Understanding the Role of Gut Microbiota in Hyperphagia in Prader-Willi Syndrome (PWSGUT)

This study aims to use a high-fiber supplementation, an intervention known to create shifts in the gut microbiota towards a healthier structure, to explore the relationship between gut microbiota, appetite control and feeding behavior in PWS patients.

Study Overview

• Status: Completed
• Conditions: Obesity; Prader-Willi Syndrome
• Intervention / Treatment: Drug: NBT-NM108

Detailed Description

This study is recruiting PWS patients aged 18-35 years who have not received growth hormone treatment in the previous 6 months. Study candidates will be recruited from Robert Wood Johnson. Participants will attend a baseline visit at the Center for Advanced Human Brain Imaging Research (CAHBIR) at Rutgers University, during which functional magnetic resonance imaging (fMRI) coupled with a meal test will be performed to assess peripheral and central feeding pathways (7, 8). fMRI scans will be performed during resting state to assess functional connectivity of feeding related networks, with a specific focus on connectivity between the hypothalamus, insula, anterior cingulate, ventromedial/orbitofrontal prefrontal cortex and amygdala (9, 10). Activation to food (vs non-food) images will be assessed to index responsivity to appetitive feeding networks including the above regions and the ventral striatum using paradigms that have previously been found to be sensitive to trait and state in multiple studies (11-13). Thereafter participants will consume a liquid meal (525 kcal; Ensure Plus, Abbott). fMRI will be repeated immediately after the meal. Participants will obtain laboratory work coupled with a meal test to assess satiety hormones and inflammatory markers. Fasting blood draw will be taken, and the participants will consume a liquid meal (525 kcal; Ensure Plus, Abbot) followed by blood draws at 30, 60, 120, 180 and 240 min post-meal. Upon completion of baseline testing and providing a fecal sample, participants will consume NBT-NM108 (a mixture of inulin, Fibersol-2, and brans of oat, wheat, corn and sorghum; Notitia Biotechnologies) daily for 4 weeks. At the completion of the 4-week intervention, all sampling and testing will be repeated as per baseline. At baseline and end of intervention, participants will be interviewed with appetite and physical activity questionnaires (Appendix C and G) and requested to complete a 24-h food recall using MyFitnessPal, a mobile health app on their phone.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Robert Wood Johnson University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Aged between 18-35 (inclusive)
• Confirmed PWS with genetic testing
• No growth hormone treatment in the previous 6 months
• Body weight < 300 lbs.

Exclusion Criteria:

