Nutrition and gut health

Severe acute malnutrition is one of the major killers of children in many countries, creating a vicious circle of infection and illness. In Africa, children who are hospitalised with severe malnutrition have poor outcomes including death, readmission and relapse.

Dairy and nut-based formula foods, mostly made in Europe, are a central part of the treatment yet mortality remains stubbornly high despite advances in nutritional and medical support. 

One possible issue is that milk-based formulas do little to improve gut function or stimulate healthy, diverse microbial communities. Children with severe malnutrition have significantly less microbial diversity compared to their well-nourished peers. To enhance gut function, it is crucial to develop feeding strategies that foster the growth of beneficial microbes.

Professor Kathryn Maitland, Director of the ICCARE Centre, said:

‘’We have conducted a series of studies using a new feed containing legumes - peas/beans - because they provide carbohydrates that feed the 'healthy' bugs, producing chemical molecules which help restore healthy microbial communities and suppress the gut function.

‘’We have also finalised the development of a new feed with a local industry partner in Uganda, RECO Limited. The MIMBLE consortium, together with members of the HUNGER consortium, aims to test this feed in a clinical trial in Kenya, Ghana, and Zambia to see if it improves outcomes in children hospitalised with severe malnutrition.’’  

Most relevant publications: 

• Walsh K, Kiosa A, Olupot-Olupot P, et al. Legume-supplemented feed for children hospitalised with severe malnutrition: a phase II trial. British Journal of Nutrition. Published online 2024:1-10.
• Walsh K, Delamare de la Villenaise de Chenevarin G, McGurk J et al. Development of a legume-enriched feed for treatment of severe acute malnutrition [version 2; peer review: 2 approved]. Wellcome Open Res 2023, 6:206.
• Calder N, Walsh K, Olupot-Olupot P, Ssenyondo T, Muhindo R, Mpoya A, Brignardello J, Wang X, McKay E, Morrison D, Holmes E, Frost G, Maitland K. Modifying gut integrity and microbiome in children with severe acute malnutrition using legume-based feeds (MIMBLE): A pilot trial. Cell Rep Med. 2021 May 18;2(5):100280.

The Partnership for Child Development (PCD), formed in 1992, works to improve the education, health and nutrition of school-age children in low- and middle- income countries. Working with governments, communities and development agencies, PCD helps to deliver effectively and sustainable demand-driven school health and nutrition (SHN) programmes, which benefit millions of children around the world.

PCD supports the development of national school health and nutrition programmes by building the evidence base through a focus of on quality science in development. By developing a wide range of partnerships, PCD provides technical assistance to governments and their development partners that is founded on academic excellence, technical expertise and high-level networks. PCD adopts a cross-sector approach to developing the most effective, scaled and sustainable programmatic solutions to a range of school health and nutrition interventions including, school feeding, deworming, inclusive education, WASH, HIV/AIDS prevention, nutrition, etc.  As well as the provision of technical assistant PCD also works to disseminate the latest school health research and best practice through its website and PCD is a founding member of the London Centre for Neglected Tropical Disease Research.

In the area of nutrition, we have undertaken a programme of prospective studies of severe malnutrition in Kilifi, Kenya and Mbale, Uganda. The scope of work includes comprehensive descriptions of the clinical spectrum and risk factors for poor outcome, pharmacokinetic studies and dose optimisation of the main antibiotics (gentamicin and ciprofloxacin) used for the treatment of concomitant gram-negative bacterial infections. Dr Bernadetter Brent through an MD and Dr Nchafatso Obonyo, through an ISSF fellowship,  have undertaken comprehensive studies of myocardial function in children with severe malnutrition in Kenya and Uganda and examined the response to fluid therapy and re-feeding. In addition, Professor Kathryn Maitland has multiple active collaborations with specialists in nutritional and digestive health at Imperial College (SMIP, MIMBLE and TRACT).

