Our results thus indicate that an additional mechanism beyond immune overactivation underlies severe COVID-19 pathology. We reveal ketogenesis as a metabolic program that promotes type 1 immunity and prevents the pathogenic remodelling of the airway epithelial tissue. Although, therapeutic (as opposed to prophylactic) relevance has yet to been assessed, our discovery highlights the potential of BHB and a ketogenic diet as a broadly applicable treatment to enhance functional T cell responses in nutrient-deprived environments, which are commonly observed in the context of infections but also tumour growth. In summary, our study establishes a better understanding of how dysregulated host metabolic adaptations to infections may contribute to poor outcomes in COVID-19.
《在“新冠”患者中，生酮受损与T细胞功能障碍相关》（《自然》2022-07-28）
（概要）厌食和禁食是宿主对急性感染的适应，并诱导代谢向酮生成和酮体的产生转变，包括β-羟基丁酸（BHB）。然而，酮体生成是否在代谢上影响肺部感染的免疫反应尚不清楚。我们在本文中表明，在SARS-CoV-2诱导的急性呼吸窘迫综合征（ARDS）患者中BHB的产生受损，但在流感诱导的ARDS患者中未受损。我们发现BHB可以促进CD4+T细胞的存活和γ干扰素的产生。应用代谢示踪分析，我们确定BHB提供了一种替代碳源，用于燃料氧化磷酸化（OXPHOS）和生物能量氨基酸和谷胱甘肽的生产，这对维持氧化还原平衡至关重要。SARS-CoV-2诱导的ARDS患者T细胞耗散并向糖酵解倾斜，但BHB可在代谢上重编程，以执行OXPHOS，从而增加其功能。最后，我们在小鼠中发现，生酮饮食和将BHB作为酮酯饮料递送可以恢复严重呼吸道感染中的CD4+ T细胞代谢和功能，最终降低感染新冠病毒的小鼠的死亡率。总之，我们的数据表明，BHB是一种可替代的碳来源，可促进肺部病毒感染中的T细胞反应，并强调生酮受损是重症“新冠”的潜在混杂因素。
（摘录）我们的结果表明，除了免疫过度激活之外，还有其他机制是重度“新冠”病理的基础。我们展示了生酮作为一种代谢程序，可促进1型免疫并预防气道上皮组织的致病性重塑。尽管治疗(相对于预防)的相关性还有待评估，但我们的发现突出表明，BHB和生酮饮食作为一种广泛适用的治疗方法，在营养缺乏的环境中增强功能性T细胞反应的潜力，这在感染和肿瘤生长的环境中很常见。总之，我们的研究更好地了解了宿主对感染的代谢适应失调可能如何导致“新冠”患者的不良结果。
（二）中文介评
《感染新冠后禁食竟有奇效？这篇nature研究给出了答案！》（生命科学前沿2022-11-20）
https://mp.weixin.qq.com/s/SDFMsYTV3q6nkAetfRvFIA
（摘录）感染诱发的厌食是一种进化上保守的疾病行为，可介导保护性或有害的免疫功能。禁食条件会明显改变代谢燃料供应，而这与癌症、心血管疾病和神经退行性疾病的疾病症状减轻相关。在禁食条件下，游离脂肪酸在肝脏中β-氧化合成酮体β-羟基丁酸（BHB），并作为替代能量被外周组织（如肌肉、心脏和大脑）吸收。BHB不仅是一种能源燃料，而且是一种具有细胞信号传导能力的多功能分子，对免疫细胞产生直接影响。
BHB生成减少与重症COVID-19患者的CD4+ T细胞功能受损相关。通过生酮饮食或口服酮酯补充BHB可增强CD4+ T细胞的生存及其产生IFN-γ的能力，增强抗病毒免疫应答。作者进行了一系列体外实验，以证明BHB可改善线粒体功能。低BHB水平可能是新冠肺炎患者发展为重症的预测危险因素。
本研究确定了酮体BHB作为线粒体OXPHOS的替代碳源，从而在感染诱导的厌食条件下对Th1细胞进行代谢重编程，并改善抗病毒免疫，建议将生酮饮食作为增强抗病毒免疫的治疗策略。这些重要的发现拓宽了对饮食影响抗病毒免疫的知识，并为与COVID-19相关的不同发病率提供了新的见解和理解。
生酮饮食（ketogenic-diet，简称KD），通常是指碳水化合物含量非常低、蛋白质含量适中、脂肪含量高的饮食，旨在诱导酮病或酮体的产生。医学监督下的极低碳水化合物的饮食，膳食脂肪与膳食蛋白质和碳水化合物的比例为4：1或3：1。
生酮饮食也存在许多对健康的长期影响，如：骨质减少、骨质疏松与低钙血症、肾结石、心肌病、继发性肉碱缺乏、缺铁性贫血、高尿酸血症、转氨酶升高、非酒精性脂肪肝、全身葡萄糖不耐受、中性粒细胞功能障碍、微量元素缺乏、低蛋白血症以及生长障碍等。2021年9月，美国责任医师协会等研究人员对生酮饮食进行了全面评估，权衡生酮饮食与慢性病的利弊关系，研究结果认为，对大多数人来说，生酮饮食的风险大于益处。
尽管此次这篇nature杂志发表的研究在小鼠和体外研究中发现生酮饮食对COVID-19重症有积极效果，但是也仅仅是基础研究层面，还需要更进一步的临床研究和长期随访来评价生酮饮食对COVID-19患者的治疗效果。
｛编者注：禁食可激发人体产生酮。生酮饮食并非禁食，而是通过特定内容的饮食直接补入酮或引发人体产生酮。｝
三、前期禁食效果调研
（一）原始论文
Association of periodic fasting with lower severity of COVID-19 outcomes in the SARS-CoV-2 prevaccine era an observational cohort from the INSPIRE registry (BMJ 2022-07-01)
https://nutrition.bmj.com/content/early/2022/06/30/bmjnph-2022-000462
(Abstract) Routine periodic fasting was associated with a lower risk of hospitalisation or mortality in patients with COVID-19. Fasting may be a complementary therapy to vaccination that could provide immune support and hyperinflammation control during and beyond the pandemic.
