Ketogenic diet alleviates cognitive dysfunction and neuroinflammation in APP/PS1 mice via the Nrf2/HO-1 and NF-κB signaling pathways

Alzheimer's disease is a progressive neurological disorder characterized by cognitive decline and chronic inflammation within the brain.The ketogenic diet,a widely recognized therapeutic intervention for refractory epilepsy,has recently been proposed as a potential treatment for a variety of neurological diseases,including Alzheimer's disease.However,the efficacy of ketogenic diet in treating Alzheimer's disease and the underlying mechanism remains unclear.The current investigation aimed to explore the effect of ketogenic diet on cognitive function and the underlying biological mechanisms in a mouse model of Alzheimer's disease.Male amyloid precursor protein/presenilin 1(APP/PS1)mice were randomly assigned to either a ketogenic diet or control diet group,and received their respective diets for a duration of 3 months.The findings show that ketogenic diet administration enhanced cognitive function,attenuated amyloid plaque formation and proinflammatory cytokine levels in APP/PS1 mice,and augmented the nuclear factor-erythroid 2-p45 derived factor 2/heme oxygenase-1 signaling pathway while suppressing the nuclear factor-kappa B pathway.Collectively,these data suggest that ketogenic diet may have a therapeutic potential in treating Alzheimer's disease by ameliorating the neurotoxicity associated with Aβ-induced inflammation.This study highlights the urgent need for further research into the use of ketogenic diet as a potential therapy for Alzheimer's disease.

Ketone bodies and inflammation modulation:A mini-review on ketogenic diet’s potential mechanisms in mood disorders

Mental disorders such as depression and anxiety inflict significant burdens on individuals and society.Commonly prescribed treatments often involve cognitive therapy and medications.However,for patients resistant to these conventional methods,alternative therapies like the Ketogenic Diet(KD)offer a promising avenue.KD and its key metabolite,β-hydroxybutyrate(BHB),have been hypothesized to alleviate mental disorders through antiinflammatory actions,a crucial pathway in the pathophysiology of depression.This mini-review examines 15 clinical trials exploring the influence of KD and BHB on inflammation and their potential roles in managing mental disorders.Both human and animal studies were scrutinized to elucidate possible cellular and molecular mechanisms.Out of the 15 trials,10 reported reduced levels of at least one inflammatory mediator or mRNA post KD or BHB treatment,while two observed an elevation in anti-inflammatory agents.These findings suggest that KD and BHB could modulate cellular inflammatory pathways,highlighting their potential for therapeutic application in mental disorders.

Very low calorie ketogenic diet and common rheumatic disorders:A case report

BACKGROUND The scientific literature provides evidence that nutritional ketosis can be an important support in the treatment of pathologies in which inflammation is present,as recent studies have shown that ketone bodies have anti-inflammatory activity in numerous diseases,including rheumatic diseases.We report the case of a 22-year-old woman with class I obesity and juvenile idiopathic arthritis who started treatment with a very low calorie ketogenic diet(VLCKD).CASE SUMMARY The patient was a 22-year-old woman diagnosed with juvenile idiopathic arthritis at age 4 years and with a body mass index(BMI)of 30.8 kg/m2,waist circumference(WC)80 cm,fat mass(FM)28.1 kg,free FM 45.7 kg,and visceral adipose tissue(VAT)3.5 kg,assessed on bioimpedance analysis.She was treated using a commercial VLCKD weight-loss program(PNK®method);this program provides high-biological-value protein preparations and natural foods.Each protein preparation contains 15 g protein,4 g carbohydrate,3 g fat,and 50 mg omega-3 docosahexaenoic acid,with an energy content of 90–120 kcal.After four months on the program,the BMI was 28.6 kg/m2,WC 73 cm,FM 23.2 kg,free FM 41.9 kg,and VAT 2.9 kg.CONCLUSION VLCKD enabled the patient to reach her target weight and to reduce her joint pain and headaches.Laboratory inflammatory indices also normalized.