• History of other gastrointestinal disorders such as small intestinal bacterial overgrowth, celiac disease, inflammatory bowel disease, or irritable bowel syndrome.
• Pregnancy or breastfeeding
• Prior gastrointestinal or bariatric surgery
• Immunocompromised e.g., cancer treatment, bone marrow/organ transplant, immune deficiency, poorly controlled HIV/AIDS, prolonged use of steroids or other immunosuppressant medications
• Antibiotic administration in the previous 30 days
• Participation in other weight-loss programs in the previous 3 months.
• Administration of pre/probiotic supplements or antibiotics.
• Growth hormone administration in the previous 6 months
• Must have access to a smartphone, tablet, computer, or other qualifying internet-enabled device and be able to follow instructions.
• Individuals who are not proficient in English
• Contraindications for MRI scanning, including Ferrous material implanted in or on the body, including flakes or filings, surgical clips, bullets, or electrical devices such as a pacemaker, or nonremovable ferrous jewelry (fillings in teeth and permanent retainers are permitted). Individuals with surgical pins or plates above the neck are excluded. Surgical pins or plates below the neck are exclusions, except when the material is fixed to bone, and considered acceptable by the Reference Manual for Magnetic Resonance Safety. Implants and Devices, 2020 Edition. Almost all recent orthopedic implants are made of materials that are not ferromagnetic and therefore are safe for scanning, and even though some screws are still made of ferromagnetic materials these are firmly screwed into bone. In cases where the material is unknown or deemed unsafe for scanning by the Reference Manual for Magnetic Resonance Safety. Implants and Devices, the participant will be excluded. History of eye injury involving metallic materials, shavings in eyes, or welding without a face mask. Lead/iron tattoos and tattoos performed by a nonprofessional artist if the pigment material is unknown. Claustrophobia (history of significant anxiety in closed places).
• Back problem that would prevent the subject from laying still comfortably for up to 60 minutes.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental Arm; All participants will receive NBT-NM108 prepared as muffin (each contains 30 g of the product) for 4 weeks. The dosage will be 2 muffins a day. This dosage of NBT-NM108 will provide 24 g/day of dietary fibers.	Drug: NBT-NM108; All patients will consume NBT-NM108 in the form of 2 muffins daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiome Analysis: Alpha Diversity	Alpha Diversity measured by Shannon index. The Shannon Index is a measure of diversity of microbial species that takes into account both abundance (the number of species present) and evenness (how close the numbers for each species are). The Shannon index can be calculated using the following equation: H= -∑(i=1)^s pi ln(pi). A value of zero for H indicates that a community has only one species. The higher the value of H, the higher the diversity of species in a particular community.	Weeks 0
Microbiome Analysis: Alpha Diversity	Alpha diversity measured by Shannon index. "The Shannon Index is a measure of diversity of microbial species that takes into account both abundance (the number of species present) and evenness (how close the numbers for each species are). The Shannon index can be calculated using the following equation: H= -∑(i=1)^s pi ln(pi). A value of zero for H indicates that a community has only one species. The higher the value of H, the higher the diversity of species in a particular community.	Week 4
Microbiome Analysis: Beta Diversity	The Bray-Curtis distance was used to compute the distances for each sample. Bray-Curtis distance uses species abundance information and membership to calculate the distance between samples. The Bray-Curtis dissimilarity index for a sample ranges between 0 and 1. A value of 0 indicates no difference between the samples, while a value of 1 represents the maximum distance between them	Week 0
Microbiome Analysis: Beta Diversity	The Bray-Curtis distance was used to compute the distances for each sample. Bray-Curtis distance uses species abundance information and membership to calculate the distance between samples. The Bray-Curtis dissimilarity index for a sample ranges between 0 and 1. A value of 0 indicates no difference between the samples, while a value of 1 represents the maximum distance between them	Week 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight	Weight in kg	Week 4
Acyl-Ghrelin Level	Early response to meal post-intervention is 0-30min. Late response phase to meal post-intervention is 60-180min.	Week 0
Acyl-Ghrelin Level	Early response to meal post-intervention is 0-30min. Late response phase to meal post-intervention is 60-180min.	Week 4
Peptide YY (PYY)	Early response to meal post-intervention is 0-30min. Late response phase to meal post-intervention is 60-180min.	Week 0
Peptide YY (PYY)	Early response to meal post-intervention is 0-30min. Late response phase to meal post-intervention is 60-180min.	Week 4
Glucagon Like Peptide 1 (GLP1)	GLP1 levels were measured in patients before fiber intervention. Early response to meal post-intervention is 0-30min. Late response phase to meal post-intervention is 60-180min.	Week 0
Glucagon Like Peptide 1 (GLP1)	GLP1 levels were measured in patients after fiber intervention. Early response to meal post-intervention is 0-30min. Late response phase to meal post-intervention is 60-180min.	Week 4
Insulin Level	Insulin levels were measured in patients before fiber intervention. Early response to meal post-intervention is 0-30min. Late response phase to meal post-intervention is 60-180min.	Week 0
Insulin Level	Insulin levels were measured in patients after fiber intervention. Early response to meal post-intervention is 0-30min. Late response phase to meal post-intervention is 60-180min.	Week 4
Glucose Level	Glucose levels were measured in patients before fiber intervention. Early phase (0-30min) and late phase response (60-180min) to a mixed meal tolerance test was collected.	Week 0
Glucose Level	Glucose levels were measured in patients after fiber intervention. Early phase (0-30min) and late phase response (60-180min) to a mixed meal tolerance test was collected.	Week 4
Calorie Count	24 hour dietary recall recorded in MyFitnessPal application measured in kcal.	Week 0
Calorie Count	24 hour dietary recall recorded in MyFitnessPal application measured in kcal.	Week 4
Hyperphagia Questionnaire	Appetite behavior measured by questionnaire measured by likert scale. The scores should improve from week 0 to week 4. Higher scores indicate worse hyperphagia.	Week 0
Hyperphagia Questionnaire	Appetite behavior measured by questionnaire measured by likert scale. The scores should improve from week 0 to week 4. Higher scores indicate worse hyperphagia. The questionnaire includes 11 questions measured on a 5-point Likert scale, which are summarized in a total hyperphagia score (range: 11-55). Three subscores were summed: hyperphagic behavior (range: 5-25), hyperphagic drive (range: 4-20) and hyperphagic severity (range: 2-10). The scores should improve from week 0 to week 4 with intervention. Higher scores indicate worse hyperphagia.	Week 4

