Ketogenic Diet Exacerbates L-Arginine-Induced Acute Pancreatitis and Reveals the Therapeutic Potential of Butyrate.

The ketogenic diet (KD) has emerged as a popular weight-loss regimen in recent years. However, it has been confirmed to elicit a mild inflammatory response in the intestinal epithelium and exacerbate various digestive disorders. The severity of acute pancreatitis (AP) is closely associated with the permeability of the intestinal epithelium and gut microbiota, yet the impact of KD on acute pancreatitis remains unclear. In this study, we induced acute pancreatitis using L-arginine in mice fed with KD. The consumption of KD resulted in an elevation of lipopolysaccharide-binding protein (LBP), accompanied by upregulated cytokines (IL-1a, IL-5, IL-12, MIP-1a, and Rantes) and dysfunction of the intestinal barrier both in control and AP groups. The bloom of Lachnospirales and Erysipelotrichales was observed as a specific profile of gut microbiota in KD-fed mice with AP, along with downregulation of carbohydrate metabolism and depletion of short-chain fatty acids (SCFAs). Antibiotic decontamination reduced the cytokine storm and tissue necrosis but did not significantly improve the integrity of the intestinal barrier in KD-fed mice with AP. The overgrowth of Mycoplasmatales in feces and Enterobacterales in colonic tissue appears to explain the limitation of antibiotic treatment to aggravate acute pancreatitis. Butyrate supplementation attenuated the depletion of SCFAs, promoted the intestinal barrier, and reduced the necrotic area in AP mice. The bloom of Bacteroidales and the correlated increase in tryptophan metabolism explain the therapeutic potential of butyrate supplements for acute pancreatitis. In conclusion, our findings suggest that the ketogenic diet exacerbates acute pancreatitis through its impact on the gut microbiota and subsequent disruption of the intestinal barrier, while butyrate supplementation reverses this effect.

Ketogenic Diet as a Possible Non-pharmacological Therapy in Main Endocrine Diseases of the Female Reproductive System: A Practical Guide for Nutritionists.

PURPOSEOF REVIEW: This narrative review explored the role of ketogenic diets (KDs) in improving fertility outcomes, low-grade inflammation, body weight, visceral adipose tissue, and its potential use in certain types of cancer, through its favorable actions on mitochondrial function, reactive oxygen species generation, chronic inflammation, and tumor growth inhibition. RECENT FINDINGS  : Nutrition is crucial to maintain the female reproductive system's health. Evidence on the association between diet and female reproductive system has greatly expanded over the last decade, leading to the identification of specific diet therapy, particularly KDs. KDs has been proved to be an effective weight-loss tool. To date, KDs is being increasingly used in the treatment of many diseases, such as obesity, type 2 diabetes mellitus. KDs is a dietary intervention capable of ameliorating the inflammatory state and oxidative stress through several mechanisms. Due to the increasing use of KDs beyond obesity, this literature review will provide the latest scientific evidence of its possible use in common disorders of the female endocrine-reproductive tract, and a practical guide to its use in these patients.

Ketogenic diet in children and adolescents: The effects on growth and nutritional status.

The ketogenic diet is known to be a possible adjuvant treatment in several medical conditions, such as in patients with severe or drug-resistant forms of epilepsy. Its use has recently been increasing among adolescents and young adults due to its supposed weight-loss effect, mediated by lipolysis and lowered insulin levels. However, there are still no precise indications on the possible use of ketogenic diets in pediatric age for weight loss. This approach has also recently been proposed for other types of disorder such as inherited metabolic disorders, Prader-Willi syndrome, and some specific types of cancers. Due to its unbalanced ratio of lipids, carbohydrates and proteins, a clinical evaluation of possible side effects with a strict evaluation of growth and nutritional status is essential in all patients following a long-term restrictive diet such as the ketogenic one. The prophylactic use of micronutrients supplementation should be considered before starting any ketogenic diet. Lastly, while there is sufficient literature on possible short-term side effects of ketogenic diets, their possible long-term impact on growth and nutritional status is not yet fully understood, especially when started in pediatric age.