Ketogenic diet poses a significant effect on imbalanced gut microbiota in infants with refractory epilepsy

AIM To investigate whether patients with refractory epilepsy and healthy infants differ in gut microbiota(GM),and how ketogenic diet(KD) alters GM.METHODS A total of 14 epileptic and 30 healthy infants were recruited and seizure frequencies were recorded. Stool samples were collected for 16 S r DNA sequencing using the Illumina Miseq platform. The composition of GM in each sample was analyzed with MOTHUR,and intergroup comparison was conducted by R software.RESULTS After being on KD treatment for a week,64% of epileptic infants showed an obvious improvement,with a 50% decrease in seizure frequency. GM structure in epileptic infants(P1 group) differed dramatically from that in healthy infants(Health group). Proteobacteria,which had accumulated significantly in the P1 group,decreased dramatically after KD treatment(P2 group). Cronobacter predominated in the P1 group and remained at a low level both in the Health and P2 groups. Bacteroides increased significantly in the P2 group,in which Prevotella and Bifidobacterium also grew in numbers and kept increasing.CONCLUSION GM pattern in healthy infants differed dramatically from that of the epileptic group. KD could significantly modify symptoms of epilepsy and reshape the GM of epileptic infants.

Neuroprotective effects of a ketogenic diet in combination with exogenous ketone salts following acute spinal cord injury

We have previously shown that induction of ketosis by ketogenic diet(KD)conveyed neuroprotection following spinal cord injury in rodent models,however,clinical translation may be limited by the slow raise of ketone levels when applying KD in the acute post-injury period.Thus we investigated the use of exogenous ketone supplementation(ketone sodium,KS)combined with ketogenic diet as a means rapidly inducing a metabolic state of ketosis following spinal cord injury in adult rats.In uninjured rats,ketone levels increased more rapidly than those in rats with KD alone and peaked at higher levels than we previously demonstrated for the KD in models of spinal cord injury.However,ketone levels in KD+KS treated rats with SCI did not exceed the previously observed levels in rats treated with KD alone.We still demonstrated neuroprotective effects of KD+KS treatment that extend our previous neuroprotective observations with KD only.The results showed increased neuronal and axonal sparing in the dorsal corticospinal tract.Also,better performance of forelimb motor abilities were observed on the Montoya staircase(for testing food pellets reaching)at 4 and 6 weeks post-injury and rearing in a cylinder(for testing forelimb usage)at 6 and 8 weeks post-injury.Taken together,the findings of this study add to the growing body of work demonstrating the potential benefits of inducing ketosis following neurotrauma.Ketone salt combined with a ketogenic diet gavage in rats with acute spinal cord injury can rapidly increase ketone body levels in the blood and promote motor function recovery.This study was approved by the Animal Care Committee of the University of British Columbia(protocol No.A14-350)on August 31,2015.

Ketogenic diets and Alzheimer’s disease

Alzheimer’s disease(AD)is a progressive neurodegenerative disorder characterized by decline in cognitive functions and associated with the neuropathological hallmarks of amyloid-peptide plaques and neurofibrillary tangles.Cerebral glucose uptake and metabolism deteriorate in AD and this hypometabolism precedes the onset of clinical signs in AD.The early decline in brain glucose metabolism in AD has become a potential target for therapeutic intervention.This has led to investigations assessing the supplementation of the normal glucose supply with ketone bodies which are produced by the body during glucose deprivation and can be metabolized by the brain when glucose utilization is impaired.The present review provides a synopsis of preclinical studies and clinical trials assessing the efficacy of ketogenic diets in the treatment of AD.Both the direct administration of ketone bodies and the use of high-fat,low-carbohydrate ketogenic diets have been shown to be efficacious in animal models of AD and clinical trials with AD patients.The mechanism underlying the efficacy of ketogenic diets remains unclear,but some evidence points to the normalization of aberrant energy metabolism.At present there is only limited evidence of the usefulness of ketogenic diets in AD.However,this dietary approach seems to be promising and deserves further clinical investigations.

