Isovalerate might be key to improving malnutrition in children, mouse study reveals

A mouse study has discovered that a cost-effective supplemental intervention could potentially help improve the health outcomes of children with malnutrition. It highlights the role of the microbial metabolite isovalerate in strengthening the gut barrier, as malnutrition damages this lining, enabling harmful bacteria to enter the body. 

Researchers at Baylor College of Medicine and Texas Children’s Hospital in the US suggest that their findings present a promising strategy for new treatments in improving gut health in malnourished children, even though further research on humans is required.

Understanding the gut barrier

The Proceedings of the National Academy of Sciences study explains that the intestinal barrier is maintained by the mucus layer, in coordination with immune cells and epithelial cells lining the gut.

“One poorly understood consequence of malnutrition is intestinal barrier erosion, which allows bacteria to escape the gut and cause invasive infections, including sepsis, leading causes of mortality in malnourished children,” says study lead and co-corresponding author Dr. Geoffrey Preidis, associate professor of pediatrics – gastroenterology, hepatology, and nutrition at Baylor and Texas Children’s. 

“In the current study, we investigated how the gut microbiota impacts the intestinal barrier in malnutrition and how we might leverage gut bacteria to develop new treatments to prevent sepsis and death in malnourished children,” says Preidis, who is also co-director of the Texas Medical Center Digestive Diseases Center.

Malnutrition impacts sexes differently

The team employed a mouse model of human malnutrition to understand whether gut bacteria were involved in damaging the gut barrier during malnutrition. 

They found that malnutrition did not cause the same gut barrier problems in germ-free mice, suggesting that the relationship between malnutrition and the gut microbiome, not just malnutrition alone, can damage the intestinal barrier.

“We discovered that, just like in malnourished children, in these mice, the gut barrier was damaged,” shares Preidis. “The mucus layer that normally coats and protects the intestine became much thinner, and the gut became more permeable, meaning that bacteria could escape the intestines and enter the body.”

“We found live bacteria invading the liver and spleen. Interestingly, these effects were present in male but not female mice, similar to how malnourished boys are at higher risk of sepsis and death than malnourished girls.”

Zooming into metabolites

The researchers also examined metabolites produced by the gut bacteria present in the mice’s intestine. 

“One class of microbial metabolites, the branched-chain fatty acids, which includes isovalerate, was depleted in malnourished mice, while these metabolites were abundant in healthy mice,” details Preidis. “This led us to identify isovalerate as a previously underappreciated microbiota-derived metabolite that supports intestinal barrier integrity.”

“We explored mechanisms by which isovalerate regulates the gut barrier using human-derived colon organoids — miniature, lab-grown versions of the human gut. We discovered that isovalerate rearranges some of the proteins that make up the gut barrier, and this rearrangement makes the barrier stronger in human organoids.”

He continues that the team provided isovalerate to mice either directly into the colon using enema or by feeding them leucine, an amino acid that gut bacteria convert into isovalerate. Both strategies were noted to improve gut barrier function. 

“This is an impactful study, and I was delighted that human colon organoids validated results from mouse models and provided new insight that isovalerate enhances barrier function by modulating tight junction processes,” comments co-corresponding author Dr. Mary Estes, distinguished service professor and Cullen Foundation Endowed Chair of molecular virology and microbiology at Baylor.

The study only provides a promising and cost-effective way to improve gut bacteria in human children.

“We are excited about the possibility of developing a novel treatment for gut barrier damage in malnutrition based on leucine,” comments Preidis. “Leucine costs pennies per dose, does not require refrigeration, and is well-tolerated by mouth. Administering leucine as a prebiotic can allow the gut microbiota to produce isovalerate in the intestine, right where it is needed.”

In related news, research found that malnutrition and stunted growth may be passed down generations through the gut microbiome in a mouse study.