Ketogenic diets composed of long-chain and medium-chain fatty acids induce cardiac fibrosis in mice.

PURPOSE: Heart diseases are the leading cause of death worldwide. Metabolic interventions via ketogenic diets (KDs) have been used for decades to treat epilepsy, and more recently, also diabetes and obesity, as common comorbidities of heart diseases. However, recent reports linked KDs, based on long-chain triglycerides (LCTs), to cardiac fibrosis and a reduction of heart function in rodents. As intervention using medium-chain triglycerides (MCTs) was recently shown to be beneficial in murine cardiac reperfusion injury, the question arises as to what extent the fatty acid (FA)-composition in a KD alters molecular markers of FA-oxidation (FAO) and modulates cardiac fibrotic outcome. METHODS: The effects of LCT-KD as well as an LCT/MCT mix (8:1 ketogenic ratio) on cardiac tissue integrity and the plasma metabolome were assessed in adult male C57/BL6NRJ mice after eight weeks on the respective diet. RESULTS: Both KDs resulted in increased amount of collagen fibers and cardiac tissue was immunologically indistinguishable between groups. MCT supplementation resulted in i) profound changes in plasma metabolome, ii) reduced hydroxymethylglutaryl-CoA synthase upregulation, and mitofusin 2 downregulation, iii) abrogation of LCT-induced mitochondrial enlargement, and iv) enhanced FAO profile. Contrary to literature, mitochondrial biogenesis was unaffected by KDs. We propose that the observed tissue remodeling is caused by the accumulation of 4-hydroxy-2-nonenal protein adducts, despite an inconspicuous nuclear factor (erythroid-derived 2)-like 2 pathway. CONCLUSION: We conclude that regardless of the generally favorable effects of MCTs, they cannot inhibit 4-hydroxy-2-nonenal adduct formation and fibrotic tissue formation in this setting. Furthermore, we support the burgeoning concern about the effect of KDs on the cardiac safety profile.

The Role of Ketogenic Diet in the Treatment of Neuroblastoma.

The ketogenic diet (KD) was initially used in 1920 for drug-resistant epileptic patients. From this point onward, ketogenic diets became a pivotal part of nutritional therapy research. To date, KD has shown therapeutic potential in many pathologies such as Alzheimer's disease, Parkinson's disease, autism, brain cancers, and multiple sclerosis. Although KD is now an adjuvant therapy for certain diseases, its effectiveness as an antitumor nutritional therapy is still an ongoing debate, especially in Neuroblastoma. Neuroblastoma is the most common extra-cranial solid tumor in children and is metastatic at initial presentation in more than half of the cases. Although Neuroblastoma can be managed by surgery, chemotherapy, immunotherapy, and radiotherapy, its 5-year survival rate in children remains below 40%. Earlier studies have proposed the ketogenic diet as a possible adjuvant therapy for patients undergoing treatment for Neuroblastoma. In this study, we seek to review the possible roles of KD in the treatment of Neuroblastoma.

The place of a ketogenic diet in the treatment of resistant epilepsy: a comprehensive review.

Objective: The ketogenic diet (KD) is a high-fat, adequate-protein, and low-carb diet. Ketone bodies increase in the blood due to low carbohydrate content and high-fat content in the diet. The most important feature of the ketogenic diet is that it causes the production of ketone bodies in the liver. Ketone bodies are an alternative fuel to glucose for the brain and form the structure necessary for the cell membrane and biosynthesis of triglycerides. The ketogenic diet provides evidence on seizure control with anticonvulsant effects. In this review, the positive/negative effects of KD on seizure control, place, importance, quality of life, cognition, and behavior in the treatment of resistant epilepsy were examined.Methods: Scientific information on the subject was obtained from the literature accessed through databases such as MEDLINE, Embase, Web of Science, Cochrane Central, www.ClinicalTrials.gov, PubMed, Science Direct, and Google Scholar.Results: Although it has started to be used as a treatment method in many diseases today, the main area of effect of KD is drug-resistant epilepsy. In order for the ketogenic diet to be successful in these patients, it is necessary to choose the appropriate patient, medical treatment and diet plan, inform the patient sufficiently, and perform frequent monitoring in accordance with the follow-up criteria. It is argued that KD is one of the most effective treatments for epilepsy.Conclusion: The fact that KDs generally have a restricted diet pattern, the need for supplementation, biochemical findings and possible side effects raise the issue of diet sustainability. More clinical studies are needed to generalize.