The effects of nutritional ketosis induced by Bigu-herbs regimen and ketogenic diet on diseases and aging

The Bigu-herbs regimen,a Taoism(Taoism is an ancient Chinese Taoist philosophy system)special health-preserving technique to achieve longevity through strict abstinence from food,limits the intake of grains and uses herbs to replace normal diet to gain energy.Practicing Bigu-herbs regimen for several weeks to several years can make one lose weight,prevent diseases,and prolong life.The modern ketogenic diet(KD)mainly limits carbohydrate intake and increase fat intake.The low-carbohydrate,high-fat,and adequate protein diet is well known for its antiepileptic and neurotrophic effects.Limiting the intake of carbohydrate results in energy metabolism reprogramming to mobilize the steatolysis,energize and promote ketone bodies(KBs)production,achieving a state of nutritional ketosis(NK).The researchers summarized how ketone bodies or NK affects diseases and the aging process,as well as the side effects of KD.NK has a favorable effect on caloric intake,lipid parameters,glycemic index,and insulin sensitivity;moreover,it can be used as a treatment option for diabetes,obesity,and other metabolic disorders.NK is recognized as being neuroprotective and is good for epilepsy,Alzheimer’s disease,and emotional disturbance.Targeting the metabolic differences between tumor and normal cells,NK limits the use of glucose and impairs energy metabolism in cancer cells,inhibiting their growth and rendering them susceptible to clinical treatments.NK also affects inflammation and the release of cytokines,regulate gut flora,extend longevity and health span,and preserve physiologic functions.The side effects of KDs are controllable under the guidance of a specially trained dietitian and medical team.

Efficacy and safety of modified medium-chain triglyceride ketogenic diet in patients with drug-resistant epilepsy

Background Medium-chain triglyceride ketogenic diet(MCTKD)is previously less commonly used in China.This study was aimed to assess the efficacy and safety of the modified MCTKD in the treatment of drug-resistant epilepsy in Chinese patients.Methods Patients with drug-resistant epilepsy were enrolled to receive treatment with modified MCTKD in Guangdong Sanjiu Brain Hospital during December 2020 and September 2022.The modified MCTKD contained fat that provided 50–70%of the total energy,as well as proteins and carbohydrates that provided 20–30%and 20%of energy,respectively.The fat component was composed of 20–30%medium-chain triglycerides(MCTs)and 30–40%long-chain triglycerides.The efficacy and safety of the diet were assessed at 1,3 and 6 months.Results A total of 123 patients aged 2.5 to 65 years,were included in this study.The response rates at 1,3 and 6 months were 49.6%,43.1%,and 30.9%,respectively.The seizure freedom rates at 1,3 and 6 months were 12.2%,10.6%,and 6.5%,respectively.The retention rates at 1,3 and 6 months were 98.4%,65.0%and 33.3%respectively.Side effects occurred in 21.14%of patients,which were predominantly gastrointestinal symptoms such as abdominal pain,diarrhea,vomiting,and constipation,and most of them resolved after dietary adjustments.A total of 82 patients(66.7%)discontinued the treatment with the reason of refusing to eat(8.1%),poor efficacy(35.0%),poor compliance(4.9%),and inability to follow-up(9.8%).Only 4 patients(3.3%)withdrew the diet due to side effects.Conclusions The modified MCTKD with MCTs providing 20–30%of energy has a good safety in patients with drug-resistant epilepsy,but its effectiveness needs to be enhanced.Further modifications of MCTKD with an optimal energy ratio are required to achieve a better efficacy and safety.

Ketogenic diet therapy in children with epilepsy caused by SLC2A1 mutations:a single-center single-arm retrospective study

Background This retrospective study assessed the efficacy and safety of ketogenic diet therapies in children with epilepsy caused by SLC2A1 genetic mutations and glucose transporter type 1 deficiency syndrome.Methods Pediatric patients with epilepsy symptoms admitted to our medical center between January 2017 and October 2021 were included if they presented with an SLC2A1 genetic mutation on whole-exome sequencing.We analyzed the patients’convulsions and treatment with antiepileptic drugs.The patients were followed up at different time periods after ketogenic diet therapies.Results Six patients with SLC2A1 mutations were included in this study.The patients had seizures of different types and frequencies,and they took antiepileptic drugs to relieve their symptoms.They were then treated with a ketogenic diet for at least four months.We analyzed epilepsy control rates at 1,2,3,6,and 12 months after ketogenic diet treatment.All patients were seizure-free within a month of receiving the diet therapy.All patients were followed up for six months,three were followed up for 12 months after the treatment,and there was no recurrence of epilepsy during this period.After antiepileptic drug withdrawal,none of the patients experienced seizure relapse when receiving ketogenic diet treatment alone.No severe adverse events occurred during the therapy.Conclusions Ketogenic diet therapy is very effective and safe for the treatment of epilepsy caused by SLC2A1 mutations.Therefore,patients with glucose transporter type 1 deficiency syndrome caused by SLC2A1 mutations should begin ketogenic diet treatment as soon as possible.

