Clinical trial NCT06204965: The Impact of Time-restricted Eating on the Outcomes Associated With Polycystic Ovary Syndrome
Official title: The Impact of Time-restricted Eating on the Composition of the Intestinal Microbiota and Metabolic and Neurohormonal Parameters of Women With Polycystic Ovary Syndrome
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Polycystic Ovary Syndrome
Keywords: Intermittent Fasting
Microbiota
Neurotransmitter Agents
Polycystic Ovary Syndrome
Lead sponsor: Poznan University of Life Sciences
Sponsor class: OTHER
First posted: 2024-01-12
Enrollment: 52
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Women with Polycystic Ovary Syndrome (n=52), aged 18-40.
Primary purpose: TREATMENT

Brief summary: Polycystic Ovary Syndrome (PCOS) is a disorder that affects approximately 10-15% of women of reproductive age. Increased activity of the hypothalamic-pituitary-ovarian (HPO) axis is considered to be one of the main factors associated with the pathogenesis of PCOS. The regulation of the activity of this axis is influenced by the following factors: insulin resistance and the activity of kisspeptins in the hypothalamus. It is suggested that intestinal dysbiosis may also play a key role in the pathogenesis of PCOS. It was noticed that the presence of bacteria producing gamma-aminobutyric acid in the intestine is positively correlated with the concentration of luteinizing hormone (LH) in the serum, which indicates the relationship between the functioning of the gut-brain axis and PCOS. A dysbiotic factor is an incorrect diet and inappropriate timing of its consumption, which may also lead to inhibition of kisspeptin expression in the hypothalamus and cause menstrual disorders.

Due to the fact that most obese women with PCOS eat significantly more meals in the second part of the day, and these meals are characterized by a significant supply of fat and simple sugars, intestinal dysbiosis seems to be an important cause of the observed disorders, while the use of chrononutrition, consisting in synchronizing meal times with endogenous 24-hour circadian rhythms may partially restore eubiosis in the intestine and improve the reproductive, metabolic and neurohormonal health of women with PCOS. Time-restricted feeding (TRF), which involves eating food usually within 8 hours followed by 16 hours of fasting, seems to be a regime that allows restoring eubiosis in the intestinal microbiota and improving the quality of life of women with PCOS. So far, only one study has been conducted among women with PCOS who used TRF for 5 weeks and a number of positive changes were demonstrated (hormonal or metabolic). However, this study did not include an assessment of the microbial and neurohormonal parameters, which seems to be a key issue.

Taking the above into account, it was hypothesized that TRF may be an appropriate therapeutic tool for women with PCOS, which will positively affect metabolic and hormonal parameters by changing the composition of the intestinal microbiota. Therefore, the main aim of the experiment is to investigate the impact of TRF on the composition of the intestinal microbiota, its metabolites, and metabolic and neurohormonal parameters in women with PCOS.

Detailed description: Fifty two women, aged 18-40, will be recruited for the study. The investigators calculated the sample size using G\*Power software (RRID:SCR_013726); the sample size of the participants was also determined. The effect size was calculated to be 1.04 on the basis of the differences in body fat mass between baseline values and values after 6-weeks of application of time-restricted eating by PCOS women. With an alpha value of 0.05, a sample size of eight mice per group would yield a power of 0.95.

Women recruited for the study will be provided with detailed information regarding: the purpose of the study, the study protocol, the measurements performed and the duration of the study. Recruitment will take place via social networking sites, i.e. Facebook, where target groups will be found, bringing together women with PCOS, and posts with an announcement and a contact form will be placed there. After obtaining consent to participate in the study, a group of qualified women will undergo a general medical interview by Jakub Noskiewicz, Ph.D., which will include a personal interview, including current medications and supplements taken, medical history and a basic physical examination - examination, percussion. If the interview reveals an existing infection, a chronic disease in the acute phase, a suspicion of e.g. anemia, infectious skin diseases or malnutrition, or the intake of medications constituting an exclusion criterion, the patient will not be qualified for the study. During this interview, participants will be asked to provide medical documentation confirming they suffer from PCOS.