Severe Malnutrition Intestinal Permeability (SMIP) and Modifying Intestinal Integrity And Microbiome in Severe Malnutrition With Legume-Based Feeds [MIMBLE Study]: A Pilot Study

The SMIP study is a collaboration with Professors Holmes and Frost investigating the role of gut-barrier dysfunction and intestinal microbiome in the pathogenesis with severe malnutrition, and whether these contribute to the high rate of treatment failure and adverse clinical outcome.  This has lead to the development of protocol  through and ISSF fellowship to Dr Nuala Calder to examine whether the integrity of the gut epithelial barrier can be supported by short chain fatty acids derived from microbiota fermentation of fermentable carbohydrate using locally-sourced legumes (cowpeas).  

TRansfusion and TReatment of severe Anaemia in African Children: a randomised controlled Trial TRACT (ISRCTN84086586)
In a sub-study of a 4000-child treatment trial of severe anaemia, we will assess the impact of anaemia and undernutrition on gut integrity, appetite regulation and susceptibility to bacterial infection. Undertaking a PhD linked to the TRACT trial  Dr Kevin Walsh, co-supervised by  Professors Holmes, Frost and Maitland combines sequential dietary intake assessment using the multi-pass method at each follow-up visit to estimate macro- and micro- nutrient intake and biomarkers of gut barrier function, gut microbiome, immunity and hormonal appetite control. 

Most relevant publications: 

• Berkley J, Mwangi I, Griffiths K, Ahmed I, Mithwani S, English M, Newton C, Maitland K: Assessment of severe malnutrition among hospitalised children in rural Kenya: comparison of weight for height and mid upper arm circumference. JAMA : the journal of the American Medical Association 2005, 294:591-597.
• Maitland K, Berkley JA, Shebbe M, Peshu N, English M, Newton CR: Children with severe malnutrition: can those at highest risk of death be identified with the WHO protocol? PLoS medicine 2006, 3:e500.
• Seaton C, Ignas J, Muchohi S, Kokwaro G, Maitland K, Thomson AH: Population pharmacokinetics of a single daily intramuscular dose of gentamicin in children with severe malnutrition. The Journal of antimicrobial chemotherapy 2007, 59:681-689.
• Akech SO, Karisa J, Nakamya P, Boga M, Maitland K: Phase II trial of isotonic fluid resuscitation in Kenyan children with severe malnutrition and hypovolemia. BMC pediatrics 2010, 10:71.
• Thuo N, Ungphakorn W, Karisa J, Muchohi S, Muturi A, Kokwaro G, Thomson AH, Maitland K: Dosing regimens of oral ciprofloxacin for children with severe malnutrition: a population pharmacokinetic study with Monte Carlo simulation. The Journal of antimicrobial chemotherapy 2011, 66:2336-2345.

The TRansfusion and TReatment of severe Anaemia in African Children: a randomised controlled Trial

TRACT ISRCTN84086586 is a randomised controlled trial involving 3954 children aged 2 months to 12 years with severe anaemia (SA) (defined as a haemoglobin (Hb) <6g/dl). Children will be enroled at admission to hospital over 2 years from 2 countries (Malawi, Uganda) and followed for 6 months to make sure longer-term outcomes are captured. The trial has been designed to address the poor outcomes following SA in children in sub-Saharan Africa, which is associated with high rates of in-hospital mortality (9-10%), 6-month case fatality (12%) and relapse or re-hospitalisation (6%) indicating that the current recommendations and/or management strategies are not working in practice.

TRACT trial is designed to answer 3 simple questions:

1. Which children should receive a transfusion? Current WHO guidelines, designed to avoid overuse of blood, recommend transfusions only in children with a Hb <4g/dl (or <6g/dl if accompanied by complications). These specific recommendations have not been evaluated in clinical trials and thus, practice varies across African countries. We don’t know if giving blood to all children with Hb <6g/dl would help.
2. How much blood should be given in a transfusion? On current recommendations, a quarter of children receiving transfusions remain severely anaemic and up to one-third get two or more blood transfusions during a single hospital admission. We don’t know if giving larger initial volumes of blood would help – this could reducing risks from additional transfusion (which include bad blood matching or blood infections), and the amount of time health personnel spend getting blood ready.
3. Would long-term support for children after hospital admission help? The major factors related to poor longer term outcome are multiple vitamin and mineral deficiencies and blood infections caused by bacteria - we don’t know if giving vitamin/mineral supplements or antibiotics to prevent infections would improve outcomes. 

