The Role of Nutrients, Gut Dysfunction and the Gut Microbiome in Determining Health Outcomes in Undernutrition

Undernutrition affects 462 million people world-wide with 165 million children having stunted height and 52 million children are wasted (very thin). Both acute and chronic malnutrition ('stunting') are associated with significant health and economic burdens in low and middle income countries (LMICs). In acute malnutrition, little progress has been made in the management of severe acute malnutrition (SAM) in children, where mortality (death) remains high. The factors underpinning SAM are complex and multifactorial, ultimately resulting in disruption of the normal gut bugs (or microbiota), reduced ammounts of vital nutrients being available, the barrier (mucosa) of the gut breaking down causing altered function such as impaired mucosal immunity and leakiness of the bugs from the gut (gram negative bacteria) into the body causing septicaemia and high risk of mortality. On top of this, poverty and the lack of foods causing undernutrition there is also poor quality water and increased environmental pathogen burden (worms and poor sanitation) all leading to an increase the gut not being able to absorp protein and vital nutrients. These form a vicious cycle and contribute to the poor outcomes in undernourished children. .
Rather than just increase the amount of proten and energy giving in refeeding programmes, which have failed to tackle the underlying problems of the poor gut barrier function and pathogenic gut bacterial (microbiome) we plan to take an alternative approach. Our overarching strategy is to develop a programme of work to understand the relationships between undernutrition, pathogen burden, gut barrier function, the gut microbiome, and health outcomes, and to develop nutritional strategies that are context-specific to overcome nutritional challenges at key stages of child development in LMICs. The nutritional feed we propose will focus upon legume (pulses) based proteins and carbohydrates since the latter are metabolised in the gut to produce fatty acids which can help repair gut barrier function and alter the micriobiome into a more 'healthy' one, with less loss of vital nutrients. Ultimately improving nutrition statue and reducing the risk of septicaemia.
Research Questions: We have six priority research questions which underpin our long-term research plans. These are:
1. To understand the role of gut barrier dysfunction in both acute and chronic malnutrition?
2. Do the use of legumes feeds help repair the gut barrier and promote a healthy gut microbiome and lead to improved health outcomes in malnutrition?
3. What are the protein requirements of malnourished children under high pathogen burden?
4. In order to help farmers in low middle income countries (LIMCs) can locally-produced legume crops help meet the protein and vital nutrients at key stages of life?
5. What intervention studies are needed to generate evidence of the benefit of legume pulses in the management of undernutrition in LMIC populations?
6. How can legume consumption be increased sustainably across LMIC populations?
To begin to achieve this we will bring the research community together with the long term aim of developing, revisit and refine current recommendations of macronutrient feeding regimens to reduce morbidity and mortality associated with gut barrier dysfunction in LMICs.

Undernutrition affects 462 million people world-wide with 165 million children being stunted and 52 million wasted. The factors underpinning SAM are complex and multifactorial, ultimately resulting in disruption of the normal gut microbiota, reduced assimilation of vital nutrients, altered gut barrier function, impaired mucosal immunity and increased risk of gram negative bacteraemia which form a vicious cycle. Environmental enteric disease (EED) shares common features of gut dysfunction with SAM including villous atrophy, disruption of the normal gut microbiota, disruption of the gut barrier function, increased local and systemic inflammation and bacterial translocation which adversely affect growth and cognitive development.
This programme will bring together leading experts from across the scientific community to investigate how legumes (pulses) can offer a joint solution to the supply of quality protein and fermentable carbohydrate to support a competent diverse gut microbiome and optimum gut barrier function needed in SAM and EED.
The focus of this application is to facilitate the development of a substantive multi-disciplinary research programme to enhance the management of malnutrition in LMICs. To achieve this, we will begin with a kick-off meeting at beginning of the project to set a research development agenda in four key areas:
1. Improved assessment of gut barrier dysfunction
2. Fermentable carbohydrate as a solution to gut barrier dysfunction and improving amino acid supply as a method of optimising small intestinal function.
3. Determine the protein requirements of malnourished children under high pathogen burden
4. Legumes as a solution to meeting protein and micronutrient requirements and improved gut barrier function
5. Sustainable intake of legumes
Our long-term plan is to develop and refine current recommendations of macronutrient feeding regimens to reduce morbidity and mortality associated with gut barrier dysfunction in LMIC.

This project will make a positive health benefit to the citizens living in LMIC. 165 million children still suffer the effect of undernutrition. Many million more are effected by environmental enteric disease. The relationship between nutrition, the gut microbiota and gut function remains a neglected area for strategic research in global health. This project will lay the foundations for a comprehensive programme of work in this area. Should we be able to demonstrate methods of supporting gut barrier function and enhancing protein uptake using commonly grown plant resources which are consumed in LMIC this will impact on the health of many millions of children. This will also have relevant to high income countries where gut barrier function is a problem in sick children and the elderly. It may be possible to take some on the learning derived from this project to inform management of vulnerable groups where gut integrity may be a problem.
Farmers in LMIC: The farmers in LMIC will be able to grow a crop that has that is of nutritional advantage to their local community. Also legumes have a good environmental impact. The aim of the plant breading side of the project is to ensure the crop can be grown by families and famers.
Nutrition Community: The nutrition community has quite rightly been focus on ensuring energy and protein requirements are met in children who live in at risk area. Should the project prove positive this will give an important nutritional target to support the recovery of vulnerable children.
Medical Community: At the present time there is no effective treatment or prevention strategy for gut derived sepsis. Should this project prove positive it could lead to new management plan for serve acute malnutrition
Public Health Community: Environmental enteric disease is common in area where there is poor water quality and parasite burgeon from worms is high. A simple message that a commonly consumed food, legumes may help gastrointestinal recovery from environmental enteric disease could have far reaching effects
Plant breading community: This project will lay the foundations for targets that could enhance the impact legumes have on gut health. This could offer legume plant breeders the opportunity to develop legumes with a high fermentable carbohydrate content, high biological value protein content and a low anti-nutrient profile.
Feed manufactures: The focus on feed manufactures has been on using cow's milk as the basis of nutritional milks and ground nuts as a high energy supplement (in community programmes). This project will offer a potential new direction in developing legume based feeds to support undernourished children