WHAT IS ALREADY KNOWN ON THIS TOPIC? During a period of energy restriction, fasting controls inflammation by dampening the cytokine cascade, it enhances autophagy, and it switches the metabolic source of energy from glucose to fats, including by increasing circulating free fatty acids such as linoleic acid.The SARS-CoV-2 receptor binding domains bind linoleic acid in pockets that, when bound, reduce spike protein affinity for ACE 2.Repeated fasting boosts basal levels of some parameters related to inflammation control and host defence against infections, including galectin-3, and it ameliorates insulin resistance and cardiovascular risks such that periodic fasting is associated with greater survival and lower risk of heart failure, coronary artery disease and type 2 diabetes.
WHAT THIS STUDY ADDS? This observational longitudinal cohort study found that routine low-frequency periodic fasting for an average of >40 years was associated with a lower risk of COVID-19, measured as a composite of hospitalisation or mortality after COVID-19 diagnosis.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY? Intermittent fasting should be further evaluated for potential short-term and long-term preventive or therapeutic use as a complementary approach to vaccines and antiviral therapies for reducing COVID-19 severity.
(Extract) Periodic fasting was previously reported to be associated with lower mortality and lower HF incidence in a cohort of almost 2000 patients.A trend towards lower MI incidence was also found in that study. Further, periodic fasting was associated with a lower risk of CAD and a lower risk of diabetes in cross-sectional studies.In the present study, in addition to the association of periodic fasting with a lower risk of hospitalisation or mortality, various factors including many comorbidities were associated with a greater risk of hospitalisation or mortality. These findings support published predictors of COVID-19 severity, and extend the list by adding routine fasting as a predictor of lower COVID-19 severity.
Previously in a study of 24-hour water-only intermittent fasting, fatty acids including linoleic acid were increased during fasting. Linoleic acid locks the spike protein of SARS-CoV-2 in a conformation that is not conducive to the effective binding to ACE2. Elevated linoleic acid during fasting may, thus, lessen the number of infected cells or the number of SARS-CoV-2 virions in cells and thereby decrease the severity of COVID-19. Ketogenic diets that cause a switch of energy source from glucose to fatty acids/ketones should also provide this benefit. This provides one mechanism in which fasting may directly enhance immune function related to COVID-19 mitigation, while other more general immune-related mechanisms exist.
A loss of appetite is a typical response to infection, which may indicate that the human body has intrinsic mechanisms for initiating fasting in order to activate the immune system, as proposed by an animal study. While that finding requires testing in humans, other evidence supports the activation of general immune responses and autophagy by fasting. Interestingly, small human studies reveal that intermittent fasting blunts CD4+ T cell responsiveness during fasting by upregulating insulin-like growth factor binding protein 1 and FOXO4/FK506-binding protein 5, and that fasting generally suppresses the production of proinflammatory cytokines. Often in severe COVID-19 the human immune system over-reacts to SARS-CoV-2 infection and the consequent hyperinflammation can result in respiratory failure. Fasting during an active infection could, thus, bolster the immune response through pathways not involved in the standard inflammatory response to infection while minimising severe inflammatory outbursts. It may also counteract the inhibition of autophagy that is caused by SARS-CoV-2. Immunomodulation by fasting and its effects on autophagy with respect to COVID-19 require further study.