The TRACT trial will simultaneously look at three ways management of SA might be improved – with the aim of reducing early and late deaths, and anaemia recurrence or readmission to hospital. The trial has 3 simultaneous randomizations that compare:

• current conservative WHO recommendations for transfusion against a more liberal approach, in terms of who gets blood and how much blood they get
• additional multi-vitamin multi-mineral supplements compared with the standard folate/iron recommended by WHO and
• an antibiotic, cotrimoxazole, to prevent new bacterial infections for 3 months compared with no antibiotic.

The primary outcome is cumulative mortality to 4 weeks (transfusion comparisons) and to 6 months for the nutritional support/antibiotic prophylaxis comparison. Secondary outcomes include mortality at 48 hours, 4 weeks, 3 months and 6 months (cumulative) (where not the primary outcome); development of new profound anaemia (Hb<4g/dl) during acute admission or development of SA (Hb<6g/dl) post discharge; readmission to hospital; proportion achieving correction of anaemia (Hb>9g/dl); adverse events relating to transfusion. 

The design has a pragmatic design with broad, largely clinical inclusion criteria. So when the results are published they will form a cheap and widely available ‘bundle’ of effective interventions, directed at both the immediate and downstream consequences of severe anaemia and which is likely to lead to substantial reductions in mortality in African children hospitalised with SA every year if widely implemented. The trial started enrolment in September 2014 and is on target for completion in December 2016. 

The trial featured on BBC Health News.  

TRACT Key References

• Mpoya A, Kiguli S, Olupot-Olupot P, Opoka RO, Engoru C, Mallewa M, Chimalizeni Y, Kennedy N, Kyeyune D, Wabwire B, M'Baya B, Bates I, Urban B, von Hensbroek MB, Heyderman R, Thomason MJ, Uyoga S, Williams TN, Gibb DM, George EC, Walker AS, Maitland K: Transfusion and Treatment of severe anaemia in African children (TRACT): a study protocol for a randomised controlled trial. Trials 2015, 16:593, 10.1186/s13063-015-1112-4, PMC4696199
• Kiguli S, Maitland K, George EC, Olupot-Olupot P, Opoka RO, Engoru C, Akech SO, Nyeko R, Mtove G, Reyburn H, Levin M, Babiker AG, Gibb DM, Crawley J: Anaemia and blood transfusion in African children presenting to hospital with severe febrile illness. BMC Med 2015, 13:21, 10.1186/s12916-014-0246-7, 4313469
• Olupot-Olupot P, Engoru C, Thompson J, Nteziyaremye J, Chebet M, Ssenyondo T, Dambisya CM, Okuuny V, Wokulira R, Amorut D, Ongodia P, Mpoya A, Williams TN, Uyoga S, Macharia A, Gibb DM, Walker AS, Maitland K: Phase II trial of standard versus increased transfusion volume in Ugandan children with acute severe anemia. BMC Med 2014, 12:67, 10.1186/1741-7015-12-67, 4101869
• Ala F, Allain JP, Bates I, Boukef K, Boulton F, Brandful J, Dax EM, El Ekiaby M, Farrugia A, Gorlin J, Hassall O, Lee H, Loua A, Maitland K, Mbanya D, Mukhtar Z, Murphy W, Opare-Sem O, Owusu-Ofori S, Reesink H, Roberts D, Torres O, Totoe G, Ullum H, Wendel S: External financial aid to blood transfusion services in sub-Saharan Africa: a need for reflection. PLoS medicine 2012, 9:e1001309, 10.1371/journal.pmed.1001309, 3439367
• Hassall O, Maitland K, Pole L, Mwarumba S, Denje D, Wambua K, Lowe B, Parry C, Mandaliya K, Bates I: Bacterial contamination of paediatric whole blood transfusions in a Kenyan hospital. Transfusion 2009, 49:2594-2598, 10.1111/j.1537-2995.2009.02344.x, 2939982
• Akech SO, Hassall O, Pamba A, Idro R, Williams TN, Newton CR, Maitland K: Survival and haematological recovery of children with severe malaria transfused in accordance to WHO guidelines in Kilifi, Kenya. Malaria journal 2008, 7:256, 10.1186/1475-2875-7-256, 2615447