Ketogenic Therapy for Cancer

Ketogenic diet(KD)has been used as a successful dietary administration for refractory epilepsy for about a century.Recently,the efficacy of KD has become a hot topic in the field of oncology.As an important therapeutic strategy,this dietary modulation can selectively inhibit tumor growth.However,some researchers dispute the efficacy,safety,feasibility and acceptability of KD.This paper reviewed the effects of KD on different cancer types and proposed the guideline for KD on clinical caner patients.

生酮饮食对2型糖尿病的防治作用

2型糖尿病已经成为我国乃至全世界严重的公共卫生问题之一。生酮饮食因其特殊的营养结构,在减重、控血糖等方面具有一定作用,在糖尿病患者饮食管理中备受关注。本文简要介绍了生酮饮食的类型,探讨了生酮饮食防治2型糖尿病的作用及其机制,分析了生酮饮食的安全性。

生酮饮食用于心脏疾病的研究综述

生酮饮食作为新型饮食辅助治疗心脏疾病的研究方向之一,具有改善危险因素、抑制心室重构、保护心脏等优势。本综述归纳整理生酮饮食对心脏疾病及处于心血管危险因素状态作用的研究成果,从多角度阐述心脏相关作用机制,分析其在减少心血管疾病危险因素、治疗心脏相关疾病等方面的积极影响,总结了生酮饮食的不良反应与禁忌证,为心脏疾病的预防和治疗提供新思路。

^(18)F-FDG与^(18)F-DPA-714 Micro PET/CT显像评价生酮饮食治疗阿尔茨海默病小鼠大脑代谢及神经炎症

目的探讨生酮饮食(KD)能否通过调节阿尔茨海默病模型小鼠大脑代谢及神经炎症促进认知。材料与方法将20只APP/PS1雄性小鼠随机分为KD组(APP/PS1+KD)与普通饮食组(APP/PS1),每组10只;同时以10只野生型C57BL/6雄性小鼠作为对照组。使用生酮饲料喂养APP/PS1+KD组,普通饲料喂养APP/PS1组和对照组,共4个月。连续喂养4周、4个月后,记录小鼠的血酮,并使用Morris水迷宫评估小鼠认知,再行^(18)F-FDG和^(18)F-DPA-714 micro PET/CT分别评估KD对阿尔茨海默病小鼠各脑区葡萄糖代谢及神经炎症的影响;完成PET/CT显像后取脑组织,选择海马CA1区制成石蜡切片进行免疫荧光检测胶质纤维酸性蛋白、离子化钙结合适配分子表达情况。结果4个月时,与对照组相比,APP/PS1组第3~4天逃避潜伏期显著延长(P<0.01、P<0.05)。与对照组相比,APP/PS1组在纹状体、海马、背侧丘脑、中央灰质、上丘、嗅球、中脑等脑区对^(18)F-FDG的标准化摄取值比值显著下降(P<0.05或P<0.01);与APP/PS1组相比,APP/PS1+KD组海马、背侧丘脑对^(18)F-FDG的标准化摄取值比值显著升高(P<0.01)。与对照组相比,APP/PS1组纹状体、海马、下丘脑等脑区对^(18)F-DPA-714的标准化摄取值比值显著上升(P<0.05或P<0.001);与APP/PS1组相比,APP/PS1+KD组降低了海马区相对^(18)F-DPA-714摄取(P<0.01)。与对照组、APP/PS1+KD组相比,APP/PS1组小鼠脑(海马)胶质纤维酸性蛋白、离子化钙结合适配分子表达显著升高(P均<0.01)。结论KD可通过提高APP/PS1小鼠大脑代谢并抑制神经炎症,促进其认知行为学改善。

