Impact Of A Phenylalanine-Restricted Diet On The Microbiota Composition And Metabolome Of Children With PKU
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 148
- 试验地点
- 1
- 主要终点
- Faecal gut microbiota taxonomic composition assessed by shotgun metagenomic sequencing
研究概览
简要总结
Phenylketonuria (PKU) is an inherited disorder of phenylalanine (Phe) metabolism. The mainstay of treatment is a Phe-restricted diet, which aims to maintain blood Phe concentrations within the recommended range and prevent neurological complications. Some individuals with PKU respond to pharmacological treatments, including sapropterin, a synthetic form of tetrahydrobiopterin (BH4), or sepiapterin. These treatments may increase Phe tolerance and allow a less restrictive diet.
Diet is an important determinant of gut microbiota composition and function. However, the effects of the Phe-restricted diet and pharmacologically enabled dietary relaxation on the gut microbiota in PKU remain poorly understood.
This observational study includes children and adolescents with PKU aged 3-17 years attending Birmingham Children's Hospital. Participants include those managed exclusively with a Phe-restricted diet, those receiving sapropterin, and those receiving sepiapterin. One healthy household control is recruited for each participant with PKU.
Faecal samples are collected for shotgun metagenomic sequencing and metabolite profiling. Dietary intake, gastrointestinal symptoms, stool characteristics, clinical information, and PKU treatment are also assessed.
The study investigates whether gut microbiota composition, microbial functional potential, and faecal metabolite profiles differ between participants managed with a Phe-restricted diet, those receiving pharmacological treatment, and healthy household controls. The findings may improve understanding of the relationships between PKU treatment, dietary restriction, gastrointestinal health, and the gut microbiome and may inform future nutritional strategies for individuals with PKU.
详细描述
This is a single-centre, cross-sectional observational study conducted at Birmingham Children's Hospital. The study investigates the association between phenylketonuria (PKU) treatment, degree of dietary restriction, gastrointestinal health, and the composition and functional potential of the gut microbiota.
Children and adolescents aged 3-17 years with early-treated PKU are recruited into one of three cohorts according to their existing clinical management: treatment with a phenylalanine-restricted diet alone (anticipated n=30), treatment with sapropterin alongside an individualised phenylalanine-restricted diet (anticipated n=30), or treatment with sepiapterin alongside an individualised phenylalanine-restricted diet (anticipated n=14). Participants receiving sapropterin or sepiapterin have been receiving treatment for at least three months and have achieved at least a 100% increase in natural protein tolerance compared with their pre-treatment prescription. Treatment allocation, medication dosage, and dietary management are determined as part of routine clinical care and are not assigned or modified by the study.
One healthy household control is recruited for each participant with PKU. Household controls are aged 3 years or older and do not have PKU or another inherited metabolic disorder. Recruiting controls from the same household aims to reduce the influence of shared environmental factors, including living conditions and food availability, when comparing gut microbiota profiles. The anticipated total enrolment is 148 participants, comprising 74 participants with PKU and 74 household controls.
Each participant provides a single faecal sample. Samples are stored at -80°C and analysed using shotgun metagenomic sequencing to characterise microbial taxonomic composition, within-sample diversity, between-sample community differences, and microbial functional potential. Taxonomic profiles are assessed at multiple levels, including phylum, genus, and species. Functional annotation is used to characterise microbial genes, enzymes, and metabolic pathways.
Dietary intake is assessed using a 24-hour dietary recall, including natural protein intake, protein substitute intake, dietary fibre intake, and consumption of special low-protein foods. Gastrointestinal symptoms are assessed using the age-appropriate self-report or parent-proxy version of the PedsQL Gastrointestinal Symptoms Module, and stool form is assessed using the Bristol Stool Form Scale. Relevant demographic and clinical information, including age, sex, anthropometric measurements, PKU treatment, and metabolic control, is also collected.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Cross Sectional
入排标准
- 年龄范围
- 3 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Participants with PKU:
- •Aged 3-17 years.
- •Confirmed diagnosis of phenylketonuria following newborn screening.
- •Receiving ongoing clinical management for PKU.
- •For the diet-only cohort: managed with standard phenylalanine-restricted dietary treatment and not receiving sapropterin or sepiapterin.
- •For the sapropterin cohort: receiving sapropterin for at least three consecutive months and having achieved at least a 100% increase in natural protein tolerance compared with the pre-treatment prescription.
- •For the sepiapterin cohort: receiving sepiapterin for at least three consecutive months and having achieved at least a 100% increase in natural protein tolerance compared with the pre-treatment prescription.
- •Healthy household controls:
- •Aged 3 years or older.
- •Living in the same household as a participating child or adolescent with PKU.
- •No known diagnosis of PKU or another inherited metabolic disorder.
排除标准
- •Congenital malformations.
- •Chronic gastrointestinal disease.
- •Endocrine, liver, or kidney disease.
- •Other chronic medical conditions likely to affect gut microbiota composition.
- •Following a therapeutic diet for a medical condition other than PKU within the six months before stool sample collection.
结局指标
主要结局
Faecal gut microbiota taxonomic composition assessed by shotgun metagenomic sequencing
时间窗: At enrolment (single faecal sample collection)
Taxonomic profiles, expressed as the relative abundance of microbial taxa at phylum, genus, and species levels, are derived from shotgun metagenomic sequencing of one faecal sample per participant. Profiles are compared among participants with PKU managed by a phenylalanine-restricted diet alone, sapropterin, or sepiapterin and healthy household controls.
次要结局
- Faecal gut microbiota alpha diversity assessed by shotgun metagenomic sequencing(At enrolment, based on a single faecal sample)
- Faecal gut microbiota beta diversity assessed by shotgun metagenomic sequencing(At enrolment, based on a single faecal sample)
- Microbial functional potential assessed by shotgun metagenomic sequencing(At enrolment, based on a single faecal sample)
- Gastrointestinal symptom burden assessed using the PedsQL Gastrointestinal Symptoms Module(At enrolment, based on a single faecal sample)
- Stool form assessed using the Bristol Stool Form Scale(At enrolment, based on a single faecal sample)
- Dietary intake assessed using a 24-hour dietary recall(At enrolment, based on a single faecal sample)