Very frequent intermittent fasting such as alternate-day fasting or uninterrupted multiple-day fasting is challenging. Even lower frequency or shorter duration fasting (eg, 16-hour time-restricted eating or 24-hour once-per-week fasting) over a long period of time (ie, years/decades) may prevent chronic disease onset or reduce the severity of existing chronic diseases and, thus, prepare the body to prevent severe COVID-19 outcomes. This may occur as fasting prevents or treats morbidities that increase the risk of severe COVID-19 outcomes, such as CAD, MI, HF and diabetes. A variety of mechanisms may be involved in the long-term prevention and treatment of those diseases (which mechanisms are beyond the scope of this study), and, as a preventive health practice, periodic fasting may indirectly prevent severe COVID-19 by its long-term impacts on those disease mechanisms and comorbidities.
The findings of this study may not generalise to the overall population and interpretation should be made with caution. Unfortunately, no data on common side effects of fasting such as muscle loss were available here and such potential side effects should be considered in future studies. As with all medical interventions, assessment of the risks and not just the benefits of intermittent fasting should be made when considering its use for health purposes, including for people with chronic diseases.
Conclusions: Routine periodic fasting was associated with a lower risk of hospitalisation or mortality in patients with COVID-19. While fasting is not a panacea or a quick fix for health problems, low-frequency fasting improves cardiometabolic health even without significant weight loss, and multiple biological mechanisms and epidemiological results support the idea that consistent fasting may limit COVID-19 severity. Fasting may do so via acute but temporary physiological changes during energy deprivation and by persistent modification of basal physiological norms and reduction of chronic disease risks across repeated fasting episodes. The primary mechanisms may include hyperinflammation control and strengthening of some immunity pathways.
Sustainable intermittent fasting regimens deserve further investigation for potential short-term and long-term preventive or therapeutic use as a complementary therapy to vaccines to reduce COVID-19 severity, both during the pandemic and postpandemic since repeat vaccinations cannot be performed every few months indefinitely for the entire world and vaccine access is limited in many nations. Investigations of the effect of fasting on long COVID-19 should be included in new studies that are conducted.
《在“新冠”疫苗前时期，定期禁食与“新冠”结果严重程度较低的关联：来自INSPIRE登记处的观察队列》（《英国医学杂志》在线2022-07-01）