Clinical and nutritional management of very-low-calorie ketogenic diet (VLCKD) in patients with psoriasis and obesity: a practical guide for the nutritionist.

Psoriasis is an immune-mediated inflammatory skin disease associated with multiple comorbidities. Considered one of the most common inflammatory skin diseases among the general population, it not only affects the skin, but also negatively impacts other organs and joints. In addition, psoriasis has been associated with several chronic cardio-metabolic diseases such as obesity, which would seem to be (i) a risk factor for the onset of psoriasis and (ii) a worsening factor of the severity of the disease. Weight loss appears to improve severity in overweight patients. Recently proposed as an obesity management nutritional strategy, the very-low-calorie ketogenic diet (VLCKD) has demonstrated significant effects in reducing inflammatory processes. In the current review, we describe the evidence available on psoriasis and VLCKD, and provide a practical guide to the prescription of VLCKD in the different phases, evaluation and management of possible adverse events, and the importance of physical activity as a lifestyle modification to reduce psoriasis and associated comorbidities. Randomized control trials are, however, necessary to determine the most effective VLCKD protocol for patients with obesity and psoriasis, optimal protocol duration, composition of micronutrients and macronutrients, choice of special supplements, and management of carbohydrate reintroduction.

Efficacy of supplemental MCT oil on seizure reduction of adult drug-resistant epilepsy - a single-center open-label pilot study.

OBJECTIVE: We set out to determine whether adding medium chain triglyceride (MCT) oil as a dietary supplement to standard diet in adult subjects with intractable epilepsy in a U.S. neurology clinical practice was associated with a reduction in number of seizures. We secondarily aimed to determine whether subjects experienced any side effects and whether there was a presence of urinary ketones while using MCT oil as a dietary supplement. METHODS: Adult patients with intractable epilepsy were recruited at standard of care clinical visits with their epileptologist. Once enrolled, subjects were instructed to supplement their diet with MCT oil as tolerated twice daily for three months (including a 1-2 week titration period, followed by a 1-2 week tapering off window) while keeping a seizure diary to record total number of seizures, presence of urinary ketones, and any side effects. RESULTS: Our data although limited by small sample size, shows that there is an estimated 42% reduction (p < 0.0001) in the rate of seizures. The MCT oil supplementation was well tolerated by most subjects except for minor GI side effects like nausea and loose stools. Most subjects developed ketones in their urine at some point during the trial. CONCLUSIONS: MCT oil supplementation reduced seizure frequency in study participants. The reported side effects included mild nausea, stomachache, loose stools. A placebo-controlled study will be more informative.

The effects of popular diets on bone health in the past decade: a narrative review.

Bone health encompasses not only bone mineral density but also bone architecture and mechanical properties that can impact bone strength. While specific dietary interventions have been proposed to treat various diseases such as obesity and diabetes, their effects on bone health remain unclear. The aim of this review is to examine literature published in the past decade, summarize the effects of currently popular diets on bone health, elucidate underlying mechanisms, and provide solutions to neutralize the side effects. The diets discussed in this review include a ketogenic diet (KD), a Mediterranean diet (MD), caloric restriction (CR), a high-protein diet (HP), and intermittent fasting (IF). Although detrimental effects on bone health have been noticed in the KD and CR diets, it is still controversial, while the MD and HP diets have shown protective effects, and the effects of IF diets are still uncertain. The mechanism of these effects and the attenuation methods have gained attention and have been discussed in recent years: the KD diet interrupts energy balance and calcium metabolism, which reduces bone quality. Ginsenoside-Rb2, metformin, and simvastatin have been shown to attenuate bone loss during KD. The CR diet influences energy imbalance, glucocorticoid levels, and adipose tissue, causing bone loss. Adequate vitamin D and calcium supplementation and exercise training can attenuate these effects. The olive oil in the MD may be an effective component that protects bone health. HP diets also have components that protect bone health, but their mechanism requires further investigation. In IF, animal studies have shown detrimental effects on bone health, while human studies have not. Therefore, the effects of diets on bone health vary accordingly.

