Application of Stable Isotope Techniques in Environmental Enteric Dysfunction Assessment and Understanding its Impact on Child Growth

Closed for proposals

Project Type

Coordinated Research Project

Project Code

E41016

CRP

2136

Approved Date

13 February 2017

Status

Closed

Start Date

12 June 2017

Expected End Date

31 December 2022

Completed Date

23 March 2023

Participating Countries

Australia
Bangladesh
India
Jamaica
Kenya
Peru
United Kingdom of Great Britain and Northern Ireland
United States of America
Zambia

Description

Retarded linear growth, widely referred to as stunting, is rampant in low and middle income countries, affecting a total of 161 million children under the age of five years; it develops in the first 1000 days of life, and becomes irreversible if no appropriate interventions are in place. Environmental Enteric Dysfunction (EED) is the presence of diffuse, upper small bowel villous atrophy accompanied by the presence of morphologic evidence of barrier disruption and inflammation. EED affects presumably 50-95% of all children under the age of 5 years in resource poor settings. Retarded growth, altered gut microbiota, and decreased vaccine responsiveness are considered the most important consequences of EED and are attributable to:  altered intestinal structure and function, defects in nutrient absorption, reduced growth hormone activity, altered host immunity and change in microbiota composition and diversity. Despite the significance of EED to infant and child nutrition and health, biomarkers and simple diagnostic techniques for the definition and classification of EED are lacking. This CRP aims to validate and apply a novel, non-invasive stable isotope technique (13C Sucrose Breath Test) to foster a better understanding of pathways underpinning EED and child growth. The key results of the CRP will be: 1) non-invasive 13C Sucrose Breath Test to diagnose EED and assess its effects on health; 2) improved technical capacity to diagnose and assess health of EED populations; 3) new data on the pathways underpinning the relationship between EED and child growth including dietary, mucosal integrity/permeability and nutrient and energy partitioning. The ultimate outcome will be a better understanding of the relationship between EED and child growth which will in turn contribute to the development of diagnostic tools for EED to facilitate its prevention, treatment and management to ensure good health.

Objectives

To validate and apply a novel, non-invasive stable isotope technique (13C Sucrose Breath Test) to foster a better understanding of pathways underpinning EED and child growth.

Impact

The main strength of the CRP was the unified and harmonised protocol used across countries. This led to comparable results with greater global public health impact than might have been achieved from smaller country-specific studies run independently of one another. This CRP has inspired new TC Projects and new CRPs in addition to elevating IAEA visibility via a joint webinar with the European Association for Gastroenterology Endoscopy and Nutrition (EAGEN) and 7 publications in peer reviewed journals. More publications are at various stages of preparation. The main paper with results on assessment of EED in children was published in the American Journal of Clinical Nutrition, the most reputable and highly impactful journal in the nutrition field. The 13C-SBT was also published in the NTR 2024, further highlighting IAEA's work among its MS.

Relevance

Retarded linear growth, widely referred to as stunting, remains rampant in low- and middle-income countries, affecting millions of children under the age of five years; it develops in the first 1000 days of life, and becomes irreversible if no appropriate interventions are in place. Environmental Enteric Dysfunction (EED) is the presence of diffuse, upper small bowel villous atrophy accompanied by the presence of morphologic evidence of barrier disruption and inflammation. EED affects presumably 50-95% of all children under the age of 5 years in resource poor settings. Retarded growth, altered gut microbiota, and decreased vaccine responsiveness are considered the most important consequences of EED and are attributable to: altered intestinal structure and function, defects in nutrient absorption, reduced growth hormone activity, altered host immunity and change in microbiota composition and diversity. Despite the significance of EED to infant and child nutrition and health, biomarkers and simple diagnostic techniques for the definition and classification of EED are lacking. This CRP has aided a better understanding of the relationship between EED and child growth.

A publication in the American Journal of Clinical Nutrition, the most reputable and high impact journal in the nutrition field, presented results from the main study in Bangladesh, Peru and India to test the applicability of a novel 13-carbon breath test (13C-SBT) to diagnose and classify EED. Increased leakiness and permeability, shortened intestinal villa, inflammation and bacterial translocation are the hallmarks of EED that can be measured using various techniques. In the 13C-SBT, an oral dose of a 13C-labeled sucrose tracer was digested, absorbed, and metabolized, appearing on the breath as 13CO2. Cumulative recovery of 13CO2 by a given time point was the standard summary measure of the 13C-SBT test. In the CRP, 13C-SBT was administered in children aged 12-15 months and was compared to endoscopy that measures intestinal villa height and to a dual sugar test that indicates permeability. Results showed that the 13C-SBT relates to neither intestinal structure nor permeability. Rather, 13C-SBT is applicable in understanding the breakdown of sucrose into fructose and glucose by the sucrase-isomaltose enzyme in the intestinal brush border; this represents nutrient absorption, one of EED domains. The test could potentially also be applied to explore sucrase activity in other related conditions that affect nutrient digestion such as severe acute malnutrition that affect pancreatic or liver function.

