Fiber Intervention on Gut Microbiota in Children With Prader-Willi Syndrome
Condition: Prader-Willi Syndrome; Hyperphagia
MeSH terms: Prader-Willi Syndrome; Syndrome; Hyperphagia
Study type: Interventional

Summary: 
      Prader-Willi syndrome (PWS) is the most common syndromic cause of obesity. Individuals with
      PWS characteristically experience excessive weight gain and severe hyperphagia with food
      compulsivity in early childhood, which often leads to the onset of obesity and metabolic
      complications. The pathogenesis of hyperphagia and progressive weight gain in PWS is far from
      being understood, and thus efficacious interventions are still under development. Emerging
      evidence indicates an important etiological contribution of dysbiotic gut microbiota in the
      hyperphagia, obesity and metabolic abnormalities associated with PWS, implicating a
      potentially effective target for appetite control and alleviation of obesity in PWS. This
      study aims to evaluate whether dietary fibers can improve hyperphagia and metabolic profile
      in children with PWS, and further will determine if these improvements correlate with
      dietary-fiber-induced changes of the gut microbiota. Twenty children with PWS (age 5-17
      years) will receive 3-week fiber or placebo treatment and 3-week alternate treatment with a
      4-week washout period in between. A validated PWS-specific hyperphagia questionnaire will be
      used to assess the severity of hyperphagia in participants. Fasting blood and fecal samples
      will be collected for the analyses of appetite-related hormones, metabolic biomarkers,
      bacterial composition and gut metabolites. This study should provide potential new approaches
      for effective non-pharmacologic treatment of excessive weight gain and hyperphagia associated
      with PWS to improve overall health and quality of life in affected patients.
    

Detailed description: 
      Background: Prader-Willi syndrome (PWS) is the most common syndromic cause of obesity.
      Individuals with PWS characteristically experience excessive weight gain and severe
      hyperphagia with food compulsivity in early childhood, which often leads to the development
      of obesity and metabolic complications. The pathogenesis of hyperphagia and progressive
      weight gain in PWS is far from being understood, and thus efficacious interventions are still
      being developed. Emerging evidence indicates an important etiological contribution of
      dysbiotic gut microbiota to the hyperphagia, obesity and metabolic abnormalities associated
      with PWS, implicating a potentially effective target for appetite control and alleviation of
      obesity in PWS. The therapeutic potential of manipulating gut microbiota through diet has
      been scarcely assessed in PWS; more comprehensive evaluations are greatly needed.

      Specific objectives: 1) to assess the effects of a 3-week dietary fiber intervention on gut
      microbiota, hyperphagia, and metabolic profile in children with PWS; 2) to determine whether
      changes in gut microbial composition and function correlate with changes in the degree of
      hyperphagia, metabolic hormones, insulin sensitivity, inflammatory markers, and metabolites
      implicated in cardiometabolic diseases.

      Methodological Approach: In a cross-sectional design, 20 children with PWS aged 5 to 17 years
      will be recruited from the Stollery Children's Hospital, Edmonton. Eligible participants will
      have normal values of free thyroxine and thyroid-stimulating hormone (either endogenous or
      with thyroxine replacement) as well as stable body weight and growth hormone dose. Children
      with other clinically significant disease (diabetes mellitus, chronic inflammatory bowel
      disease, chronic severe liver or kidney disease), or recent use of medications known to
      affect body weight and gut microbiota (investigational drugs, antibiotics, prebiotic and/or
      probiotic supplements) will be excluded. Participants will be randomly assigned to consume
      either 35 g supplemental fiber mixture/d (oligofructose, resistant maltodextrin, acacia gum,
      whole foods, and resistant starch type II) or an equicaloric dose of a 17.6-g maltodextrin
      placebo/d (GLOBE® Plus 10 DE Maltodextrin 100200; Ingredion) for 3 wk. This will be followed
      by a 4-wk washout period and an alternate treatment for another 3 wk. Fecal samples will be
      collected to analyze gut microbiota composition (using 16S ribosomal ribonucleic acid [rRNA]
      tag sequencing) and function (metabolites produced by microbiota: SCFAs and bile acids).
      Microbiota composition will be characterized at phylum to genus level, and sequences will be
      clustered to Operational Taxonomic Units to calculate alpha-diversity (by Shannon index).
      Fasting blood samples will be used to measure appetite-related hormones, and metabolic and
      inflammatory markers. A validated PWS-specific hyperphagia questionnaire will be used to
      assess participants' food-related behaviors. A 3-day dietary record including physical
      activity questions will be administered for the assessment of macro- and-micronutrient intake
      and diet quality as well as physical activity level of the participants. In addition,
      anthropometric data (body weight, height and waist circumference [WC]) will be obtained to
      track changes.

      Outcomes: 1) Primary outcome: Change in hyperphagia score; 2) Secondary outcomes: Changes in:
      a. Fecal microbial composition and function; b. Hormones (acylated ghrelin, PYY, GLP-1,
      adiponectin and leptin; c. Metabolic and inflammatory markers (glucose, insulin, lipids, AST,
      ALT, hs-CRP); d. Metabolomics profile (amino acids, branched chain keto acids,
      acylcarnitines, ceramides, TMAO, choline and betaine); and e. body weight, height and WC.

      Deliverables: 1) the feasibility of using a fiber intervention to reduce hyperphagia and
      improve metabolism and inflammation via beneficial changes in the microbiota in children with
      PWS; 2) the particular microbial composition and functional profiles associated with
      metabolic improvement and/or weight loss can aid in the future development of
      microbial-targeted prebiotic therapies. Results from this study will be used to guide the
      design of effective treatment strategies to reduce hyperphagia and improve metabolic health
      in children with PWS.
    

Intervention name(s): Fiber intervention; Placebo treatment
Intervention type(s): Other; Other
Intervention description(s): Each subject will supplement his/her normal dietary intake with 35 grams of dietary fiber daily for three consecutive weeks.; Each subject will supplement his/her normal dietary intake with an 18.53-g maltodextrin placebo daily for three consecutive weeks.
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Participants will receive 3-week fiber/placebo treatment and 3-week alternate fiber/placebo treatment with a 4-week washout period in between.
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Fiber; Gut microbiome; Hyperphagia; Prader-Willi Syndrome