Effect of Dietary Restrictions and Ketogenic Diet on Mitochondrial Function and Gut Microbiota in Subjects With Obesity

Effect of Intermittent Fasting, Caloric Restriction and Ketogenic Diet on Mitochondrial Function and Gut Microbiota in Subjects With Obesity

The benefits of nutritional interventions with dietary restrictions are associated with improvement and preservation of mitochondrial function. Evidence suggests that dietary restrictions, including modifications in caloric intake (caloric restriction), or in the timing of food intake (e.g., intermittent fasting), play an important role in stimulating cell and mitochondrial autophagy, favoring the elimination of old and dysfunctional mitochondria. In addition to the observed effects on mitochondrial function, there is evidence that intermittent fasting, caloric restriction, and the ketogenic diet also generate changes in gut microbiota and microbial metabolite composition. The main aim of this study is to evaluate the effect of intermittent fasting, caloric restriction and ketogenic diet on mitochondrial function determined by respirometry in monocytes, modulated by the gut microbiota in subjects with obesity. An open randomized controlled clinical trial will be conducted with 80 participants divided by a draw in 4 nutritional interventions groups for 1 month, each for 20 participants, then participants will receive 550 mg of rifaximin and will finish the study with the assigned nutritional intervention for another month of follow-up. Knowledge of these dynamics will allow us to explore and understand the relationship between metabolites from the gut microbiota and their effect on mitochondrial function associated with the dietary interventions mentioned above.

The study consists of an open-label randomized controlled clinical trial. Selected subjects will be randomized to one of 4 dietary intervention groups for 1 month with energy intake according to the resting energy expenditure obtained by indirect calorimetry.

The intervention groups will be as follows; a) ketogenic diet, b) caloric restriction diet, c) intermittent fasting diet and, d) usual diet.

1. Ketogenic diet: A dietary recommendation will be given which will be isocaloric according to the resting energy expenditure obtained by indirect calorimetry, containing the following macronutrient distribution: 25% protein, 10% carbohydrates, 65% fat.
2. Caloric restriction diet: A dietary recommendation will be given according to their usual diet, 500 kcal will be restricted, containing the following macronutrient distribution: 25-35% protein, 45-55% carbohydrates, 20-30% fat.
3. Intermittent fasting 16/8: Participants will have the same diet as the participants from the caloric restriction diet group, with the difference that intermittent fasting will be employed, with a time-restricted pattern of 16:8. During 16 hours; for example, from 04.00 pm to 08.00 am or from 05.00 pm to 09.00 am (fasting hours) participants will be fasted and no calories can be eaten or drunk. But participants in the fasting hours can drink water, unsweetened tea, unsweetened coffee and mineral water. In the other 8 hours, participants need to adhere to the energy restriction diet.
4. Usual diet: Participants will not be recommended any diet, participants will be referred to follow their usual diet until the end of the study.

After one month of the assigned intervention, the antibiotic rifaximin will be prescribed to the participants in doses of 550mg, twice a day for 7 days. After the 7 days with the antibiotic, participants will complete another month with the dietary intervention according to the group that the participants were initially randomized.

Participants will be required to complete food logs (2 on weekdays and 1 for weekends) during each week in order to monitor adherence to the dietary plan. For this, a nutritionist will teach them how to complete the food log, where participants must record the type, quantity and place where the food was consumed at each feeding time. Also, 2 phone calls will be made each week to evaluate adherence to treatment. The adherence will be determined with the % of adherence to the dietary treatment as obtained in the analysis of the food logs. Similarly, urine ketone concentration will be determined to measure adherence to the ketogenic diet. A logbook will be provided by the investigator to the participants to record the consumption of the medication, which should be filled out daily by the participant.

Inclusion Criteria:

• Male and female.
• Adults between 18 and 60 years of age.
• BMI ≥ 30 and ≤ 50 kg/m2.

Exclusion Criteria:

• Patients with any type of diabetes.

• Patients with high blood pressure.

• Patients with acquired diseases secondarily producing obesity and diabetes.

• Patients who have suffered a cardiovascular event.

• Patients with gastrointestinal diseases.

• Weight loss > 3 kg in the last 3 months.

• Catabolic diseases such as cancer and acquired immunodeficiency syndrome.

• Pregnancy status.

• Positive smoking.

• Drug treatment:

  • Antihypertensive drugs or treatment
  • Treatment with hypoglycemic agents or insulin and antidiabetic drugs.
  • Treatment with statins, fibrates or other drugs to control dyslipidemia.
  • Use of antibiotics in the three months prior to the study.
  • Use of steroid drugs, chemotherapy, immunosuppressants, or radiation therapy.
  • Anorexigenic or that accelerate weight loss such as sibutramine or orlistat.
  • Supplements with any of the functional foods used in the study.
  • Probiotic, prebiotic or symbiotic supplements.