Participants will be randomly assigned (using a specialized program) to two groups - control and intervention. Research participants assigned to the control group will receive dietary recommendations consistent with the healthy eating plate. Additionally, the recommended daily energy intake will be individually determined for each patient. Participants assigned to the TRF group will be instructed to continue eating their usual diet during the experiment (without any qualitative or quantitative restrictions), but to eat it within a limited time frame - from 9:00 a.m. to 5:00 p.m., and then fast until the next day ( protocol 8/16). The duration of the study will be 3 months (12 weeks).

A nutritional assessment of the diet will be carried out (KomPAN questionnaire). The nutritional assessment will be additionally supplemented by an interview from the last 24 hours. Then, the recruited women will be randomly assigned to the intervention group, using time-restricted nutrition, or the control group, using the principles of the healthy eating plate. The duration of the experiment will be 12 weeks, with follow-up visits scheduled at 4-week intervals. At the beginning of the experiment and at follow-up visits, women will have blood drawn (per 18 ml) to assess biochemical parameters. Each time, a stool sample will also be collected to assess the composition of the intestinal microbiota and short-chain fatty acids, and an analysis of body composition, bone density and anthropometric parameters will be carried out. During the last visit in week 12, women will be asked to fill out the KomPAN questionnaire again, which will be supplemented by an interview from the last 24 hours. Each time, an interview will be conducted regarding the women's well-being and adherence to the recommendations provided. The level of adherence to the eating window will be verified using a diary in which women will write down each day when they ate their first and last meals.

The following specific analyses are planned:

* Assessment of anthropometric parameters (body weight, height, waist circumference, hip circumference) as well as body composition and bone density.
* Assessment of carbohydrate metabolism parameters (concentration of glucose, insulin, calculation of HOMA-IR, HOMA-β, QUICKI), lipid metabolism (concentration of total cholesterol (T-C), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C) , non-HDL cholesterol (non-HDL-C) and triglycerides)
* Assessment of hormonal parameters (FSH, LH, testosterone, SHBG) and lipopolysaccharide in the blood.
* Assessment of neurohormonal parameters (kisspeptin, gamma-aminobutyric acid) in the blood.
* Assessment of the composition of intestinal microbiota and short-chain fatty acids in women's feces.

Normality of the obtained data distribution will be tested using the Shapiro-Wilk test. The Kruskal-Wallis test then will be used for nonnormally distributed data and the Tukey HSD test will be used for normally distributed data. A p value of less than 0.05 was considered statistically. The microbiota composition will be analyzed using RStudio (R version 4.0.3 (2020-10-10)) with packages including phyloseq, microbiome, and vegan. Taxa will be filtered by removing all those not assigned to any phylum. Only taxa with abundances over 0.25% in at least one sample will left in the dataset. All analyses of gut microbiota composition will be performed on the basis of the relative abundances (RA) of the OTUs.

The data collected in the planned studies will include the results of measurements and their statistical analyzes. All data will be collected directly by team members and coded. Detailed instructions on data collection will be prepared by the team leader and each member will need to read and receive appropriate training. All biochemical and anthropometric measurements will be performed in at least two repetitions and will be checked by another team member. All used specialized equipment will be properly calibrated before each use (scale, body composition analyzer, Nanodrop spectrophotometer).

Eligibility criteria: Inclusion criteria

* Age 18-40
* suffering from Polycystic Ovary Syndrome, confirmed by appropriate medical documentation
* BMI \>25 kg\^m2

Exclusion criteria

* Taking medications regulating carbohydrate, lipid as well as medications affecting body weight in the last 3 months (will be assessed during a general medical interview conducted by Jakub Noskiewicz, MD, PhD)
* Taking antibiotics in the last 3 months
* Smoking in the last 3 months and alcohol consumption \>100 g per week
* Competitive sports practice
* Significant body weight fluctuations in the 3 months before the start of the study (\>5%)
* Pregnant or breastfeeding women
* BMI \<25 kg\^m2