Impact of Dietary Factors on Brugada Syndrome and Long QT Syndrome.

A healthy regime is fundamental for the prevention of cardiovascular diseases (CVD). In inherited channelopathies, such as Brugada syndrome (BrS) and Long QT syndrome (LQTS), unfortunately, sudden cardiac death could be the first sign for patients affected by these syndromes. Several known factors are used to stratify the risk of developing cardiac arrhythmias, although none are determinative. The risk factors can be affected by adjusting lifestyle habits, such as a particular diet, impacting the risk of arrhythmogenic events and mortality. To date, the importance of understanding the relationship between diet and inherited channelopathies has been underrated. Therefore, we describe herein the effects of dietary factors on the development of arrhythmia in patients affected by BrS and LQTS. Modifying the diet might not be enough to fully prevent arrhythmias, but it can help lower the risk.

Octanoic acid a major component of widely consumed medium-chain triglyceride ketogenic diet is detrimental to bone.

Octanoic acid is a medium-chained saturated fatty acid found abundantly in the ketogenic dietary supplements containing medium chained triglycerides (MCT) along with decanoic acid. The MCT ketogenic diet is commonly consumed for weight loss but has also showcased neuroprotective potential against neurodegenerative disorders. However, recent clinical findings have reported a critical disadvantage with the long-term consumption of ketogenic diet i.e. bone loss. The following study was employed to investigate whether the two major components of MCT diet also possess bone loss potential as observed with classical ketogenic diet. Swiss albino mice aged between 10 and 12 weeks, were divided into 3 treatment groups that were administered with oral suspensions of octanoic acid, decanoic acid and a combination of both for 4 weeks. Bone specific markers, microarchitectural parameters, using micro computed tomography, and biomechanical strength were analyzed. Remarkably deleterious alterations in the trabecular bone microarchitecture, and on bone markers were observed in the octanoic acid treated groups. Our results suggest significant negative effects on bone health by octanoic acid. These findings require further investigation and validation in order to provide significant clinically relevant data to possibly modify dietary composition of the MCT ketogenic diet.

Florid Scurvy in an Autistic Child on a Ketogenic Diet.

ABSTRACT: Ketogenic diets used for treating various neurological disorders can have potentially serious adverse effects. Among these is scurvy, a rarely reported, yet potentially fatal adverse effect of the ketogenic diet caused by vitamin C deficiency. We report a case of a 5-year-old patient with autism, who presented with scurvy secondary to the dietary restrictions of a ketogenic diet. Our review of the literature showed a single previously reported case of vitamin C deficiency in a patient on ketogenic diet. We have also reviewed the clinical indications and adverse effects of ketogenic diets with special reference to scurvy. This case emphasizes the importance of vitamin supplements in patients consuming a special diet.

Acute Ketogenic Diet and Ketone Ester Supplementation Impairs Race Walk Performance.

