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.

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.

Raf/MEK/ERK Signaling Pathway Is Involved in the Inhibition of Glioma Cell Proliferation and Invasion in the Ketogenic Microenvironment

Objective:A high-fat,low-carbohydrate ketogenic diet has been used to treat malignant glioma,in which the Raf/MEK/ERK signaling pathway is overactivated.However,whether the Raf/MEK/ERK signaling pathway is involved in the therapeutic effect of ketone bodies remains unknown.In this study,we investigated the effects of a major ketone body,3-hydroxybutyric acid(3-HBA),on the proliferation and metastasis of malignant glioblastoma cells and the underlying mechanism.Methods:Two human malignant glioblastoma cell lines(U87 and U251)were treated with different concentrations of 3-HBA with or without the Raf inhibitor PAF C-16 for 24 h.Cell proliferation,cell cycle,cell invasion,and phospholipase D1(PLD1)activity were determined.Protein and gene expression levels of Raf/MEK/ERK signaling pathway members were examined.Results:3-HBA significantly decreased cell proliferation,invasion,and intracellular PLD1 activity in both U87 and U251 glioblastoma cell lines.3-HBA treatment significantly increased the proportion of cells in the G1 phase and decreased the proportion of cells in S phase in U87 cells.In the U251 line,the proportion of treated cells in S phase was increased and proportion of cells in G2 was decreased.3-HBA treatment also significantly decreased the protein expression levels of Raf,MEK,p-MEK,ERK,p-ERK,and PLD1 while increasing p53 expression;an effect that was similar to treatment with the Raf inhibitor.Co-treatment of 3-HBA with the Raf inhibitor further enhanced the effects of the 3-HBA in both cell lines.Conclusion:We confirmed that a ketogenic microenvironment can inhibit glioma cell proliferation and invasion by downregulating the expression of PLD1 through the Raf/MEK/ERK signaling pathway.

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 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.

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.

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.

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 dietary therapy in adult status epilepticus:current progress and clinical application

Status epilepticus(SE)is a common fatal neurological disease with high morbidity and mortality,Even if a large proportion of patients might be relieved from anti-seizure medications,sedatives and anesthetics,some still remain out of control.The ketogenic dietary(KD)has been proven useful in patients refractory to medications and/or who have failed to respond to surgical intervention.Recently,KD has shown beneficial therapeutic effects in children with SE,but studies in adults have rarely been reported.In this paper,we review the efficacy and utility of KD in adult SE patients and highlight its application for clinical reference and management.

Safety and tolerability of the ketogenic diet used for the treatment of refractory childhood epilepsy: a systematic review of published prospective studies

Background:To review the available evidence from prospective studies on the safety and tolerability of the ketogenic diet (KD) for the treatment of refractory childhood epilepsy.Methods:A comprehensive bibliographic search was performed with the aim of retrieving prospective studies that monitored adverse effects (AEs) in children after receiving the classic or medium-chain triglyceride KD therapy for refractory epilepsy.Results:A total of 45 studies were retrieved,including 7 randomized controlled trials.More than 40 categories of AEs were reported.The most common AEs included gastrointestinal disturbances (40.6%),hyperlipidemia (12.8%),hyperuricemia (4.4%),lethargy (4.1%),infectious diseases (3.8%) and hypoproteinemia (3.8%).Severe AEs,such as respiratory failure and pancreatitis,occurred in no more than 0.5% of children.Specifically,patients receiving KD therapy should be monitored for osteopenia,urological stones,right ventricular diastolic dysfunction,and growth disturbance.The total retention rates of the diet for 1 year and 2 years were 45.7% and 29.2%,respectively.Nearly half of the patients discontinued the diet because of lack of efficacy.AEs were not the main reason for the KD discontinuation.None of the 24 deaths reported after initiation of the diet was attributed to the KD.Conclusions:KD is a relatively safe dietary therapy.However,because the KD can cause various AEs,it should be implemented under careful medical supervision.Continuous follow-up is needed to address the long-term impact of the diet on the overall health of children.

