Dietary Modulation of Gut Microbiota in Overweight/Obese Adolescents and COVID-19 Infection (DIVINE)

Dietary Modulation of Gut Microbiota on Nutritional Status and COVID-19 Infection in Adolescents: Gut-Lung-Axis

Probiotic intervention has been currently suggested to provide supportive benefits in promoting health, including alleviating disease symptoms, protecting against diarrhea and respiratory infection, affecting growth and modulating the immune system by improving the beneficial gut microbiota colonization, giving direction on the gut-lung-axis pathway. This indicates that probiotics may become alternative to improve nutrition and reduce the risk of viral infections which may reduce the risk against Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2). Introduction to probiotics during adolescence can alleviate inflammation and invert dysbiosis. However, evidence on the effect of probiotic supplementation on enhancing antibody response to SARS COV-2 in adolescents is lacking. Moreover, previous studies showed the potential effect of probiotic supplementation to improve overweight and obesity in adolescents. A bi-directional relationship exists among nutrition, infection, and immunity as changes in one element will affect the others. The main objective of this study is to investigate the effect of dietary modulation of overweight and obese adolescent's gut microbiota through probiotic supplementation combined with healthy eating and physical activity counseling and psychosocial stimulation on nutritional status and antibody response to COVID-19 vaccination. This trial will conduct a 20-week intervention for overweight and obese adolescents.

Study Overview

• Status: Recruiting
• Conditions: Adolescent Obesity; Child Development; Health Behavior
• Intervention / Treatment: Dietary supplement: Probiotics; Behavioral: Counselling on healthy eating, physical activity, and psychosocial stimulation; Dietary supplement: Placebo probiotics

Detailed Description

The adolescence period is the transition from childhood to adulthood. Adolescents are vulnerable to many biomedical exposures, such as a low-quality diet, fewer fruits and vegetable intake, low physical activities, smoking habits, and alcohol consumption; and non-biomedical aspects such as mental depression, parental distress, and household income, which were known to be associated with increased risk of many health outcomes. Obese adolescents are vulnerable to many infections, poor disease outcomes and complications, and lower antibody response to vaccinations. Studies that have investigated Covid-19 incidence in overweight and obese individuals are still scarce. Adolescence is also a sensitive period to microbial change or dysbiosis due to practicing poor diet, low physical activity, inadequate sleep, stress, and substance use (smoking, drugs, and alcohol). Despite the existing prevalence of SARS-COV-2 infections is increasing in adolescents, and the vaccine program is not prioritized in this population, making the prevention strategy for SARS-COV-2 infection may become less effective in this population. Besides, low-quality diet and lifestyle habits and family cluster transmission at home are often not fully addressed in the policy. These factors may be the contributors to the potential highest COVID-19 exposure for children and adolescents. Since exposure among adolescents is linked to serious adverse health effects, effective interventions to improve nutritional outcomes and reduce the risk of COVID-19 infection will provide substantial long-term returns. However, such interventions for adolescents in Indonesia and globally are lacking.

This study is a randomized clinical trial (RCT) and placebo parallel controlled study. The research will be conducted in junior and senior high schools in Jakarta, Surabaya, and Yogyakarta, Indonesia.

In light of COVID-19 outbreak, if face-to-face activities are permitted by (1) national government (Indonesian Ministry of Health), (2) local government (DKI Jakarta), (3) the university, (4) Data Safety Monitoring Board, and (5) by consent of the subject, then the activities need to be strictly adjusted with the COVID-19 prevention measures for both personnel and subjects. All personnel and subjects who will be involved in the activities are required to fill out the COVID-19 symptom screening form prior to the visit and have been vaccinated with a complete dose.

• Study Type: Interventional
• Enrollment (Estimated): 440
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Rina Agustina, PhD; Phone Number: 201052 +622129189160; Email: dr.rinaagustina@gmail.com
• Study Contact Backup: Name: Rahyussalim Rahyussalim, PhD; Phone Number: 201908 +622129189160; Email: manajer.riset.fkui1@gmail.com

