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

Obesity Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05200468
• Other study ID #: 3728
• Status: Completed
• Phase: N/A
• Start date: July 28, 2022
• Est. completion date: March 27, 2023

Study information

• Verified date: March 2023
• Source: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 63
• Est. completion date: March 27, 2023
• Est. primary completion date: November 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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.

Related Conditions & MeSH terms

• Obesity

Intervention

Other:
• Ketogenic diet
Weekly menus will be delivered according to diet with the following macronutrient distribution: 25% protein, 10% carbohydrate, 65% fat. Participants will receive a 30-day food menu guide.
• Caloric restriction diet
Weekly menus will be provided according to their usual diet with 500 kcal restriction with the following macronutrient distribution 25-35% protein, 45-55% carbohydrates, 20-30% fat. Participants will receive a 30-day food menu guide.
• Intermittent fasting 16/8
Calorie-restricted menus will be provided with a 16:8 time-restricted feeding. The feeding window will be 8 hours with a fasting time of 16 hours (04.00 pm- 08.00 am or 05.00 pm - 09.00 am), during the fasting window participants will only be allowed to drink water, unsweetened tea, mineral water and coffee without added sugar. Participants will receive a 30-day food menu guide.

Locations

Country	Name	City	State
Mexico	Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán	Mexico City

Sponsors (1)

Lead Sponsor	Collaborator
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Country where clinical trial is conducted

Mexico, 

References & Publications (11)

Ang QY, Alexander M, Newman JC, Tian Y, Cai J, Upadhyay V, Turnbaugh JA, Verdin E, Hall KD, Leibel RL, Ravussin E, Rosenbaum M, Patterson AD, Turnbaugh PJ. Ketogenic Diets Alter the Gut Microbiome Resulting in Decreased Intestinal Th17 Cells. Cell. 2020 J — View Citation

Anson RM, Guo Z, de Cabo R, Iyun T, Rios M, Hagepanos A, Ingram DK, Lane MA, Mattson MP. Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake. Proc Natl Acad — View Citation

Cignarella F, Cantoni C, Ghezzi L, Salter A, Dorsett Y, Chen L, Phillips D, Weinstock GM, Fontana L, Cross AH, Zhou Y, Piccio L. Intermittent Fasting Confers Protection in CNS Autoimmunity by Altering the Gut Microbiota. Cell Metab. 2018 Jun 5;27(6):1222- — View Citation

Fabbiano S, Suarez-Zamorano N, Chevalier C, Lazarevic V, Kieser S, Rigo D, Leo S, Veyrat-Durebex C, Gaia N, Maresca M, Merkler D, Gomez de Aguero M, Macpherson A, Schrenzel J, Trajkovski M. Functional Gut Microbiota Remodeling Contributes to the Caloric R — View Citation

Goodpaster BH, Sparks LM. Metabolic Flexibility in Health and Disease. Cell Metab. 2017 May 2;25(5):1027-1036. doi: 10.1016/j.cmet.2017.04.015. — View Citation

Hamanaka RB, Chandel NS. Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes. Trends Biochem Sci. 2010 Sep;35(9):505-13. doi: 10.1016/j.tibs.2010.04.002. Epub 2010 Apr 27. — View Citation

Lanza IR, Zabielski P, Klaus KA, Morse DM, Heppelmann CJ, Bergen HR 3rd, Dasari S, Walrand S, Short KR, Johnson ML, Robinson MM, Schimke JM, Jakaitis DR, Asmann YW, Sun Z, Nair KS. Chronic caloric restriction preserves mitochondrial function in senescence — View Citation

Paoli A, Mancin L, Bianco A, Thomas E, Mota JF, Piccini F. Ketogenic Diet and Microbiota: Friends or Enemies? Genes (Basel). 2019 Jul 15;10(7):534. doi: 10.3390/genes10070534. — View Citation

Rizza W, Veronese N, Fontana L. What are the roles of calorie restriction and diet quality in promoting healthy longevity? Ageing Res Rev. 2014 Jan;13:38-45. doi: 10.1016/j.arr.2013.11.002. Epub 2013 Nov 27. — View Citation