Collaborators and Investigators

• Sponsor: Rutgers, The State University of New Jersey

Publications and helpful links

General Publications

• Dykens EM, Maxwell MA, Pantino E, Kossler R, Roof E. Assessment of hyperphagia in Prader-Willi syndrome. Obesity (Silver Spring). 2007 Jul;15(7):1816-26. doi: 10.1038/oby.2007.216.
• Zhang C, Yin A, Li H, Wang R, Wu G, Shen J, Zhang M, Wang L, Hou Y, Ouyang H, Zhang Y, Zheng Y, Wang J, Lv X, Wang Y, Zhang F, Zeng B, Li W, Yan F, Zhao Y, Pang X, Zhang X, Fu H, Chen F, Zhao N, Hamaker BR, Bridgewater LC, Weinkove D, Clement K, Dore J, Holmes E, Xiao H, Zhao G, Yang S, Bork P, Nicholson JK, Wei H, Tang H, Zhang X, Zhao L. Dietary Modulation of Gut Microbiota Contributes to Alleviation of Both Genetic and Simple Obesity in Children. EBioMedicine. 2015 Jul 10;2(8):968-84. doi: 10.1016/j.ebiom.2015.07.007. eCollection 2015 Aug.
• Holland AJ, Treasure J, Coskeran P, Dallow J, Milton N, Hillhouse E. Measurement of excessive appetite and metabolic changes in Prader-Willi syndrome. Int J Obes Relat Metab Disord. 1993 Sep;17(9):527-32.
• Fieldstone A, Zipf WB, Sarter MF, Berntson GG. Food intake in Prader-Willi syndrome and controls with obesity after administration of a benzodiazepine receptor agonist. Obes Res. 1998 Jan;6(1):29-33. doi: 10.1002/j.1550-8528.1998.tb00311.x.
• Proffitt J, Osann K, McManus B, Kimonis VE, Heinemann J, Butler MG, Stevenson DA, Gold JA. Contributing factors of mortality in Prader-Willi syndrome. Am J Med Genet A. 2019 Feb;179(2):196-205. doi: 10.1002/ajmg.a.60688. Epub 2018 Dec 19.
• Martinez Michel L, Haqq AM, Wismer WV. A review of chemosensory perceptions, food preferences and food-related behaviours in subjects with Prader-Willi Syndrome. Appetite. 2016 Apr 1;99:17-24. doi: 10.1016/j.appet.2015.12.021. Epub 2015 Dec 20.
• Purtell L, Sze L, Loughnan G, Smith E, Herzog H, Sainsbury A, Steinbeck K, Campbell LV, Viardot A. In adults with Prader-Willi syndrome, elevated ghrelin levels are more consistent with hyperphagia than high PYY and GLP-1 levels. Neuropeptides. 2011 Aug;45(4):301-7. doi: 10.1016/j.npep.2011.06.001. Epub 2011 Jul 1.

Study record dates

Study Major Dates

• Study Start (Actual): January 6, 2023
• Primary Completion (Actual): May 29, 2023
• Study Completion (Actual): May 30, 2023

Study Registration Dates

• First Submitted: September 1, 2022
• First Submitted That Met QC Criteria: September 14, 2022
• First Posted (Actual): September 15, 2022

Study Record Updates

• Last Update Posted (Actual): July 16, 2024
• Last Update Submitted That Met QC Criteria: July 11, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Congenital Abnormalities; Signs and Symptoms, Digestive; Overnutrition; Nutrition Disorders; Overweight; Genetic Diseases, Inborn; Intellectual Disability; Abnormalities, Multiple; Chromosome Disorders; Obesity; Imprinting Disorders; Syndrome; Prader-Willi Syndrome; Hyperphagia
• Other Study ID Numbers: Pro2022000828

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No