SickKids team identifies promising pathways to improve metabolic function in malnourished children

Malnutrition, a state of poor nutrition, remains an important burden of health and is related to 45 per cent of all mortality in children under the age of five worldwide.

Previous research has shown that disturbances in metabolic functions play a key role in the high mortality rate of acutely ill children who are severely malnourished.

In a new study published on December 8, 2022 in Nature Communications, a multi-disciplinary team at The Hospital for Sick Children (SickKids) assessed the role of mitochondria – cellular structures that provide energy for cells – in liver metabolic function and uncovered new potential treatment pathways for malnourished children.

“Children with malnutrition are more susceptible to poor outcomes not from the malnutrition directly, but because they are unable to cope with common childhood infections. As an inability to perform important metabolic functions is related to mortality in these vulnerable children, we wanted to dig deeper into the metabolic functions involved in malnutrition,” says Dr. Robert Bandsma, the principal investigator of the study, Principal Investigator at the SickKids Centre for Global Child Health, Scientist in the Translational Medicine program and Staff Physician in the Division of Gastroenterology, Hepatology and Nutrition. “Any serious disease puts a child at risk of developing malnutrition, making malnutrition an important health problem in children in both low- and high-resource geographies.”

Discoveries through collaboration

The production of healthy mitochondria is extremely important, especially in children who are malnourished, as they are the energy factories of the cells and provide the energy to sustain normal cellular functions.

The study team discovered the function of mitochondria were impaired by low-protein diets. Specifically, the tryptophan-nicotinamide adenine dinucleotide (TRP-NAD+) pathway, which is important for mitochondrial health, was disrupted, leading to an inability to process nutrients.

“The irony here is that the cellular processes needed to balance energy production in the liver during poor nutrient conditions are so damaged that they end up worsening the cells’ health. We would have never guessed it,” says Dr. Peter Kim, co-author of the paper and Senior Scientist in the Cell Biology program at SickKids. “But discoveries such as this were made possible by placing two researchers from different fields, in this case, a malnutrition clinical scientist and an organelle cell biologist, in one building here at SickKids.”

The team also discovered that simple interventions such as providing nutritional supplements that restore the TRP-NAD+ pathway can help stimulate the production and function of mitochondria and restore metabolic functions in the liver.

New pathways to restore the metabolic function of malnourished children

Results from this study may provide an opportunity to harness a unique pathway to restore metabolic function in severely malnourished children.

Knowing that metabolic function can be restored in a malnourished state paves the way for assessing whether nutritional supplements, such as nicotinamide, can be given to malnourished children to improve their resilience – the ability to cope with the acute stage of a serious infection.

“This study suggests that if you have a child who’s admitted to the hospital with an acute illness and who is also very malnourished, you can potentially improve their resilience by improving metabolic function. That could lead to improved survival in this vulnerable population,” says Bandsma.

Precision nutrition in a global health context

The research team is optimistic about what the findings could mean for children around the world who are malnourished or living with other diseases that are associated with poor nutritional states.

“The possible new interventions that we can now further explore are a form of what we call precision nutrition,” says Bandsma. “Giving a very targeted nutritional support for a very particular group of patients who are malnourished and facing a critical illness is aligned with SickKids’ vision for Precision Child Health, in which we can provide much more individualized care to patients. At the SickKids Centre for Global Child Health, we want to think about how we can develop precision nutrition approaches that are relevant in a global health context.”

This study was funded by the Bill & Melinda Gates Foundation and the Canadian Institutes of Health Research (CIHR).

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