PURPOSE: This study aimed to determine if LCHF and ketone ester (KE) supplementation can synergistically alter exercise metabolism and improve performance. METHODS: Elite race walkers (n = 18, 15 males and 3 females; V˙O2peak, 62 ± 6 mL·min-1·kg-1) undertook a four-stage exercise economy test and real-life 10,000-m race before and after a 5-d isoenergetic high-CHO (HCHO, ~60%-65% fat; CHO, 20% fat; n = 9) or LCHF (75%-80% fat, <50 g·d-1 CHO, n = 9) diet. The LCHF group performed additional economy tests before and after diet after supplementation with 573 mg·kg-1 body mass KE (HVMN; HVMN Inc., San Francisco, CA), which was also consumed for race 2. RESULTS: The oxygen cost of exercise (relative V˙O2, mL·min-1·kg-1) increased across all four stages after LCHF (P < 0.005). This occurred in association with increased fat oxidation rates, with a reciprocal decrease in CHO oxidation (P < 0.001). Substrate utilization in the HCHO group remained unaltered. The consumption of KE before the LCHF diet increased circulating KB (P < 0.05), peaking at 3.2 ± 0.6 mM, but did not alter V˙O2 or RER. LCHF diet elevated resting circulating KB (0.3 ± 0.1 vs 0.1 ± 0.1 mM), but concentrations after supplementation did not differ from the earlier ketone trial. Critically, race performance was impaired by ~6% (P < 0.0001) relative to baseline in the LCHF group but was unaltered in HCHO. CONCLUSION: Despite elevating endogenous KB production, an LCHF diet does not augment the metabolic responses to KE supplementation and negatively affects race performance.

Branched chain amino acids and carbohydrate restriction exacerbate ketogenesis and hepatic mitochondrial oxidative dysfunction during NAFLD.

Mitochondrial adaptation during non-alcoholic fatty liver disease (NAFLD) include remodeling of ketogenic flux and sustained tricarboxylic acid (TCA) cycle activity, which are concurrent to onset of oxidative stress. Over 70% of obese humans have NAFLD and ketogenic diets are common weight loss strategies. However, the effectiveness of ketogenic diets toward alleviating NAFLD remains unclear. We hypothesized that chronic ketogenesis will worsen metabolic dysfunction and oxidative stress during NAFLD. Mice (C57BL/6) were kept (for 16-wks) on either a low-fat, high-fat, or high-fat diet supplemented with 1.5X branched chain amino acids (BCAAs) by replacing carbohydrate calories (ketogenic). The ketogenic diet induced hepatic lipid oxidation and ketogenesis, and produced multifaceted changes in flux through the individual steps of the TCA cycle. Higher rates of hepatic oxidative fluxes fueled by the ketogenic diet paralleled lower rates of de novo lipogenesis. Interestingly, this metabolic remodeling did not improve insulin resistance, but induced fibrogenic genes and inflammation in the liver. Under a chronic "ketogenic environment," the hepatocyte diverted more acetyl-CoA away from lipogenesis toward ketogenesis and TCA cycle, a milieu which can hasten oxidative stress and inflammation. In summary, chronic exposure to ketogenic environment during obesity and NAFLD has the potential to aggravate hepatic mitochondrial dysfunction.

Ketogenic and low-sugar diets for patients with cancer: perceptions and practices of medical oncologists in Canada.

PURPOSE: Many patients with cancer are interested in complementary therapies, including strategies such as reduced carbohydrate diets. Guidelines regarding the use of these diets during cancer treatment are lacking; therefore, we aimed to explore the perceptions and practices of medical oncologists in Canada regarding low-sugar and ketogenic diets. METHOD: A cross-sectional, online multiple-choice survey was distributed to 206 Canadian medical oncologists. Questions explored frequency of patient interactions, oncologist perceptions of efficacy, advice given to patients, and concerns about side effects related to reduced carbohydrate diets. RESULTS: Responses were received from 57 medical oncologists in seven of thirteen provinces and territories, with an overall response rate of 28%. Forty-nine percent of respondents were asked at least weekly about a low-sugar diet, and 9% about the ketogenic diet. Eighty-five percent supported the use of a low-added sugar diet in patients with diabetes or hyperglycemia, while conversely 87% did not support the use of a ketogenic diet for any of their patients undergoing active cancer treatment. Respondents felt either that a ketogenic diet was not effective (31%) or that the effect on cancer outcomes was unknown (69%). Ninety-six percent of respondents had concerns about a ketogenic diet for patients receiving active cancer treatment. CONCLUSION: The role of reduced carbohydrate diets during cancer treatment is topical. Canadian oncologists are particularly reluctant to support a ketogenic diet for patients on active cancer treatment, with concerns about side effects and unknown efficacy. There may be a role for continuing medical education and institutional guidelines to inform these discussions with patients.