Study Locations

• Indonesia
  • DKI Jakarta
    • Jakarta Pusat, DKI Jakarta, Indonesia, 10430
      • Recruiting
      • Department of Nutrition (FKUI-RSCM); and Human Nutrition Research Center, Indonesian Medical Education Research Institute (HNRC-IMERI) Faculty of Medicine, Universitas Indonesia
      • Sub-Investigator: Erfi Prafiantini, MSc
      • Sub-Investigator: Dian N Chandra, PhD
      • Sub-Investigator: Alfi R Putri, MSc
      • Sub-Investigator: Mira Mutiyani, MSc
      • Sub-Investigator: Emy Huriyati, PhD
      • Sub-Investigator: Wahyu Damayanti, MSc
      • Sub-Investigator: Ainun Nisa, SGz
      • Sub-Investigator: Purwo S Rejeki, PhD
      • Sub-Investigator: Lilik Djuari, PhD
      • Sub-Investigator: Adi Pranoto, MKes
      • Sub-Investigator: Fhadilla Amelia, MSc
      • Principal Investigator: Rina Agustina, PhD
      • Contact: Rina Agustina, PhD; Phone Number: +6221 2912477; Email: dr.rinaagustina@gmail.com
      • Sub-Investigator: Julie Bines, PhD
      • Sub-Investigator: Susan Sawyer, PhD
      • Sub-Investigator: Murdani Abdullah, PhD
      • Sub-Investigator: Dwiana Ocviyanti, PhD
      • Sub-Investigator: Karina R Ekawidyani, PhD
      • Sub-Investigator: Triska S Nindya, PhD
      • Sub-Investigator: Mohammad Juffrie, PhD
      • Sub-Investigator: Dwi Susanti, PhD
      • Sub-Investigator: Alpha F Athiyyah, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 17 years (Child)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. living in Jakarta, Surabaya, and Yogyakarta City for at least 6 months permanently;
2. apparently healthy;
3. male and female, age 12-17 years old;
4. overweight or obese (BMI-for-age z-score >+1SD);
5. have completed at least two dosages of COVID-19 vaccine, the vaccine must be CoronaVac® (Sinovac);
6. minimal 6 months post vaccinated prior to recruitments.
7. parents willing to sign the informed consent and adolescents give informed assent;
8. Must have an active health insurance, for instance BPJS or similar health insurance.

Exclusion Criteria:

1. having a history of COVID-19 infection within the last month confirmed by PCR or antigen from health care facilities or independent laboratory;
2. having a history of chronic and non-communicable diseases, congenital diseases, and disabilities;
3. reported current diagnosed as suspected active Tuberculosis (primary lung TB, miliary TB, bleeding cough bone TB, meningitis TB);
4. having a history of gastrointestinal or malabsorption disorder (such as celiac disease and inflammatory bowel disease) within the last three months or during the study;
5. taking antibiotics during 2 weeks before the start of the study (adolescents will be included after 3 weeks of last antibiotic intake);
6. taking other medications or having diseases that may influence the immune response - i.e. immune deficiencies, immunosuppressants medications, blood transfusion or other blood products;
7. taking insulin and/or anti-dyslipidemia medication;
8. being pregnant and/or breastfeeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention; 220 overweight/obese adolescents will be given Probiotics and counselling on healthy eating, physical activity, and psychosocial stimulation.	Dietary supplement: Probiotics; Combination of 3 probiotic strains: Lactobacillus rhamnosus (LGG), Bifidobacterium animalis subsp. lactis (BB-12), and Lactobacillus acidophilus (LA-5); Behavioral: Counselling on healthy eating, physical activity, and psychosocial stimulation; Counselling on healthy eating, physical activity, and psychosocial stimulation.
Placebo Comparator: Control; 220 overweight/obese adolescents will be given placebo probiotics and counselling on healthy eating, physical activity, and psychosocial stimulation.	Behavioral: Counselling on healthy eating, physical activity, and psychosocial stimulation; Counselling on healthy eating, physical activity, and psychosocial stimulation.; Dietary supplement: Placebo probiotics; Maltodextrin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
BMI-for-age z-scores (BAZ)	Change in BAZ obtain from anthropometric measurements, i.e., weight (kg) and height (m) converted to BMI	5, 10, 15, and 20 weeks
Immunoglobulin G (IgG) specific to SARS-COV-2 titer concentrations	Change in IgG specific to SARS-COV-2 titer concentrations assessed by electro chemiluminescence immunoassay (ECLIA)	10 and 20 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
α-gut microbiota diversity	Change in α-diversity measured by 1) Chao1, 2) phylogenetic diversity, and 3) the Shannon index.	20 weeks
β-gut microbiota diversity	Change in β -diversity: as the variability in community composition (the identity of taxa observed) among samples	20 weeks
Monoclonal antibody affinity against SARS-COV-2	Change in equilibrium dissociation constant (KD) of monoclonal antibody against SARS-COV-2 spike protein measured by competitive ELISA	10 and 20 weeks
Secretory Immunoglobulin A (sIgA) specific to SARS-COV-2 titer concentrations	Change in sIgA specific to SARS-COV-2 titer concentrations assessed by competitive ELISA	10 and 20 weeks
Dietary quality	Change in score of dietary quality assessed by Healthy Eating Index 2015 from 24 hour recalls data	5, 10, 15, and 20 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
SARS-COV-2 infection	Changes in proportion of symptomatic COVID-19 and positive PCR	20 weeks
Body height	Changes in height-for-age z-score by anthropometric measurement	5, 10, 15, and 20 weeks
Abdominal obesity (waist circumference)	Changes in waist circumference by anthropometric measurement	5, 10, 15, and 20 weeks
Abdominal obesity (waist-hip ratio)	Changes in waist-hip ratio by anthropometric measurement	5, 10, 15, and 20 weeks
Middle upper arm circumference	Changes in middle upper arm circumference by anthropometric measurement	5, 10, 15, and 20 weeks
Immunoglobulin M (IgM) against SARS-Cov-2	Changes in IgM titer concentrations assessed by electro chemiluminescence immunoassay (ECLIA)	10 and 20 weeks
Neutralizing antibody against SARS-Cov-2	Changes in total neutralizing antibody titer assessed by Surrogate Virus Neutralization Test (sVNT)	10 and 20 weeks
Gut microbiota profiling	Changes in composition of gut microbiota assessed by next-generation sequencing (NGS)	20 weeks
Short Chain Fatty Acids (SCFA)	Change in concentration of the SCFA by gas chromatograph	20 weeks
Physical activity	Changes in International Physical Activity Questionnaire for Adolescent (IPAQ-A) score, the minimum is 0 metabolic equivalents of task (MET) minutes/week, and the maximum score is 3000 MET minutes/week. Higher score means better outcome.	5, 10, 15, and 20 weeks
Body image	Changes in Body Shape Questionnaire-34 (BSQ-34) score. The minimum score is 34, and the maximum is 204. Higher score means worse outcome	20 weeks
Depression	Changes in Patient Health Questionnaire for Adolescents (PHQ-A) score. The minimum score is 0, and the maximum is 27. Higher scores mean worse outcome.	20 weeks
Self-esteem	Changes in Rosenberg Self Esteem Scale. The minimum score is 0, and the maximum score is 37. Higher scores mean better outcome.	20 weeks
Quality of life score	Changes in the score of Youth Quality of Life for adolescents-Research version (YQOL-R). The minimum score is 0, and the maximum score is 100. Higher scores mean better outcome.	20 weeks
Morbidity	Type and frequency of illness	5, 10, 15, and 20 weeks
Mortality	Type and frequency of illness	5, 10, 15, and 20 weeks
Wechsler Intelligence Scale for Children score	Changes in Wechsler Intelligence Scale for Children (WISC). The minimum score is 70, and the maximum score is 159. Higher scores mean better outcome.	20 weeks
Brain Derived Neurotropic Factor level	Changes in level of Brain Derived Neurotropic Factor (BDNF) assessed by ELISA	20 weeks
Anemia status	Changes in hemoglobin concentration	20 weeks
Gut integrity (zonulin)	Changes in the level of serum zonulin assessed by ELISA and Changes in the level of fecal zonulin assessed by ELISA	20 weeks
Gut integrity (occludin)	Changes in the level of fecal occludin assessed by ELISA	20 weeks
Gut inflammation	Changes in concentration of fecal calprotectin assessed by ELISA	20 weeks

