Targeting Hyperphagia in Prader–Willi Syndrome: The Therapeutic Potential of Dietary Fibre and Gut Microbiota Modulation
Creators: Tan, Qiming
Publisher: name: University of Alberta Library
Year: 2024

<p>Prader–Willi syndrome (PWS), a rare neurodevelopmental disorder affecting roughly 1 in 10,000 to 30,000 individuals, is characterized by hyperphagia, an insatiable hunger emerging in early to mid-childhood. This relentless drive to eat significantly impacts all aspects of life for those with PWS and their families, limiting independence and creating substantial caregiver burden. While no cure exists, treatments to manage hyperphagia are actively being developed.<br>
The first goal of this research was to comprehensively review the current and emerging therapies for PWS, providing vital insights for clinicians and researchers. While dietary management and regular physical activity remain fundamental in managing PWS, their implementation is exceptionally challenging due to the presence of hyperphagia. Recombinant human growth hormone, the only approved treatment for PWS that is authorized in numerous countries, offers benefits beyond normalizing growth, including improved body composition, energy expenditure and metabolism. In extreme cases, bariatric surgery could be considered, although its use in PWS remains controversial. The landscape of PWS treatment is evolving, with several promising pharmacological and device-based interventions currently under investigation. This includes medications, including bitter taste receptor agonist, setmelanotide, carbetocin, and diazoxide choline-controlled release, which target appetite suppression and satiety signaling. Additionally, devices such as transcranial direct current stimulation and transcranial magnetic stimulation aim to modulate brain circuits involved in hunger regulation. These emerging therapies hold the promise to fundamentally transform treatment for PWS, pending further research and validation.<br>
Recent research suggests the gut microbiome may play a role in PWS, offering a novel avenue for exploring potential therapeutic targets. The second goal of this research was to characterize the gut microbiota profile and investigate its associations with hyperphagia in children with PWS. In a cross-sectional study, fecal samples were collected from 25 children with PWS and 25 controls matched for age, sex, and body mass index z-score. Overall bacterial communities were similar between the PWS and control groups. However, significant differences were identified in specific bacterial and fungal species. These differences were largely independent of dietary intake or PWS genotype. Most notably, hyperphagia scores correlated with increased fungal diversity and an altered abundance of certain taxa, including Staphylococcus, Clostridium, SMB53, and Candida. <br>
Building on the link between hyperphagia and gut microbiota changes, we investigated the potential of actively modifying the gut microbiota with dietary fibres in the management of hyperphagia in individuals with PWS. The fibre study assessed how various dietary fibres (including purified and whole food sources) impact hyperphagia, metabolic health outcomes, and gut microbiota in PWS. It also explored links between gut bacteria changes and health outcomes. In a crossover design, participants received high-dose fibre (35 g/day) or control for 3 weeks, followed by a washout period and treatment switch. Fourteen participants reported high tolerance to the fibre intervention, which did not significantly alter hyperphagia or key metabolic markers but led to shifts in gut microbiota and serum metabolome. Specifically, differences in β-diversity, as assessed by Bray-Curtis dissimilarity, were detected between fibre and control at week 3 (p=0.01) but not at baseline (p=0.99). The fibre intervention also significantly reduced bacterial α-diversity compared to both baseline and the control intervention (Chao1 index: p=0.01 and p=0.025, respectively). Notably, 23 amplicon sequence variants were identified as differing post-fibre compared to baseline, including significant increases in Bifidobacterium longum, Faecalibacterium prausnitzii, and Lachnospiraceae. Further, fecal concentrations of total and individual branched-chain fatty acids (isobutyrate and isovalerate) were significantly decreased, while serum C4-OH acylcarnitine concentration increased after the fibre intervention compared to both the control intervention and baseline (all p&lt;0.05). <br>
A major finding of this research was the altered gut microbiota composition in individuals with PWS, and the potential of dietary fibre to modulate both its composition and metabolic output. Further research is warranted, particularly longitudinal studies examining changes in the microbiota alongside hyperphagia severity, and integrated analyses that consider multiple biological factors, to better understand the potential role of the gut microbiota in PWS. More rigorously designed randomized controlled trials with longer duration are needed to assess the efficacy of specific fibre types or combinations in managing hyperphagia, modulating the gut microbiota, and improving health outcomes in PWS.</p>