Discovering how malnutrition stunts children’s growth via the microbiome

What are the aims of your GGGH project?

Sub-Saharan Africa and South Asia have a very high burden of growth faltering, which is when children fall short of their optimal weight and height as defined by World Health Organization standards. Stunted growth is an outcome of chronic malnutrition, and malnutrition in the first months and years of life raises the risk of developing non-communicable diseases as an adult. While it’s very difficult to reverse the effects of malnutrition, much can be done to prevent it. In our most recent research, we followed a cohort of children from birth until two years of age to identify the determinants of growth related to their nutritional intake. We found that two essential dietary nutrients — choline and polyunsaturated fatty acids (PUFAs) — have a strong and consistent association with growth patterns in children. With our GGGH project, we hope to find further evidence to support a combined supplementation strategy that will provide choline- and PUFA-based supplements to children in low- and middle-income countries.

What do scientists already know about choline, PUFAs and their association with the developing gut microbiome?

Choline and PUFAs are both key substrates for the gut microbiome — they’re targeted by gut microbes, which metabolize them to create other critical compounds for our bodies. The microbiome metabolizes choline to trimethylamine, which the liver then oxidizes to generate trimethylamine N-oxide. Excessive levels of either metabolite trigger systemic inflammation, which can lead to obesity and other metabolic syndromes. On the other end of the scale, low intake of meat or other choline-rich foods leads to growth faltering. We believe that, over time, the gut microbiome may dictate the metabolism (and hence the availability) of choline and PUFA metabolites in young children, thereby influencing their growth patterns.

How will this project lead to new insights in this field?

Much nutritional-science research to date has focused on Western problems. Despite the world’s undernourished children greatly outnumbering obese children, comparatively few papers address the health burden of malnutrition. As very few studies have considered children in low- and middle-income countries, I’m delighted to have this opportunity to extend our work and gather more detailed data.

How will you find the answers?

Metabolites of choline and PUFAs are present in blood plasma and stool samples. We will collect longitudinal data on both nutrients from an existing cohort of children in Malawi, from birth to two years old. This longitudinal dimension is vital when you consider that we’re taking snapshots from a highly dynamic gastrointestinal system in each individual participant. We will analyse multiple samples from each child to observe how their gut microbiome matures over time, and how this dictates the metabolism of choline and the resulting effects on growth. We will also analyse samples from an existing clinical trial in Kenya, where children recovering from malnutrition were given daily antibiotics or a placebo for six months. This is a unique opportunity for us to examine the role of the gut microbiome in a specific clinical setting linked with malnutrition. It is standard practice for children who have been hospitalized with severe malnutrition to be given antibiotics to improve their chances of survival. We’re interested in examining the maturity of the gut microbiomes of this cohort.

Do you foresee any challenges in this project?

The main challenges are logistical. The field sites in Malawi are remote, which will make it difficult to maintain the cold chain and to ensure that samples are collected, stored and transported correctly. I applaud our collaborators in Malawi for ensuring high-quality sampling throughout the process. It’s also vital to remember that we’re working in the wider context of poverty. These children are malnourished for many reasons, and the environment is also manipulating their young bodies — for example through pollution, infections and extreme weather events. They’re exposed to multiple internal and external factors that could influence their gut microbiome, growth and development. Another limitation is the collection of stool samples; it’s still a taboo subject in that culture, and it’s difficult to get people to commit to providing regular samples. We hope to collect five or six samples from each child during the project, with the help of local social workers who can explain our purposes to the community.

What are the practical applications of your study?

Ideally, we’d like to be able to give back to the communities that support us — we hope to develop a viable intervention, such as providing young children with easy-to-access, inexpensive supplements to boost gut health. We want to conduct a larger scale clinical trial, backed by evidence from this study, to identify a suitable intervention. More importantly, we will train local scientists in Malawi, giving them the knowledge and tools to conduct research in their own communities. They know what the problems are in their country, and they could apply gut microbiome research and metabolomics technology to solve those problems. I’m passionate about providing scientists with the means to solve local issues directly.

What plans do you have for future research?

Whether malnourished children are given antibiotics or not, their microbiota are probably fundamentally altered. If we can demonstrate that the gut microbiome is mediating growth by controlling the availability of choline and PUFA metabolites, then we need to think about not just dietary supplements, but also the overall health of the gut in youngsters. We might want to examine the balance of the gut microbiota more closely in malnourished children, for example. Ultimately, we’re hoping to obtain funding to follow this cohort of children even longer, possibly into adolescence. This would help us see how the early-life microbiome impacts reproductive health or the incidence of specific diseases.

Biography

Gerard Bryan Gonzales studied Food Technology at the University of the Philippines Mindanao. In 2010, he obtained an Erasmus Mundus Scholarship to study an MSc in food science at the University of Copenhagen (Denmark) and Universitat Autonoma de Barcelona (Spain). He then moved to Belgium to pursue a PhD in applied biological science (chemistry) at Ghent University, where he studied polyphenols using mass spectrometry. After a consulting stint with the World Health Organization Europe in Turkmenistan, he obtained a Research Foundation Flanders (FWO) Fellowship at Ghent University to work on the molecular mechanisms driving different phenotypes of childhood severe malnutrition, especially kwashiorkor, in collaboration with and funded by the Médecins Sans Frontiéres. During his postdoc, he was a visiting scientist at the Hospital for Sick Children (Toronto, Canada), Kenya Medical Research Institute–Wellcome Trust (Kilifi, Kenya), and the University of Cambridge (Cambridge, UK). In 2020, he joined Wageningen University as assistant professor in nutri-informatics and metabolism.