生酮饮食在减重中的临床应用进展

世界范围内肥胖发病率逐渐增高,饮食控制已被证实是最有效的减重措施之一。其中,生酮饮食是一种高脂肪,适当蛋白质和低碳水化合物的饮食,以往用于儿童难治性癫痫的辅助治疗。近年来有研究关注到生酮饮食可以有效控制食欲,提高脂肪氧化等,具有良好的减重效果。本文就生酮饮食在减重中的临床应用、作用机制、副作用等方面的研究进展进行综述。

生酮饮食与肿瘤治疗研究进展

生酮饮食(KD)是一种以高比例脂肪、极低碳水化合物、适量蛋白质摄入为特征的饮食方案,机体热量的主要来源转为酮体,通过“模拟饥饿”状态最早成功应用于难治性癫痫的治疗。由于肿瘤细胞葡萄糖高度依赖、线粒体功能缺陷等特征,KD通过增强氧化应激、抑制炎症、加强免疫反应、抑制葡萄糖/胰岛素等多种途径发挥抗肿瘤作用。然而,也有文献发现KD可加快肿瘤例如肺癌、结直肠癌、肝癌等疾病恶化的风险。说明KD与肿瘤治疗仍存在争议,故对其潜在分子机制进行研究,可能具有一定应用价值。文章主要就KD抗癌和促瘤相关研究及其作用机制,临床应用时不良反应、用药期间注意事项等进行综述。

极低热量生酮饮食的管理及临床应用

膳食治疗是超重与肥胖人群体重管理的关键措施之一。研究表明,相较于其他膳食治疗方案,极低热量生酮饮食(very low-calorie ketogenic diet,VLCKD)具有短期减重效果明显、改善胰岛素抵抗等优势,具备较高的潜在临床应用价值。然而VLCKD在调节血脂、共病改善、长期减重及副作用严重程度等方面仍存在一定争议,对其临床应用产生一定困扰。本文在概述VLCKD概念与临床应用的基础上,重点阐述VLCKD对肥胖人群体重、血糖、血脂、其他疾病等的影响以及副作用的产生与预防,进而为肥胖临床膳食治疗提供参考与证据支持。

生酮饮食治疗结直肠癌的研究进展

结直肠癌是一种以高发病率和高死亡率为特征的肿瘤疾病,其发生和发展由基因、环境、生活方式等多方面因素共同决定。结直肠癌在发展过程中,肿瘤细胞的能量代谢发生异常改变导致癌细胞的葡萄糖摄取增加,葡萄糖供能成为肿瘤细胞主要的能量来源。生酮饮食是一种低碳水化合物的饮食模式,在此模式下,酮体成为机体细胞的主要能量来源,肿瘤细胞能量来源受到抑制,故生酮饮食被认为具有潜在的辅助抗肿瘤作用。该文将生酮饮食在结直肠肿瘤治疗方面的相关机制的研究结果进行综述分析,并探讨目前在治疗中应用生酮饮食所面临的主要问题。

基于Web of Science数据库分析2013—2022年生酮饮食的研究热点与趋势

目的基于Web of Science(WOS)数据库分析生酮饮食相关文献,明确该领域的研究热点与趋势。方法基于WOS核心数据库检索生酮饮食相关文献,时间范围为2013年1月1日—2022年12月31日。应用文献计量学方法和CiteSpace软件,对国家/地区、研究机构、发表期刊、关键词等文献特征进行统计学分析。结果本研究共获取有效文献4548篇,包括论著3317篇、综述1231篇。2013—2022年生酮饮食研究领域的发文量总体呈增长趋势,并于2021年达到峰值(756篇);年被引频次呈逐年增长趋势,于2022年达到峰值(25643次)。该领域发文量最多的国家和研究机构分别为美国(1695篇,占37.27%)和约翰·霍普金斯大学(88篇,占1.93%),且研究机构以高校为主。Nutrients载文量最多(241篇,占5.30%),Epilepsia的篇均被引频次最高(33.19次)。被引频次前10位的文献中,5篇文献阐述了酮体在疾病治疗中的代谢与作用机制,4篇文献的研究主题与癫痫相关。研究热点包括生酮饮食在癫痫与肥胖治疗中的应用和疗效评价,酮体的脂肪酸氧化、代谢、氧化应激、Warburg效应等常见调控机制,肠道菌群介导生酮饮食的作用研究;研究趋势为生酮饮食在心力衰竭中的应用前景。结论生酮饮食已被应用于多种疾病的治疗中,且其全球关注度持续增长,后续研究热点应聚焦于临床试验,以验证其临床疗效与耐受性。