Primary outcomes:
measure: Change in body weight
timeFrame: Week 0 (pre-intervention), week 4, week 8 and week 12 (post-intervention)
measure: Change in circumferences
timeFrame: Week 0 (pre-intervention), week 4, week 8 and week 12 (post-intervention)
measure: Change in body composition
timeFrame: Week 0 (pre-intervention), week 4, week 8 and week 12 (post-intervention)
measure: Change in composition of the intestinal microbiota
timeFrame: Week 0 (pre-intervention), week 4, week 8 and week 12 (post-intervention)
measure: Change in selected hormonal parameters
timeFrame: Week 0 (pre-intervention), week 4, week 8 and week 12 (post-intervention)
measure: Change in lipid profile
timeFrame: Week 0 (pre-intervention), week 4, week 8 and week 12 (post-intervention)
measure: Change in glucose metabolism
timeFrame: Week 0 (pre-intervention), week 4, week 8 and week 12 (post-intervention)
Secondary outcomes:
measure: Assessment of changes in eating behavior pre- and post-intervention
timeFrame: Week 0 (pre-intervention), week 4, week 8 and week 12 (post-intervention)
measure: Change in bone density
timeFrame: Week 0 (pre-intervention), week 4, week 8 and week 12 (post-intervention)
measure: Change in the concentration of short-chain fatty acids in feces
timeFrame: Week 0 (pre-intervention), week 4, week 8 and week 12 (post-intervention)
measure: Change in the expression of genes encoding kisspeptin and gamma-aminobutyric acid
timeFrame: Week 0 (pre-intervention), week 4, week 8 and week 12 (post-intervention)
measure: Change in intestinal barrier integrity
timeFrame: Week 0 (pre-intervention), week 4, week 8 and week 12 (post-intervention)
measure: Change in neurohormonal status
timeFrame: Week 0 (pre-intervention), week 4, week 8 and week 12 (post-intervention)
Other outcomes:
Locations:
city: Poznań
country: Poland
facility: Poznań University of Life Sciences
state: Wielkopolskie
Study officials:
affiliation: Department of Human Nutrition and Dietetics, Poznań University of Life Sciences
name: Agata Chmurzyńska, Prof.
role: STUDY_CHAIR
References:
citation: Li C, Xing C, Zhang J, Zhao H, Shi W, He B. Eight-hour time-restricted feeding improves endocrine and metabolic profiles in women with anovulatory polycystic ovary syndrome. J Transl Med. 2021 Apr 13;19(1):148. doi: 10.1186/s12967-021-02817-2.
citation: Torres PJ, Ho BS, Arroyo P, Sau L, Chen A, Kelley ST, Thackray VG. Exposure to a Healthy Gut Microbiome Protects Against Reproductive and Metabolic Dysregulation in a PCOS Mouse Model. Endocrinology. 2019 May 1;160(5):1193-1204. doi: 10.1210/en.2019-00050.
citation: Liao B, Qiao J, Pang Y. Central Regulation of PCOS: Abnormal Neuronal-Reproductive-Metabolic Circuits in PCOS Pathophysiology. Front Endocrinol (Lausanne). 2021 May 28;12:667422. doi: 10.3389/fendo.2021.667422. eCollection 2021.
citation: Tremellen K, Pearce K. Dysbiosis of Gut Microbiota (DOGMA)--a novel theory for the development of Polycystic Ovarian Syndrome. Med Hypotheses. 2012 Jul;79(1):104-12. doi: 10.1016/j.mehy.2012.04.016. Epub 2012 Apr 27.
citation: Minabe S, Iwata K, Tsuchida H, Tsukamura H, Ozawa H. Effect of diet-induced obesity on kisspeptin-neurokinin B-dynorphin A neurons in the arcuate nucleus and luteinizing hormone secretion in sex hormone-primed male and female rats. Peptides. 2021 Aug;142:170546. doi: 10.1016/j.peptides.2021.170546. Epub 2021 Mar 29.