CRP Publications

Type

Web article

Year

2017

Publication URL

https://www.iaea.org/newscenter/news/stable-isotope-techniques-used-to-study-lin…

Description

Stable isotope techniques used to study link between gut health and child growth.

Country/Organization

IAEA

Type

Peer reviewed mechanistic modelling paper

Year

2023

Publication URL

https://road.iaea.org/livelink/cs.exe?func=ll&objId=110007189&objAction=Open&nex…

Description

Brouwer et al 2023. Mechanistic inference of the metabolic rates underlying 13Cbreath test curves. J Pharmacokinet Pharmacodyn; 50(3): 203–214.

Country/Organization

Australia, UK, USA

Type

Peer reviewed mechanistic modelling paper

Year

2024

Publication URL

https://road.iaea.org/livelink/cs.exe?func=ll&objId=110085762&objAction=Open&nex…

Description

Brouwer et al 2024. A Model-Based 13C-Sucrose Breath Test Diagnostic for Gut Function Disorders Characterized by a Loss of Sucrase-Isomaltase Enzymatic Activity. J Nutr; 154: 815-825

Country/Organization

UK, USA

Type

Peer reviewed publication on 13C-SBT optimization

Year

2022

Publication URL

https://road.iaea.org/livelink/cs.exe?func=ll&objId=110055286&objAction=Open&nex…

Description

Schillinger et al 2022. 13C-sucrose breath test for the non-invasive assessment of environmental enteropathy in Zambian adults. Front Med (Lausanne);9:904339

Country/Organization

UK, USA, Zambia

Type

Peer reviewed publication of main study

Year

2024

Publication URL

https://road.iaea.org/livelink/cs.exe?func=ll&objId=110142168&objAction=Open&nex…

Description

Shivakumar et al. A cross-sectional study of associations between the 13C-sucrose breath test, the lactulose rhamnose assay, and growth in children at high risk of environmental enteropathy. Am J Clin Nutr. 2024; https://doi.org/10.1016/j.ajcnut.2024.10.001

Country/Organization

ALL CRP sites

Type

Peer reviewed protocol paper

Year

2020

Publication URL

http://road.iaea.org/livelink/llisapi.dll/fetch/2000/357463/358058/358724/379839…

Description

Lee G et al 2020. Optimisation, validation and field applicability of a 13C-sucrose breath test to assess intestinal function in environmental enteropathy among children in resource poor settings: study protocol for a prospective study in Bangladesh, India, Kenya, Jamaica, Peru and Zambia. BMJ Open. 10:e035841. doi:10.1136/bmjopen-2019-035841

Country/Organization

ALL CRP Countries

Type

Peer reviewed mechanistic modelling paper

Year

2024

Publication URL

https://road.iaea.org/livelink/cs.exe?func=ll&objId=109991336&objAction=Open&nex…

Description

Van Wyk et al 2024. Performance of empirical and model-based classifiers for detecting sucrase-isomaltase inhibition using the 13C-sucrose breath test. J Breath Res;18(4):041003.

Country/Organization

UK, USA

Type

Peer reviewed protocol paper

Year

2020

Publication URL

http://road.iaea.org/livelink/llisapi.dll/fetch/2000/357463/358058/358724/379839…

Description

Lee G et al 2020. Optimisation, validation and field applicability of a 13C-sucrose breath test to assess intestinal function in environmental enteropathy among children in resource poor settings: study protocol for a prospective study in Bangladesh, India, Kenya, Jamaica, Peru and Zambia. BMJ Open. 10:e035841. doi:10.1136/bmjopen-2019-035841

Country/Organization

ALL CRP Countries

Type

Nuclear Technology Review

Year

2024

Publication URL

https://www.iaea.org/sites/default/files/gc/gc68-inf-4.pdf

Description

Non-invasive Assessment of Gut Digestive Function: An Optimized Carbon-13 Sucrose Breath Test

Country/Organization

IAEA

Type

Peer reviewed publication on challenges related to 13C-SBT

Year

2024

Publication URL

https://road.iaea.org/livelink/cs.exe?func=ll&objId=110085838&objAction=Open&nex…

Description

Jaika et al. 2024. Challenges associated with a stable isotope based sucrose breath test for environmental enteric dysfunction assessment in a rural Kenyan setting in the context of covid-19 pandemic. East African Medical Journal Vol. 101 No. 2: 6751-6760

Country/Organization

Kenya

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