Selenium and antioxidant levels in children with intractable epilepsy receiving ketogenic diet.

Ketogenic diet is a high-fat, low-carbohydrate, and adequate-protein diet. It is well-established as a treatment option for drug-resistant childhood epilepsies. Our study aimed to evaluate Selenium levels and oxidative stress in children receiving ketogenic diet for intractable seizures for 6 months. This is a comparative case-control study included 90 children under 6 years age. They were subdivided into three groups. Group I: Thirty patients with drug-resistant epilepsy under antiepileptic drugs only. Group II: Thirty patients with drug-resistant epilepsy under treatment with ketogenic diet for 6 months and antiepileptic drugs. Group III: Thirty age and sex-matched healthy children as controls. Full history taking with special emphasis on severity and frequency of seizures, neurological examination, anthropometric measurements and laboratory analysis for serum Malonaldehyde, and total antioxidant capacity and Selenium were done for all participants. The frequency and severity of seizures were significantly lower in group II receiving ketogenic diet than group I on antiepileptic drugs only. Selenium levels were significantly lower in epileptic patients in comparison to controls. However, it was markedly lower in the ketogenic diet group. Malonaldehyde levels were significantly higher in epileptic children in comparison to controls, with lower values among ketogenic diet group when compared to patients on antiepileptic drugs only. Total antioxidant capacity levels were significantly lower in epileptic patients in comparison to controls, with higher values among ketogenic diet group as compared to epileptic patients on pharmacological treatment. Ketogenic diet is an effective treatment for refractory epilepsy for its anti-epileptic mechanism. It also may exert antioxidant effects. The nutrient content of the ketogenic diet may not meet the recommended daily allowance for selenium. So, this should be taken into consideration for supplementation of minerals in adequate amounts for patients receiving this diet.

Potassium citrate and metabolic acidosis in children with epilepsy on the ketogenic diet: a prospective controlled study.

AIM: To investigate if potassium citrate, a mild alkaline compound, can prevent metabolic acidosis in children with epilepsy treated with the ketogenic diet without reducing antiepileptic efficacy. METHOD: In this prospective controlled study, we investigated the frequency of initial uncompensated metabolic acidosis in 51 participants. There were 22 participants with and 29 without potassium citrate supplementation. The ketogenic diet was used as add-on treatment to children with drug resistant epilepsy. We also estimated the proportion of participants with a greater than 50% seizure reduction after 7 months. RESULTS: None of the 22 participants (15 males, seven females; median age 1y 7mo, interquartile range [IQR] 3y 3mo) with, and 10 of 29 (12 males, 17 females; median age 6y 1mo, IQR 4y 8mo) without potassium citrate developed metabolic acidosis (odds ratio=0.04, 95% CI 0.00-0.75 [p<0.01]); median pH 7.32 vs 7.24; [p<0.001]), and median bicarbonate 19.7mmol/L vs 14.0mmol/L (p<0.001). The number of seizures was reduced by more than 50% in 9 of 22 with potassium citrate and 8 of 29 participants without potassium citrate, 7 months after introducing a ketogenic diet (p=0.4). INTERPRETATION: In the ketogenic diet, potassium citrate supplementation can prevent metabolic acidosis, without reducing antiepileptic efficacy. WHAT THIS PAPER ADDS: Citrate supplementation prevents metabolic acidosis in children treated with a ketogenic diet. Efficacy of the ketogenic diet is not affected by supplementation with citrate. Citrate supplementation does not affect beta-hydroxybuturate concentration. Potassium citrate reduces the time needed to reach an optimal ketogenic ratio. This article is commented on by Schoeler on page 8 of this issue.