Severe malnutrition does more than deprive the body of calories and nutrients. It can also damage the intestinal barrier, making it easier for bacteria that normally stay inside the gut to move into other parts of the body and potentially contribute to dangerous infections.
In a new experimental study, researchers at Baylor College of Medicine and Texas Children’s Hospital identified a compound made by gut bacteria that appears to help maintain that protective barrier. They also found that giving malnourished mice the amino acid leucine helped restore levels of the compound and improved measures of gut barrier function.
The findings, published in the Proceedings of the National Academy of Sciences, are early stage. The treatment was tested primarily in mice, not children, and the study did not show that leucine prevents sepsis, reduces deaths or improves outcomes in people with malnutrition.
“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,” said study lead and co-corresponding author Dr. Geoffrey Preidis, an associate professor of pediatrics at Baylor College of Medicine and Texas Children’s Hospital.
The intestinal lining normally acts as a barrier between the contents of the digestive tract and the rest of the body. In the malnourished mice, researchers found that the mucus layer protecting the intestine became thinner and the intestinal barrier became more permeable. Live bacteria were also found in the liver and spleen, indicating they had escaped the gut.
Those changes occurred in male mice but not female mice. The researchers noted that boys with severe malnutrition also have a higher risk of sepsis and death than girls, although the mouse findings do not establish why that difference occurs in children.
The team next studied germ-free mice, which are raised without gut microbes. Malnutrition did not produce the same intestinal damage in those animals, suggesting that the gut microbiome plays an important role in how malnutrition affects the intestinal barrier.
Researchers then looked at compounds produced when gut bacteria break down nutrients. One group, known as branched-chain fatty acids, was much lower in malnourished mice. Among them was isovalerate, a compound made when certain gut bacteria metabolize leucine.
“This led us to identify isovalerate as a previously underappreciated microbiota-derived metabolite that supports intestinal barrier integrity,” Preidis said.
To explore whether isovalerate could directly affect the intestinal barrier, the researchers tested it in human-derived colon organoids, miniature laboratory models made from human cells. The compound altered proteins involved in keeping intestinal cells tightly connected, producing changes consistent with a stronger barrier.
The researchers then tested whether restoring isovalerate could improve the damaged gut barrier in malnourished mice. They used two approaches: delivering isovalerate directly to the colon and giving mice leucine, which gut bacteria can convert into isovalerate.
Both approaches improved measures of intestinal barrier function.
The leucine findings are particularly interesting because leucine is an essential amino acid found naturally in protein-containing foods and is widely available as a supplement. But the study does not provide evidence that leucine supplements improve gut health in otherwise healthy people, nor does it establish an appropriate dose or treatment for children with malnutrition.
Instead, the researchers see leucine as a possible way to influence the gut microbiome so that it produces isovalerate where it is needed.
“We are excited about the possibility of developing a novel treatment for gut barrier damage in malnutrition based on leucine,” Preidis said. “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.”
Much more research will be necessary before that possibility can be translated into treatment. Researchers would need to determine whether the same biological pathway operates in malnourished children, whether leucine safely increases isovalerate in their intestines and, ultimately, whether strengthening the intestinal barrier reduces infections or improves survival.
Co-corresponding author Dr. Mary K. Estes said the use of human colon organoids added support for the biological mechanism seen in mice.
“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,” Estes said.
For now, the study offers a potential explanation for how malnutrition, gut microbes and the intestinal barrier interact, along with an inexpensive nutritional strategy researchers can investigate further in people.
The research was supported by several federal grants from the National Institutes of Health, including the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of General Medical Sciences and National Cancer Institute, as well as the Cancer Prevention and Research Institute of Texas, Texas Children’s Hospital, Baylor College of Medicine, the Dan L Duncan Comprehensive Cancer Center, the Diana Helis Medical Research Foundation and the Adrienne Helis Malvin Medical Research Foundation.