Roberts MN, Wallace MA, Tomilov AA, Zhou Z, Marcotte GR, Tran D, Perez G, Gutierrez-Casado E, Koike S, Knotts TA, Imai DM, Griffey SM, Kim K, Hagopian K, McMackin MZ, Haj FG, Baar K, Cortopassi GA, Ramsey JJ, Lopez-Dominguez JA. A Ketogenic Diet Extends L — View Citation

Vidali S, Aminzadeh S, Lambert B, Rutherford T, Sperl W, Kofler B, Feichtinger RG. Mitochondria: The ketogenic diet--A metabolism-based therapy. Int J Biochem Cell Biol. 2015 Jun;63:55-9. doi: 10.1016/j.biocel.2015.01.022. Epub 2015 Feb 7. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	mitochondrial function	Change in mitochondrial function determined by mitochondrial oxygen consumption rate in monocytes	Baseline to 4, 5 and 8 weeks
Secondary	gut microbiota composition	Change in microbiota composition determined by alpha and beta diversity analysis to compare the baseline and final microbiota composition between different nutritional interventions in subjects with obesity.	Baseline to 4, 5 and 8 weeks
Secondary	oxidative stress markers	Change in markers of oxidative stress determined by levels of malondialdehyde and reactive oxygen species to compare the baseline and final markers of oxidative stress between different nutritional interventions in subjects with obesity.	Baseline to 4, 5 and 8 weeks
Secondary	body composition	Change in body composition determined by multifrequency electrical bioimpedance to compare the baseline and final fat mass, lean mass and skeletal muscle mass percentage between different nutritional interventions in subjects with obesity	Baseline to 4, 5 and 8 weeks
Secondary	body weight	Change in body weight to compare the baseline and final body weight between different nutritional interventions in subjects with obesity	Baseline to 4, 5 and 8 weeks
Secondary	grip strength	Change in grip strength determined by dynamometry to compare the baseline and final grip strength between different nutritional interventions in subjects with obesity.	Baseline to 4 and 8 weeks
Secondary	glucose serum	Change in glucose in the serum determined by autoanalyzer to compare the baseline and final concentration of serum glucose between different nutritional interventions in subjects with obesity.	Baseline to 4 and 8 weeks
Secondary	total cholesterol	Change in total cholesterol in the serum by autoanalyzer to compare the baseline and final concentration of serum total cholesterol between different nutritional interventions in subjects with obesity	Baseline to 4 and 8 weeks
Secondary	HDL cholesterol	Change in HDL cholesterol serum by autoanalyzer to compare the baseline and final concentration of serum HDL-cholesterol between different nutritional interventions in subjects with obesity.	Baseline to 4 and 8 weeks
Secondary	triglycerides	Change in triglycerides in the serum by autoanalyzer to compare the baseline and final concentration of serum triglycerides between different nutritional interventions in subjects with obesity.	Baseline to 4 and 8 weeks
Secondary	LDL cholesterol	Change in LDL cholesterol in the serum by autoanalyzer to compare the baseline and final concentration of serum LDL cholesterol between different nutritional interventions in subjects with obesity.	Baseline to 4 and 8 weeks
Secondary	leptin	Change in leptin concentration in the serum determined by ELISA kit to compare the baseline and final concentration of serum leptin between different nutritional interventions in subjects with obesity.	Baseline to 4 and 8 weeks
Secondary	adiponectin	Change in adiponectin concentration in the serum determined by ELISA kit to compare the baseline and final concentration of serum leptin between different nutritional interventions in subjects with obesity.	Baseline to 4 and 8 weeks
Secondary	C-reactive protein	Change in C-reactive protein concentration in the serum to compare the baseline and final concentration of serum C- reactive protein between different nutritional interventions in subjects with obesity.	Baseline to 4 and 8 weeks
Secondary	blood pressure	Change in systolic and diastolic blood pressure to compare the baseline and final blood pressure between different nutritional interventions in subjects with obesity.	Baseline to 4 and 8 weeks