A multicenter retrospective cohort study of ketogenic diet therapy in 481 children with infantile spasms

Background:Ketogenic diet(KD)therapy is one of the main treatments for drug-resistant epilepsy.However,the KD therapy has been applied in only a small number of infantile spasm cases.In this large multicenter study,we investigated the efficacy of KD therapy in the treatment of infantile spasms.Methods:In this retrospective,multicenter cohort study,clinical data from main epilepsy centers were analyzed.Patients were classified into different groups according to age,type of drug and whether glucocorticoid was used before initiation of KD.Results:From October 2014 to March 2020,481 patients(308 males and 173 females)with infantile spasms were treated with the KD therapy.The age of the patients ranged from 2 months to 20 years,with a mean age of 1 year and 10 months.The number of anti-seizure medications(ASMs)used before KD initiation ranged 0-6,with a median of 3.In different time from initiation(1,3,6,and 12 months),the rates of seizure freedom after KD were 6.9,11.6;16.0 and 16.8%,respectively(x^(2)=27.1772,P<0.0001).There was a significant difference in the rate of seizure freedom between 3 months and 1 month(x^(2)=6.5498,P=0.0105)groups,and 6 months and 3 months(x^(2)=3.8478,P=0.0498)groups,but not between 12 months and 6 months(x^(2)=0.1212,P=0.7278)groups.The rates of effectiveness were 44.7;62.8,49.1 and 32.0%(x^(2)=93.2674,P<0.0001),respectively.The retention rates were 94.0,82.5,55.7 and 33.1%(x^(2)=483.7551,P<0.0001),correspondingly.The rate of effectiveness and the retention rate of KD were significantly different among the 1,3,6 and 12 months.KD treatment was the first choice in 25 patients(5.2%),55 patients(11.4%)started KD after the failure of the first ASM,158 patients(32.8%)started KD after the failure of the second ASM,157 patients(32.6%)started KD after the failure of the third drug,and 86 patients(17.9%)started KD after the failure of the fourth and more.The KD effect was not related to the number of ASMs used before KD startup(P>0.05).Two hundred and eighteen patients(45.3%)failed to respond to corticotropin or glucocorticoid before initiation.There was no significant difference in the effectiveness rate at different time points between the group of KD therapy after glucocorticoid failure and the group after non-hormone failure (x^(2)=0.8613,P=0.8348).The rate of adverse events of KD in 1,3,6,and 12 months after KD initiation were 22.3,21.7,16.8 and 6.9%,respectively.The adverse events mainly occurred during the first 3 months of KD,and the main adverse events were gastrointestinal disturbance and constipation.Conclusions:The efficacy of the KD treatment for infantile spasms was not affected by age,medication,and glucocorticoid use before initiation.KD is one of the effective treatments for infantile spasms.

Current Evidence Concerning Effects of Ketogenic Diet and Intermittent Fasting in Patients with Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) is emerging globally, while no therapeutic medication has been approved as an effective treatment to date, lifestyle intervention through dietary modification and physical exercise plays a critical role in NAFLD management. In terms of dietary modification, Mediterranean diet is the most studied dietary pattern and is recommended in many guidelines, however, it may not be feasible and affordable for many patients. Recently, a ketogenic diet and intermittent fasting have gained public attention and have been studied in the role of weight management. This article reviews specifically whether these trendy dietary patterns have an effect on NAFLD outcomes regarding intrahepatic fat content, fibrosis, and liver enzymes, the scientific rationales behind these particular dietary patterns, as well as the safety concerns in some certain patient groups.

Effect of ketogenic diet on hippocampus mossy fiber sprouting and GluR_5 expression in kainic acid induced rat model

Ketogenic diet （KD） is a high fat, low protein, low carbohydrate diet. Its antiepileptic effect is certain but the underlying mechanism is unknown. Mossy fiber sprouting in the inner molecular layer of the dentate gyrus causes the synaptic reorganization in the hippocampus, which is an important cause of temporal lobe epilepsy in animals and humans. It is also essential to the genesis and development of epilepsy. As the predominant excitatory neurotransmitter in the central nervous system, glutamate plays a role in synaptic reorganization and development of epilepsy.

Efficacy and tolerability of ketogenic diet therapy in 55 Chinese children with drug-resistant epilepsy in Northwest China

Background:Due to the tradition of carbohydrate-rich diet,challenges exist for ketogenic diet(KD)implementation in Northwest China.This study was aimed to investigate the efficacy and tolerability of KD therapy administered with gradual initiation protocols in Chinese children with pharmacoresistant epilepsy in Northwest China.Methods:In this single-center study,55 children with drug-resistant epilepsy were enrolled from June 2013 to June 2019.The efficacy of KD,reasons for discontinuation,duration of retention and rate of adverse events were evaluated.Results:Fifty-five children aged from 2.2 months to 169.7 months were included,with a median age at KD initiation of 14.1 months,and 32 cases(58.2%)responded to the diet therapy at the last contact.The responder rates were 16.4%(9/55);36.4%(20/55),30.9%(17/55),27.3%(15/55)at 1,3,6 and 12 months,respectively.Univariate analysis indicated that the duration of epilepsy and the duration of KD therapy were predictors for KD effectiveness.Poor compliance and lack of response were main reasons for discontinuation of KD.There are a few side effects of KD,most of which were minor.Conclusions:The KD therapy with a gradual-initiation protocol is effective and tolerable for children with drug-resist-ant epilepsy in Northwest China.Early start of KD and KD duration of more than 6 months may be predictive factors for KD efficacy.

