Immunomodulatory effect
Dr. Crujeiras said that her research group also observed the modulatory role of the very-low-calorie ketogenic diet in the functioning of the immune system, “something that was not seen after similar weight loss induced by bariatric surgery. We analyzed this data in the context of the situation created by COVID-19, taking into account the evidence that people with obesity, compared to those with normal weight, have a higher risk of becoming infected and of having a poor evolution of the infection.”
In this regard, Dr. Crujeiras’ team launched an investigation to study the ACE2 gene methylation pattern, comparing obesity with normal weight and the situation after following a very-low-calorie ketogenic diet or undergoing bariatric surgery. “We observed that the methylation pattern of this gene in obese people was increased, compared to normal-weight people,” she explained, “and this increase was observed mainly in visceral adipose tissue. However, we did not see this in subcutaneous adipose tissue, which is in agreement with the hypothesis that visceral adipose tissue is that mostly associated with obesity-related comorbidities.
“Likewise, the very-low-calorie ketogenic diet was associated with decreased ACE2 methylation, along with increased exposure of this gene. However, after bariatric surgery, no significant changes were observed, so we deduce that we are protecting the patient in some way from inflammation and, therefore, from the potential of serious illness if they become infected.
“In light of these results, we wanted to dig deeper into what was happening with the immune system of obese patients and that inflammation after a very-low-calorie ketogenic diet. We conducted a new study, currently under review in the journal Clinical Nutrition, with the same approach, comparing this diet with a standard hypocaloric balanced diet and bariatric surgery, in which we analyzed a wide battery of cytokines (32). We have observed a differential pattern between the very-low-calorie ketogenic diet and bariatric surgery.
“The results confirm our hypothesis that the very-low-calorie ketogenic diet remodels the inflammatory status of obese patients, and we were also able to verify that the increase in ketone bodies has immunomodulatory properties that were previously demonstrated in preclinical and animal models, which is associated with increased immune function in these patients,” added Dr. Crujeiras.
Personalization and weight regain
In regard to the next steps to take in the knowledge and clinical application of the benefits of this dietary strategy, Dr. Crujeiras said that despite the fact that this diet is known to be effective, it is currently prescribed in a standard manner to all patients, “but there is some variability in the response and also a high risk of regaining weight, as is the case with any nutritional intervention strategy, with that ‘regain’ of lost weight being the main challenge in the treatment of obesity. In this sense, the epigenomic and epigenetic markers that we have identified could help us optimize treatment.”
She added that the future lies in establishing an algorithm that encompasses the patient’s exposome data, along with their genetic and epigenetic profile, to properly classify patients and prescribe a personalized precision therapeutic strategy.
Luca Busetto, MD, cochair of the Obesity Management Task Force (OMTF) of the European Association for the Study of Obesity (EASO), also insisted on the challenge posed by the individualized application of the very-low-calorie ketogenic diet, emphasizing that this diet should always be prescribed by a doctor after an appropriate assessment of the patient. “Obesity is not a matter of willpower or motivation, and most people with obesity have struggled their entire lives and failed because their biology tends to cause weight regain. Therefore, we should try to offer them the options that we currently have, including the very-low-calorie ketogenic diet, adapting them as much as possible to the profile of each patient.”
During his speech, Dr. Busetto presented the recent European guidelines for the management of obesity in adults with a very-low-calorie ketogenic diet, endorsed by EASO, and analyzed the main strengths of these recommendations.
Dr. Busetto remarked that three important points clearly justify the use of the very-low-calorie ketogenic diet. The first is the speed with which the initial weight loss occurs. Recent studies have looked at the benefits of a significant loss of excess weight early in a weight-loss diet, and although this is an association rather than a cause, the results strongly suggest that rapid initial weight loss increases the chance of the result being maintained in the long term. This clashes with the traditional recommendation of losing weight little by little as a strategy to achieve long-term results, but it must be taken into account that there are many myths in the treatment of obesity that current evidence is dismantling with new data – and this is one of them.
Secondly, the effect of the very-low-calorie ketogenic diet can be added to other treatments. This has been demonstrated by studies carried out with liraglutide that showed that this dietary strategy optimizes results, compared with patients who had been treated only with this drug. The third point that justifies the use of the very-low-calorie ketogenic diet is the management of obesity comorbidities. Several investigations demonstrate the effectiveness of this diet in this regard, especially in the case of type 2 diabetes. Data suggest that the substantial weight reductions achieved with it also favor the remission of these comorbidities in many patients.