Collaborators and Investigators

• Sponsor: Indonesia University
• Collaborators: University of Melbourne; Gadjah Mada University; Universitas Airlangga; The Indonesia Endowment Funds for Education, Ministry of Finance Indonesia
• Investigators: Principal Investigator: Rina Agustina, PhD, Dep of Nutrition and Human Nutrition Research Center, IMERI, Fac of Medicine Universitas Indonesia

Publications and helpful links

General Publications

• Agustina R, Kok FJ, van de Rest O, Fahmida U, Firmansyah A, Lukito W, Feskens EJ, van den Heuvel EG, Albers R, Bovee-Oudenhoven IM. Randomized trial of probiotics and calcium on diarrhea and respiratory tract infections in Indonesian children. Pediatrics. 2012 May;129(5):e1155-64. doi: 10.1542/peds.2011-1379. Epub 2012 Apr 9.
• Petta I, Fraussen J, Somers V, Kleinewietfeld M. Interrelation of Diet, Gut Microbiome, and Autoantibody Production. Front Immunol. 2018 Mar 6;9:439. doi: 10.3389/fimmu.2018.00439. eCollection 2018.
• Rajput S, Paliwal D, Naithani M, Kothari A, Meena K, Rana S. COVID-19 and Gut Microbiota: A Potential Connection. Indian J Clin Biochem. 2021 Jul;36(3):266-277. doi: 10.1007/s12291-020-00948-9. Epub 2021 Jan 21.
• Abenavoli L, Scarpellini E, Colica C, Boccuto L, Salehi B, Sharifi-Rad J, Aiello V, Romano B, De Lorenzo A, Izzo AA, Capasso R. Gut Microbiota and Obesity: A Role for Probiotics. Nutrients. 2019 Nov 7;11(11):2690. doi: 10.3390/nu11112690.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2022
• Primary Completion (Estimated): April 30, 2025
• Study Completion (Estimated): December 30, 2025

Study Registration Dates

• First Submitted: October 31, 2022
• First Submitted That Met QC Criteria: November 17, 2022
• First Posted (Actual): November 21, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 23, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: overweight; adolescent; COVID-19; probiotics; obese
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; Overweight; Obesity; COVID-19; Pediatric Obesity
• Other Study ID Numbers: DIVINE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: We will make data from the clinical trials available upon reasonable request subject to approval from the Ministry of Health of the Republic of Indonesia. This will be in accordance with the following regulations: (1) Regulation of the Ministry of Health No. 85 Year 2020 concerning the Transfer and Use of Materials, Information Content, and Data; (2) Law No. 17 Year 2023 on Health; (3) Government Regulation No. 28 Year 2024 on the Implementation Regulation of Law No. 17 of 2023 on Health; (4) Law No. 27 of 2022 on Personal Data Protection. The individual data will be kept anonymous.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No