The ketogenic diet for paediatric patients with super-refractory status epilepticus in febrile infection-related epilepsy syndrome

Objective:To investigate the effect and safety of ketogenic diet(KD)for the treatment of paediatric patients with super-refractory status epilepticus(SRSE)in febrile infection-related epilepsy syndrome(FIRES).Method:From January 1,2015 to October 31,2017,ten critically ill paediatric patients with SRSE in FIRES were included in this study and treated with KD.The treatment effects of KD were evaluated by using continuous encephalography(CEEG)and amplitude-integrated electro-encephalography(aEEG).Results:All 10 patients fulfilled the diagnostic criteria of SRSE in FIRES and achieved ketosis within 24–72 h following the administration of KD.CEEG and aEEG were monitored for several weeks to assess the efficacy of KD on status epilepticus(SE).SE was contained in 8 patients within 2 to 19 days after initiation of KD,and KD was discontinued in the other 2 patients.One of the 10 patients demonstrated severe adverse effects.Conclusion:KD may be an alternative and safe treatment option in critical paediatric patients with SRSE in FIRES.

Chinese expert recommendations on ketogenic diet therapy for super-refractory status epilepticus

Super-refractory status epilepticus(SRSE)is a serious and life-threatening neurological condition.Ketogenic diet(KD)is a diet characterized by high fat,low carbohydrate,and moderate protein.As KD shows effectiveness in controlling seizures in more than half of SRSE patients,it can be a treatment option for SRSE.Currently,KD treatment for SRSE is based on personal experience and observational evidence has been published.In the context of a lack of a validated guideline,we convened a multicenter expert panel within the China Association Against Epilepsy(CAAE)Ketogenic Diet Commission to work out the Chinese expert recommendations on KD for SRSE.We summarize and discuss the latest clinical practice of KD for SRSE in critical care settings.Recommendations are given on patient selection,the timing of KD,diet implementation,and follow-up.More research data are needed in this area to support better clinical practice.

Calculation and management of ketogenic diet parenteral nutrition in super-refractory status epilepticus

Super-refractory status epilepticus(SRSE)is an important neurological emergency associated with high mortality and morbidity and poses a heavy economic burden on patients.Ketogenic diet parenteral nutrition(KD-PN)is ketogenic diet therapy provided through parenteral administration and may be an adjuvant treatment for these who cannot accept enteral diet.However,the calculation and management of KD-PN presents a challenge for clinicians.This review focuses on the practical aspects of KD-PN therapy for treatment of SRSE,including the dietary composition,potential drug-diet interactions,and monitoring during KD-PN treatment.As with all SRSE treatments,KD-PN has many adverse effects,like hyperlipemia,hepatotoxicity,metabolic acidosis,insufficient ketosis or hyper-ketosis,and propofol infusion syndrome.We summarize monitoring and treatment methods in our review.This review provides some practical aspects for treatment of SRSE.

Therapeutic effect of ketogenic diet treatment on type 2 diabetes

Diet plays an important role in diabetes development.The effect of ketogenic diet on type 2 diabetes remains elusive.In this study,we collect diabetes related physiological parameters and abdominal MRI images to evaluate the effect of ketogenic diet after 3-months of consecutive treatment.Ketogenic diet mitigates the diabetes symptom inferring from the statistically significant reduction of key diabetic physiological parameters such as Hemoglobin A1c(HbA1c)concentration,Triglyceride(TG),Fasting blood glucose(FBG),Body Mass Index(BMI),and adipose tissue volume.Moreover,we propose a new parameter to quantify the treating effect of ketogenic diet since Slope and Offset of Oral Glucose Tolerance Test(SOOGTT)incorporate more sampling points by fitting OGTT(Oral Glucose Tolerance Test)curve.SOOGTT shows statistically significant(P<0.001)treating effect of ketogenic diet on type 2 diabetes.We use artificial intelligence to segment adipose tissue for treatment evaluation,which shows that ketogenic diet reduces the amount of adipose tissue.