Researchers at Baylor College of Medicine and Texas Children's Hospital have uncovered an intervention that can potentially improve the outcome of children with malnutrition, a condition that contributes to nearly half of all deaths in children under 5 years of age. The study appears in the Proceedings of the National Academy of Sciences.
"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, associate professor of pediatrics – gastroenterology, hepatology and nutrition and member of the USDA/ARS Children's Nutrition Research Center at Baylor and Texas Children's. Preidis also is co-director of the Texas Medical Center Digestive Diseases Center.
The intestinal barrier is a dynamic system that is maintained through coordinated functions of the mucus layer, the junctions between epithelial cells lining the gut and immune cells. In addition, gut microbes and products of their metabolism also play a role in regulating intestinal barrier function, but how this occurs is not well understood.
"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," Preidis said.
The researchers worked with a mouse model of human malnutrition. "We discovered that, just like in malnourished children, in these mice the gut barrier was damaged. 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."
To understand whether gut bacteria were involved in damaging the gut barrier during malnutrition, the researchers applied the model of malnutrition to germ-free mice, which are raised without any microbes. Interestingly, malnutrition did not cause the same gut barrier problems in germ-free mice. This suggested that the interaction between malnutrition and the gut microbiome, rather than malnutrition alone, plays a key role in damaging the intestinal barrier.
The team also analyzed the products of gut bacterial metabolism, or metabolites, that were present in mice intestines. "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," Preidis said. "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," Preidis said. "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." Would providing isovalerate to malnourished mice rescue gut barrier dysfunction in these animals?
"We provided isovalerate using two therapeutic approaches. One approach delivered isovalerate directly into the colon with enemas. In the second approach, we fed the mice leucine, an amino acid that gut bacteria convert into isovalerate," Preidis said. "Both strategies improved gut barrier function in malnourished mice."
Although the research was conducted mainly in mice and future studies will be needed to see whether this approach works in malnourished children, the results point toward a promising new strategy for improving outcomes in child malnutrition.
"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."
"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," said co-corresponding author Dr. Mary K. Estes , Distinguished Service Professor and Cullen Foundation Endowed Chair of molecular virology and microbiology at Baylor. Estes also is the co-director of the Gastrointestinal Experimental Model Systems core at the Texas Medical Center Digestive Diseases Center and a member of Baylor's Dan L Duncan Comprehensive Cancer Center .
Other contributors to this work include Lauren E. Lynch, Krishnakant G. Soni, Jennifer K. Spinler, Chandra Shekar R. Ambati, Nagireddy Putluri, Stephanie W. Fowler, Margaret E. Conner, Hoa Nguyen-Phu, Xi-Lei Zeng and Sarah E. Blutt. The authors are affiliated with Baylor College of Medicine and/or Texas Children's Hospital.
For a complete list of financial support for this work, see the publication.
