Impact Of A Phe-Restricted Diet On Gut Health In Children With PKU
Impact Of A Phenylalanine-Restricted Diet On The Microbiota Composition And Metabolome Of Children With PKU
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.
調査の概要
状態
条件
詳細な説明
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.
The findings from this study may support the development of nutritional strategies and protein substitutes that more effectively promote gastrointestinal and metabolic health in individuals with PKU.
研究の種類
入学 (推定)
連絡先と場所
研究連絡先
- 名前：Anita MacDonald, PhD
- 電話番号：+44 121 333 9999
- メール：anita.macdonald@nhs.net
研究連絡先のバックアップ
- 名前：Catarina Rodrigues, MSc
- 電話番号：+44 121 472 1377
- メール：catarina.rodrigues1@nhs.net
研究場所
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Birmingham
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Birmingham、Birmingham、イギリス、B4 6NH
- 募集
- Birmingham Children's Hospital
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コンタクト：
- Anita MacDonald, PhD
- 電話番号：+44 121 333 9999
- メール：anita.macdonald@nhs.net
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-
参加基準
適格基準
就学可能な年齢
- 子
健康ボランティアの受け入れ
サンプリング方法
調査対象母集団
Children and adolescents aged 3-17 years with early-treated phenylketonuria receiving clinical care at Birmingham Children's Hospital are recruited into one of three cohorts according to their current treatment: a phenylalanine-restricted diet alone, sapropterin, or sepiapterin.
One healthy household control aged 3 years or older, without phenylketonuria or another inherited metabolic disorder, is recruited for each participant with phenylketonuria. All participants are enrolled according to predefined eligibility criteria.
説明
Inclusion Criteria:
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.
Exclusion Criteria:
- 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.
研究計画
研究はどのように設計されていますか？
デザインの詳細
コホートと介入
グループ/コホート |
介入・治療 |
|---|---|
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PKU - Diet Only
Children and adolescents aged 3-17 years with early-treated phenylketonuria who are managed exclusively with a phenylalanine-restricted diet and are not receiving sapropterin or sepiapterin.
Participants provide a faecal sample and undergo dietary, clinical, gastrointestinal symptom, and stool assessments.
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Participants are managed with a phenylalanine-restricted diet and prescribed protein substitutes as part of their usual clinical care.
They are not receiving sapropterin or sepiapterin.
Dietary treatment is not assigned or modified by this observational study.
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PKU - Sapropterin
Children and adolescents aged 3-17 years with early-treated phenylketonuria who have been receiving sapropterin for at least 3 months and have achieved at least a 100% increase in natural protein tolerance compared with before treatment.
Sapropterin treatment is not assigned as part of this observational study.
Participants provide a faecal sample and undergo dietary, clinical, gastrointestinal symptom, and stool assessments.
|
Participants receive sapropterin as part of their usual clinical care, alongside an individualised phenylalanine-restricted diet.
Sapropterin treatment and dosage are prescribed independently of this observational study and are not assigned or modified by the investigators.
他の名前：
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PKU - Sepiapterin
Children and adolescents aged 3-17 years with early-treated phenylketonuria who have been receiving sepiapterin for at least 3 months and have achieved at least a 100% increase in natural protein tolerance compared with before treatment.
Sepiapterin treatment is not assigned as part of this observational study.
Participants provide a faecal sample and undergo dietary, clinical, gastrointestinal symptom, and stool assessments.
|
Participants receive sepiapterin as part of their existing clinical management, alongside an individualised phenylalanine-restricted diet.
Sepiapterin treatment and dosage are determined independently of this observational study and are not assigned or modified by the investigators.
他の名前：
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Healthy Household Controls
Healthy household members without phenylketonuria who are recruited at a ratio of one control for each participant with phenylketonuria.
Controls provide a faecal sample and complete the relevant dietary, gastrointestinal symptom, and stool assessments.
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Faecal gut microbiota taxonomic composition assessed by shotgun metagenomic sequencing
時間枠：At enrolment (single faecal sample collection)
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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.
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At enrolment (single faecal sample collection)
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Faecal gut microbiota alpha diversity assessed by shotgun metagenomic sequencing
時間枠：At enrolment, based on a single faecal sample
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Within-sample microbial diversity is assessed from shotgun metagenomic sequencing data using alpha-diversity indices, including Shannon, Simpson, Chao1, ACE, and observed species.
Alpha-diversity measures are compared across the study cohorts.
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At enrolment, based on a single faecal sample
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Faecal gut microbiota beta diversity assessed by shotgun metagenomic sequencing
時間枠：At enrolment, based on a single faecal sample
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Differences in overall microbial community composition between participants are assessed using beta-diversity measures derived from shotgun metagenomic sequencing data, including Bray-Curtis dissimilarity.
Microbial community profiles are compared across the study cohorts.
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At enrolment, based on a single faecal sample
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Microbial functional potential assessed by shotgun metagenomic sequencing
時間枠：At enrolment, based on a single faecal sample
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Microbial genes and functional pathways are characterised from shotgun metagenomic sequencing data using functional annotation databases.
The relative abundance of microbial genes, enzymes, and metabolic pathways is compared across the study cohorts.
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At enrolment, based on a single faecal sample
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Gastrointestinal symptom burden assessed using the PedsQL Gastrointestinal Symptoms Module
時間枠：At enrolment, based on a single faecal sample
|
Gastrointestinal symptoms are assessed using the age-appropriate self-report or parent-proxy version of the PedsQL Gastrointestinal Symptoms Module.
Total and individual symptom-domain scores are calculated, with lower scores indicating a greater gastrointestinal symptom burden, and compared across the study cohorts.
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At enrolment, based on a single faecal sample
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Stool form assessed using the Bristol Stool Form Scale
時間枠：At enrolment, based on a single faecal sample
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Usual stool form is classified using the Bristol Stool Form Scale, ranging from type 1, representing separate hard lumps, to type 7, representing entirely liquid stool.
Stool-form distributions are compared across the study cohorts.
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At enrolment, based on a single faecal sample
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Dietary intake assessed using a 24-hour dietary recall
時間枠：At enrolment, based on a single faecal sample
|
Dietary intake is assessed using a 24-hour dietary recall.
Nutrient and food-group measures, including natural protein intake, protein substitute intake, dietary fibre intake, and consumption of special low-protein foods, are estimated and compared across the study cohorts.
|
At enrolment, based on a single faecal sample
|
協力者と研究者
捜査官
- 主任研究者：Anita MacDonald, PhD、Birmingham Children's Hospital
研究記録日
主要日程の研究
研究開始 (実際)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
- IRAS project ID: 353831
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
IPD プランの説明
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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