Stunting in young children refers to attenuated linear growth. In the year 2020, 149.2
million children under the age of 5 years of age were stunted, accounting for 22% of
stunting globally. Stunting has short- and long-term consequences of increased morbidity
and mortality, impairment of neurocognitive development5 , impaired responses to oral
vaccines, and increased risk of non-communicable diseases. Stunting is partly driven by
Environmental Enteric Dysfunction (EED), an enteropathic condition characterised by
altered gut permeability, infiltration of immune cells and changes in villous
architecture and cell differentiation. EED may help explain why nutritional
supplementation either during pregnancy or early childhood has minimal value in
correcting childhood stunting. Indeed, EED is believed to be responsible for 40% of
childhood stunting. Disruption in intestinal barrier function affects gut immune
homeostasis, nutrient flows, and consequently dysbiosis in the gut microbiome. The gut
microbiota consists of 100 trillion bacteria which interact with epithelial cells, the
mucus layer and the mucosal immune system that balances tolerance and effector functions.
Thus the gut microbiome has an important role in shaping the responsiveness of the gut
immune system. The mucus barrier and the normal gut microbiota limit enteropathogen
colonisation. Influx of bacteria from the lumen to the systemic circulation represents
microbial translocation and initiation of systemic of inflammatory process through
recognition of pathogen-associated molecular patterns (PAMPs) by Pattern Recognition
Receptors (PRRs) present on Antigen Presenting Cells (APCs). Three fundamental processes
drive the epithelial damage which is so important in EED: infection, undernutrition, and
immune dysfunction. Multiple clinical trials show that efforts to correct malnutrition
through conventional therapies and improving hygiene and sanitation do not overcome
growth deficits by more than about 10%. There is increasing interest in the use of
probiotics which may allow pathogen decolonization, improve barrier function and restore
overall gut homeostasis. Such therapies are at early stage of trials but may have
potential in addressing the global burden of EED, by improving barrier function and gut
pathophysiology.
Colonization of gut by enteropathogens is common in children with EED. These include
ETEC, Campylobacter, Shigella and Salmonella species. Consistent data from Bangladesh and
Zambia show that children with refractory stunting carry over four pathogens on average,
whilst controls carry less than two. There is also clear evidence of altered composition
of the microbiota in children with EED.
Probiotics may serve to overcome the problem of EED through all mechanisms of
pathogenicity, by providing additional bacteria that may help in intestinal
decolonization of pathogenic microorganisms (changing the microbiological niche),
promoting epithelial healing, improving nutrient absorption, and restoration of an
appropriate immune balance between tolerance and responsiveness.
To date the focus of research on childhood stunting has been on the young child. It is
increasingly appreciated, however, that stunting often begins in utero and the focus has
shifted to women's health and pregnancy. For example, the Lancet 2021 Series on maternal
and child undernutrition states that "Investments to reduce undernutrition in women are
important not only for women's own health but also for the health and nutrition of their
children". Results from rural Bangladesh reveal poor gestational weight gain that
ultimately leads to intrauterine growth restriction, low birth weight and ultimately
stunting and wasting. Furthermore, another study recently completed in slum settlements
of Dhaka, Bangladesh demonstrated a high prevalence of EED among undernourished women.
Intestinal histopathology was abnormal in more than 80% of women. We postulate that
growth retardation in utero is a consequence of EED in the mother during pregnancy and
lactation. This leads to systemic inflammation, which leads to disadvantageous
partitioning of nutrients, and reduced nutrient availability.
This trial will explore the conceptual framework that a well known probiotic, that can
improve the composition of the gut microbiota, can reduce biomarkers of intestinal
inflammation and gut health. This will restore healthy microbial signalling to the host
epithelium, ameliorate barrier function through secretion of mucus and antimicrobial
factors, and improve nutrient availability.
The primary objective of this trial is to determine if a probiotic, Vivomixx, can reduce
inflammation and epithelial damage in pregnant women with environmental enteropathy in
the target countries.
The secondary objectives of this trial are:
To determine if Vivomixx can reduce enteropathogen colonisation To determine if Vivomixx
can impact the structure and function of the microbiome To determine if Vivomixx can
reduce permeability. To determine if Vivomixx can impact the host metabolome in pregnant
woman To evaluate variability in endpoints across geographies and participating
laboratories.