中链甘油三酯的生酮饮食在化疗3个月以上乳腺癌患者中的随机对照研究

目的分析基于中链甘油三酯(MCT)的生酮饮食在接受化疗3个月以上的乳腺癌患者中的应用价值。方法选取武汉市第三医院2021年3月至2023年3月期间入院的乳腺癌患者(接受化疗干预3个月以上)120例,简单随机将其分为对照组(60例)、干预组(60例)。其中,对照组接受传统化疗饮食干预,干预组接受基于MCT的生酮饮食干预,两组患者均实施为期5周的临床观察。比较两组患者干预前、干预1周、2周、3周、5周血酮、血糖及体重情况。同时,比较两组患者炎症指标[C反应蛋白(CRP)、肿瘤坏死因子(TNF)-α、白介素-1β(IL-1β)]、免疫指标(CD3^(+)、CD4^(+)、CD8^(+)T细胞)、肠道门水平优势菌群(厚壁菌门、拟杆菌门、变型菌门)、不良反应(恶心、呕吐、腹泻、便秘)、低血糖发生率差异。结果干预1周至5周,干预组血酮水平较干预前升高,且干预组血酮水平高于对照组[(1.84±0.12)mmol/L比(0.41±0.10)mmol/L]、[(2.10±0.11)mmol/L比(0.42±0.09)mmol/L]、[(2.01±0.15)mmol/L比(0.44±0.10)mmol/L]、[(2.00±0.19)mmol/L比(0.43±0.08)mmol/L](P<0.05)。干预1周至5周,干预组血糖水平较干预前升高,且干预组血糖水平低于对照组(P<0.05)。干预5周,与干预前相比,两组患者体重均下降(P<0.05)。干预后,干预组CD3^(+)、CD4^(+)T细胞占比高于对照组[(70.15±6.07)%比(57.62±5.09)%]、[(54.02±5.62)%比(43.06±4.98)%],CD8^(+)T细胞占比[(30.62±3.45)%比(35.62±3.11)%]、炎症指标低于对照组(P<0.05)。干预后,两组患者厚壁菌门、变型菌门丰度均较干预前下降,拟杆菌门较干预前上升,且干预组拟杆菌门丰度高于对照组,厚壁菌门、变型菌门丰度低于对照组(P<0.05)。干预组不良反应总发生率(13.33%,8/60)显著低于对照组(31.67%,19/60)(P<0.05)。结论对接受化疗3个月以上的乳腺癌患者而言,基于MCT的生酮饮食干预可改善患者的整体健康状况、减少化疗的不良反应等,生酮饮食治疗乳腺癌过程安全、可行,可为临床乳腺癌化疗及不良反应改善提供参考。

生酮饮食治疗CDKL5基因突变所致婴儿痉挛症1例报告并文献复习

目的通过报道1例接受生酮饮食治疗的CDKL5基因突变所致婴儿痉挛症的病历资料,以提高对CDKL5基因突变所致婴儿痉挛症及生酮饮食治疗的认识。方法男患儿,出生后1月24天起出现癫痫局灶性发作,2月16天来我院就诊并逐渐出现痉挛发作。对此例患儿的临床资料及治疗进行总结并进行相关文献复习。结果①体格检查:患儿入院时发育水平与同龄儿比较无明显差异,随着癫痫发作的增加,发育逐渐落后并倒退。脑电图监测到成串痉挛发作及高度失律。基因结果显示CDKL5基因嵌合新生变异。②治疗过程中先后应用ACTH及多种抗癫痫发作药物,癫痫发作曾一度有所控制,再次发作加重后应用生酮饮食,癫痫控制较好,且智力、运动能力有所改善。结论此例CDKL5基因突变所致痉挛症患儿在口服抗癫痫发作药物控制发作的前提下,采用生酮饮食治疗可减少发作,改善预后。