Modifying Intestinal Integrity and MicroBiome in Severe Malnutrition with Legume-Based Feeds (MIMBLE 2.0): protocol for a phase II refined feed and intervention trial

Abstract

Background: Changes in intestinal mucosal integrity and gut microbial balance occur in severe acute malnutrition (SAM), resulting in treatment failure and adverse clinical outcomes (gram-negative sepsis, diarrhoea and high case-fatality). Transient lactose intolerance, due to loss of intestinal brush border lactase, also complicates SAM, thus milk based feeds may not be optimal for nutritional rehabilitation. Since the gut epithelial barrier can be supported by short chain fatty acids, derived from microbiota fermentation by particular fermentable carbohydrates, we postulated that an energy-dense nutritional feed comprising of legume-based fermentable carbohydrates, incorporated with lactose-free versions of standard World Health Organization (WHO) F75/F100 nutritional feeds will enhance epithelial barrier function in malnourished children, reduce and promote resolution of diarrhoea and improve overall outcome. Methods: We will investigate in an open-label trial in 160 Ugandan children with SAM, defined by mid-upper arm circumference <11.5cm and/or presence of kwashiorkor. Children will be randomised to a lactose-free, chickpea-enriched feed containing 2 kcal/ml, provided in quantities to match usual energy provision (experimental) or WHO standard treatment F75 (0.75 kcal/ml) and F100 (1 kcal/ml) feeds on a 1:1 basis, conducted at Mbale Regional Referral Hospital nutritional rehabilitation unit. The primary outcomes are change in MUAC at day 90 and survival to day 90. Secondary outcomes include: i) moderate to good weight gain (>5 g/kg/day), ii) de novo development of diarrhoea (>3 loose stools/day), iii) time to diarrhoea resolution (if >3 loose stools/day), and iv) time to oedema resolution (if kwashiorkor) and change in intestinal biomarkers (faecal calprotectin). Discussion: We hypothesize that, if introduced early in the management of malnutrition, such lactose-free, fermentable carbohydrate-based feeds, could safely and cheaply improve global outcome by reducing lactose intolerance-related diarrhoea, improving mucosal integrity and enhancing immunity, and limiting the risk of systemic infection and associated broad-spectrum antibiotic resistance. Registration: ISRCTN 10309022.

Modifying gut integrity and microbiome in children with severe acute malnutrition using legume-based feeds (MIMBLE): A pilot trial

“…58 In our proof-of-concept study, we demonstrated no adverse effects of the feed, which has resulted in a phase II trial using a food industry standard feed developed by a commercial partner. 59 The children randomized to the CpF gain a similar amount of weight, had increased mid-upper arm circumference, and had no difference in diarrheal episodes compare to ConFs. In fact, our data indicated legume-enriched feeds reduced the impact of antibiotics on further lowering the diversity of the microbiota early in the course of admission/nutritional rehabilitation.…”

Development of a legume-enriched feed for treatment of severe acute malnutrition

“…The safety and efficacy of the resultant product will be assessed in a phase II randomised controlled trial 25 . Briefly, the MIMBLE II trial is an open-label controlled trial in 160 Ugandan children with SAM, defined by mid-upper arm circumference < 11.5cm and/or presence of kwashiorkor.…”

“…We describe the development process of a lactose-free, fermentable carbohydrate-containing alternative to traditional F75 and F100 formulae for the treatment of SAM, for use in a phase II controlled clinical trial in Uganda: Modifying Intestinal MicroBiome using Legume-based feeds (MIMBLE II) 25 .…”

Development of a legume-enriched feed for treatment of severe acute malnutrition

“…However, this has not been translated to the formulae used in children with SAM in low- and middle-income countries where case fatality remains a major problem 24 . Our research group have developed and tested in a Phase II trials legume-based formulae for children with SM aimed at optimising gut function and ‘feeding the microbiome’, which has provided early indications of improved gut health and better clinical outcomes 25 , 26 .…”

“…We describe the development process of a lactose-free, fermentable carbohydrate-containing (chick-pea) alternative to traditional F75 and F100 formulae for the treatment of SAM, for use in a phase II controlled clinical trial in Uganda: Modifying Intestinal MicroBiome using Legume-based feeds (MIMBLE II) 25 .…”