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Study Authors: Felix Locker, Julia Leitner, et al.

Target Audience and Goal Statement: Dermatologists, rheumatologists, weight loss specialists, primary care physicians

The goal of this study was to examine how ketogenic diets affected psoriasiform-like skin inflammation.

Question Addressed:

• Did an array of ketogenic diets impact psoriasiform-like skin inflammation differently in mice?

Study Synopsis and Perspective:

About 40% of U.S. adults and 19% of U.S. children are considered obese. No wonder low-carbohydrate diets such as the ('keto') diet (consisting of high fats, moderate proteins, and very low carbohydrates) have skyrocketed in for those in search of a healthy body. Deprived of dietary sugars and starches on a very low carbohydrate diet, the body tends to reduce insulin secretion and switches to burning fat. Nutritional ketosis drives the liver to convert fatty acids into compounds called ketone bodies that can penetrate the blood-brain barrier and provide fuel to the brain, as well as the body's other tissues.

Devotees extol the weight-loss virtues of a well-formulated ketogenic diet and provide beach-ready bodies as anecdotal evidence, while experts contend that if people on the diet choose , there can be health risks. The point that not all fats, and by implied extension not all ketogenic diets, are equal was driven home by Felix Locker, PhD, of Paracelsus Medical University in Salzburg, Austria, in a study published in the .

Ketogenic diets rich in medium-chain triglycerides (MCTs), such as coconut, exacerbate psoriasis, especially when combined with omega-3 fatty acids from fish oil and plant sources like nuts and seeds.

While the preclinical study did not confirm the authors' original hypothesis that high-fat ketogenic diets would dampen psoriasiform-like skin inflammation progression and that partial supplementation of long-chain triglycerides (LCTs) with MCTs and/or omega-3 fatty acids would further enhance these effects, they were able to show that an LCT-based ketogenic diet skin inflammation.

Locker's group derived their conclusions from a study of 6-week-old male C57BL/6N mice fed six diets supplemented with the same amounts of antioxidants, vitamins, and trace elements. Diets under investigation were the standard diet, LCT diet, LCT/MCT diet, standard diet + omega-3 fatty acids, LCT diet + omega-3 fatty acids, and LCT/MCT diet + omega-3 fatty acids. Notably, a ketogenic diet is for non-dieting humans, but may aid in the treatment of certain conditions such as . In the current study, mice receiving the ketogenic diets were gradually adapted to those diets over a period of 10 days.

in mice mimics human psoriasis, in which the interleukin (IL)-23/IL-17 cytokine axis plays a pivotal role in the skin thickening, red plaques, and dry scales characteristic of the disease. Locker's group initiated the ketogenic diets 7 days prior to imiquimod treatment to allow adaptation to the diets and to ensure ketosis at the time of induction of psoriasiform-like skin inflammation. In addition to metabolic parameters, the researchers monitored the effects of ketogenic feeding on murine skin at the molecular and cellular levels. Semi-quantitative evaluations were also made of the impact of dietary composition on the severity of imiquimod-induced inflammation and basal skin health in mice.

Elevations of blood beta-hydroxybutyrate as a consequence of a ketogenic diet (75%-80% kcal from fat, 5%-10% kcal from carbohydrates, and 15%-25% kcal from protein) were associated with reduced blood glucose and anti-inflammatory effects in prior studies. Compared with the standard diet, all ketogenic diets had increased levels of these ketone bodies in the blood. "Interestingly, blood glucose levels were increased in the LCT/MCT ± omega-3 fatty acid cohorts on day 1 of imiquimod treatment and dropped significantly on day 4, compared to the standard diet ± omega-3 fatty acid control group," the authors wrote.

Mice exhibited increased erythema at 4 days when fed with an LCT/MCT diet, compared with mice on a standard diet. In addition, the LCT/MCT group showed a trend toward increased cumulative disease severity (based on a 12-point scale) compared with the standard diet group (8.2 ± 1.1 vs 6.2 ± 0.7), which was significant in comparison with the LCT diet group (8.2 ± 1.1 vs 5.9 ± 1.7) after 4 days of imiquimod treatment.

Omega-3 fatty acid-rich nutrition was of high interest for dietary interventions in inflammatory skin diseases because of its anti-inflammatory and anti-angiogenic effects.

However, in the current study, Locker's group found that a LCT/MCT diet with omega-3 supplementation induced skin inflammation, even in Vaseline-treated mice, which was reflected by significant increases in erythema, scaling, and thickening, as well as the cumulative disease severity scores, compared with mice on a standard diet at day 4.

Locker and colleagues also observed that skin with the LCT/MCT + omega-3 diet "showed neutrophil-derived myeloperoxidase levels that were significantly higher than standard diet + omega-3 skin upon psoriasis induction and Vaseline treatment."

"Accordingly, we detected a significantly higher number of [the rat monoclonal neutrophil antibody] NIMP-R14+ neutrophils in LCT/MCT +[ omega-3] skin compared to [standard diet + omega-3] skin," the researchers reported.

Source Reference: 2019; DOI: 10.1016/j.jid.2019.07.718

Study Highlights and Explanation of Findings:

Low-carbohydrate content in a ketogenic diet might protect from the previously reported pro-inflammatory effects of saturated fatty acid intake. However, the fatty acid composition of a ketogenic diet needs to be taken into consideration, since supplementation with MCTs and omega-3 fatty acids exacerbate imiquimod-induced psoriasis, as well as elicit basal skin alterations, according to Locker's group.

"This study leads to a broader understanding of possible effects of ketogenic diets with a very high fat content on skin inflammation and underlines the importance of the composition of fatty acids in the diet," said co-lead investigator Barbara Kofler, PhD, also of Paracelsus Medical University, in a . "We found that a well-balanced ketogenic diet, limited primarily to long-chain triglycerides ... like olive oil, soybean oil, fish, nuts, avocado, and meats, does not exacerbate skin inflammation. However, ketogenic diets containing high amounts of MCTs especially in combination with omega-3 fatty acids, should be used with caution since they may aggravate preexisting skin inflammatory conditions."

Co-lead investigator Roland Lang, PhD, elaborated on the study's results: "Ketogenic diets supplemented with MCTs not only induce the expression of pro-inflammatory cytokines, but also lead to an accumulation of neutrophils in the skin resulting in a worse clinical appearance of the skin of the mice. Neutrophils are of particular interest since they are known to express a receptor for MCTs and therefore a ketogenic diet containing MCTs may have an impact on other neutrophil-mediated diseases not limited to the skin."

Asked for his perspective, Bruce Brod, MD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia, who was not involved with the research, said the study "raises some good and important points," but that there are many factors that influence psoriasis, and a lot more work needs to be done to determine how translatable the findings are to humans -- "for example, is this translatable to all patients with psoriasis, or just patients with certain subsets of psoriasis?"

"There are multiple factors that can influence psoriasis," Brod continued. "One is body mass index. Infections can play a role, medications can play a role, as can things like stress and alcohol. So [a ketogenic diet] might be another factor that plays a role in psoriasis in certain subsets of patients. But at this point in time it is probably too early to have this study influence our clinical practice."

"I think when we're counseling our patients on dietary recommendations that those recommendations need to be made very carefully within the clinical context of that patient, and that patient's specific medical condition," he said.

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