Trans-vaccenic acid (TVA), the most abundant trans fatty acid found in human breast milk, helps boost immune system development and has long-term effects on immune system health in mice, according to a new study by University of Chicago researchers.
The study, published this week in Scienceshowed that lactating female mice fed a TVA-enriched diet passed the nutrient on to their pups, leading to increased production of immune cells during early development. Genetic analyzes also showed that exposure to TVA during lactation reprogrammed immune cells to improve responses to pathogens. Mice fed TVA-fortified milk responded more quickly to infections with viruses or common bacteria, even into adulthood.
Breastfeeding is known to be important for immune development and the overall health of the newborn, but breast milk is so complex that it seems almost impossible that a single molecule would be enough to alter a baby’s immune development. So it was very surprising to see that at this critical stage of development, a nutrient that comes from the mother’s diet and is provided through breastfeeding has such a tremendous effect.”
Jing Chen, PhD, the Janet Davison Rowley Distinguished Service Professor of Medicine at UChicago and one of the senior authors of the new study
Long-term immune imprinting
Trans-vaccenic acid is a long-chain fatty acid found in meat and dairy products from grazing animals such as cows and sheep. The human and mouse body cannot produce TVA on its own, so it must be obtained through the diet. In a 2023 study, Chen and colleagues found that it improves the ability of CD8+ T cells to infiltrate tumors and kill cancer cells in adult mice. Because TVA is also abundant in human breast milk, the researchers wanted to understand how it might affect immune development early in life.
In a series of experiments on mice, the team fed lactating mothers a TVA-enriched diet. The nutrient was passed on to their offspring through breast milk, where it promoted the development of a broader and more effective population of immune cells, particularly the CD4+ T cells that are important for adaptive immunity.
Working with Chuan He, PhD, the John T. Wilson Distinguished Service Professor of Chemistry and a senior author of the study, the researchers also conducted genetic analyzes that revealed how increased TVA helped reprogram CD4+ T cells in mice in a way that shifted their natural immune responses to favor fighting microbes and other pathogens. Later experiments showed that when mice raised on mother’s milk enriched with TVA were exposed to the influenza virus or salmonella, they responded faster and had better survival rates than controls.
Interestingly, this advantage only occurred when mice were exposed to TVA during lactation. Pups exposed to TVA through the mother’s diet during pregnancy but then nursed by a foster mother not on a TVA-rich diet did not have these enhanced responses to infection.
“We saw that only postnatal exposure to TVA through breastfeeding is important for training neonatal T cells, and this can have long-lasting imprinting effects,” Chen said. “Even in adulthood, when we challenged the mice with influenza, those exposed to higher levels of TVA during lactation responded better when they fought off the infection.”
Chen also collaborated with Erika Claud, MD, the Stephen Family Professor of Pediatrics and Director of the UChicago Center for the Science of Early Trajectories (SET), who studies the biology of early development in long-term health and wellness. Claud’s work with the SET Center complements Chen’s long-standing interest in the impact of nutrition on immune system development and health outcomes. The research team collaborated with the Metabolomics Platform at the UChicago Integrative Cancer Center, led by Hardik Shah, to analyze TVA levels in breast milk and blood samples from human nursing mothers and infants from a biorepository maintained by the SET Center.
They found that higher TVA levels in breast milk were closely associated with higher TVA levels in the infants’ blood. In premature infants, levels of circulating TVA were associated with similar changes in immune responses as the researchers saw in mice. Higher levels of TVA in human breast milk were also associated with a reduced risk of bronchopulmonary dysplasia, a chronic inflammatory lung disease that affects premature infants with underdeveloped lungs, and increased susceptibility to respiratory infection.
“A question with a huge impact on health”
Chen said working with collaborators such as He, with his extensive experience in RNA sequencing and epigenetic analysis, and Claud, with her expertise in early infant development, was critical to the success of this study. “This was truly ‘group science.’ It certainly reflects the great collaborative environment here at UChicago,” he said. “This is our strong suit, with three different departments working together to address a question that has a huge impact on health.”
With multiple studies now showing the immune benefits of TVA, particularly early in life, Chen said he hopes there will be more research into the potential of supplementing diets with TVA during pregnancy and breastfeeding or adding it to infant formula. The team wants to investigate other fatty acids and nutrients found in breast milk to understand their benefits as well.
“There are nearly 40 fatty acids in total in breast milk, along with hundreds of other components,” Chen said. “So I think it’s safe for us to say that we think there could be additional fatty acids and nutrients that can do something similar.”
The study, “Maternal trans-vaccenic acid modulates neonatal T cell development and early life immune imprinting,” was supported by the National Institutes of Health, the National Cancer Institute, the Ludwig Center at UChicago, the Sigal Fellowship in Immuno-oncology, and the Harborview Foundation Gift Fund.
Additional authors include Hao Fan, Zhong Zheng, Kaitlyn Oliphant, Jiacheng Li, Cheng Wei Ju, Brandon Trandai, Jiayi Tu, Freya Q. Zhang, Rukang Zhang, Zhicheng Xie, Chunzhao Yin, Chufan Cai, Megan S. Kennedy, Tess McNeemka, Robert Canda M. Mutlu, and Eugene B. Chang from UChicago. Ryan Mack and Jiwang Zhang from Loyola University Chicago. Lei Dong from the University of Texas Southwestern Medical Center. Rui Su from the Beckman Research Institute of City of Hope. Camilia R. Martin of Weill Cornell Medicine. Brian T. Layden of the University of Illinois at Chicago. and Hongbo Chi from St. Jude Children’s Research Hospital.