（概要）定期常规禁食与“新冠”患者较低的住院或死亡风险相关。禁食可能是疫苗接种的一种补充疗法，可提供免疫支持以及在疫病期间和疫病之后控制过度炎症。
关于这一主题，我们已经知道了什么？在能量限制期间，禁食通过抑制细胞因子级联来控制炎症、增强自噬，并将能量的代谢来源从葡萄糖转换为脂肪，包括增加循环中的游离脂肪酸（如亚油酸）。新冠病毒受体结合域与亚油酸结合在一起，当亚油酸结合时，会降低刺突蛋白对ACE2的亲和力。反复禁食可提高与炎症控制和宿主抵御感染有关的某些参数的基础水平，包括半乳糖凝集素-3，并可改善胰岛素抵抗和心血管风险，因此定期禁食可提高生存率，降低心力衰竭、冠心病和2型糖尿病的风险。
这项研究补充了什么？这项观察性纵向队列研究发现，常规的低频率定期禁食平均超过40年与较低的“新冠”风险相关——以“新冠”诊断后的住院或死亡的复合指标衡量。
这项研究可能会对研究、实践或政策产生何种影响？应进一步评估间歇性断食在短期和长期预防或治疗中的潜在作用，作为疫苗和抗病毒治疗的补充，以降低“新冠”的严重程度。
（摘录）此前有报道称，在一个由近2000例患者组成的队列中，定期禁食与较低的死亡率和较低的心力衰竭发生率相关。该研究还发现了心肌梗死发病率较低的趋势。此外，在横断面研究中，定期禁食与较低的冠心病风险和较低的糖尿病风险相关。在本研究中，除了定期断食与较低的住院或死亡风险相关外，包括许多合并症在内的多种因素与较高的住院或死亡风险相关。这些调查结果支持了已发表的“新冠”严重程度的预测因子，并通过增加常规禁食作为较低“新冠”严重程度的预测指标。
在之前的一项仅间断禁食24小时喝水的研究中，包括亚油酸在内的脂肪酸在禁食期间增加。亚油酸将新冠病毒的刺突蛋白锁定在不利于与ACE2有效结合的构象中。因此，禁食期间亚油酸升高可能会减少感染细胞的数量或细胞内新冠病毒粒子的数量，从而降低“新冠”的严重程度。导致能量来源从葡萄糖向脂肪酸/酮类转换的生酮饮食也应提供这一益处。这提供了一种机制，禁食可能直接增强与“新冠”缓解有关的免疫功能，同时还存在其他更普遍的免疫相关机制。
食欲下降是对感染的典型反应，这可能表明人体有内在机制开始禁食，以激活免疫系统，正如一项动物研究提出的。虽然这一发现需要在人体中进行测试，但其他证据支持通过禁食激活全身免疫应答和自噬。有趣的是，小规模人体研究表明，通过上调胰岛素样生长因子结合蛋白1和FOXO4/FK506结合蛋白5减弱禁食期间CD4+ T细胞的反应性，禁食一般会抑制促炎细胞因子的产生。通常在重症“新冠”中，人类免疫系统对新冠病毒感染产生过度反应，随后的过度炎症可导致呼吸衰竭。因此，在活动性感染期间禁食可以通过未参与对感染的标准炎症反应的途径增强免疫应答，同时将严重炎症爆发降至最低。它还可能抵消新冠病毒引起的自噬抑制。禁食的免疫调节及其对“新冠”相关自噬的影响需要进一步研究。
非常频繁的间歇性断食（如隔日断食或不间断的多日断食）具有挑战性。甚至更低频率或更短时间的断食（例如16小时的时间限制性进食，或每周禁食一次24小时），经历一个长的时期（几年/几十年），可以预防慢性疾病的发生或降低现有慢性疾病的严重程度，因此让身体做好准备而预防“新冠”重症的结果。这可能是因为禁食可以预防或治疗疾病——这疾病增加了“新冠”重症的风险，如冠心病、心肌梗死、心力衰竭和糖尿病。这些疾病的长期预防和治疗可能涉及多种机制（那些机制超出了本研究的范围），而且，作为一种预防性的卫生实践，定期禁食可能通过其对这些疾病机制和合并症的长期影响间接预防“新冠”重症。
本研究的结果可能不能推广到整个人群，应谨慎解读。遗憾的是，本研究没有关于禁食的常见副作用（如肌肉减少）的数据，在未来的研究中应考虑这些潜在的副作用。与所有医疗干预措施一样，在考虑将间歇性断食用于健康目的（包括用于慢性病患者）时，应评估其风险，而不仅仅是其益处。
结论：常规定期禁食与新冠患者住院或死亡风险较低相关。虽然禁食不是灵丹妙药或快速解决健康问题的方法，但低频禁食即使没有显著的体重减轻，也能改善心脏代谢健康，多种生物机制和流行病学结果，即持续禁食可能会限制“新冠”的严重程度。禁食可以通过在能量剥夺期间发生急性但暂时的生理变化，以及在反复禁食期间持续改变基础生理指标和降低慢性疾病风险来实现这一点。其主要机制可能包括控制过度炎症和加强某些免疫途径。可持续间歇性禁食方案值得进一步研究，以作为疫苗的短期和长期预防或治疗补充疗法，以减轻新冠的严重程度，无论是在疫情期间还是疫情之后，因为全世界不可能无限期地每隔几个月进行重复疫苗接种，而且许多国家的疫苗获取受到限制。关于禁食对新冠长期后遗症影响的调查应纳入正在进行的新研究中。
（二）中文介评
《少吃一顿就能减轻新冠重症风险？最新医学研究：定期禁食可降低死亡风险，未来可用作新冠补充治疗》（澎湃新闻2022-08-12）
https://m.thepaper.cn/newsDetail_forward_19425911
（摘录）一项最新的医学研究表明，定期饿自己一顿并坚持五年以上的人，得新冠后重症住院或死亡风险更低。研究者认为，这项发现值得进一步深入挖掘，以作为除疫苗之外，对抗新冠疫情的补充性疗法。
在205名新冠患者中，有11%的定期禁食者和28.8%的非定期禁食者出现住院治疗和死亡情况。在1319名实验对象中，有1012名不禁食者，其中132名核酸阳性，比例为13%。而定期禁食组的阳性概率为14.3%。分析数据之后发现，定期禁食与病毒感染概率之间没有显著相关关系。也就是说，定期禁食虽然不能让你远离新冠病毒的感染风险，但在感染新冠之后，可以降低新冠患者成为重症的风险。
而这背后的生命机制，研究团队没有深挖下去，只是根据之前的研究成果，做出了可能性判断：主要的机制可能是定期禁食可以减轻炎症，同时加强身体免疫途径。
虽然还是可能性的推测，但定期禁食可以降低新冠加重风险的事实，是实实在在摆在这里了。
最后，研究团队还表示，这一研究成果值得进一步深挖，评估其潜在的短期以及长期的预防或治疗用途。当然，研究团队也表示，定期节食并不能代替疫苗的作用，“打疫苗+定期节食”对新冠的治疗作用更好。
｛编者注：上述文章对断食法防治“新冠”的评论严谨而积极，但这个主题的科研文章稀少，且都没有长断食（持续断食48小时、72小时乃至更久）在治疗“新冠”轻症、重症上以及消除“新冠”后遗症上的试验研究。期待有较多的相关试验研究和更多的此主题科研文章，促进全球“新冠”疫病的高效抑制、消除。｝