Study finds nutrient in breast milk that shapes immune development in mice

Trans-vaccenic acid (TVA), the most abundant trans fatty acid found in human breast milk, helps boost immune system development and has long-lasting effects on immune system health in mice, according to a new study by researchers from the University of Chicago.

The study, published this week in Science, showed that nursing female mice fed a diet enriched with TVA passed the nutrient to their pups, leading to increased production of immune cells during early development. Genetic analyses also showed that TVA exposure during breastfeeding reprogrammed immune cells to improve responses to pathogens. Mice that were nursed on TVA-enriched milk responded faster to infections with viruses or common bacteria, even into adulthood.

“It’s common knowledge that breastfeeding is important for neonatal immune development and overall health, but breast milk is so complex that it seems almost impossible that one single molecule would be sufficient to change a baby’s immune development,” said Jing Chen, PhD, the Janet Davison Rowley Distinguished Service Professor of Medicine at UChicago and one of the senior authors of the new study. “So, it was very surprising to see that during this crucial stage of development, one nutrient derived from the mother’s diet and delivered through breastfeeding has such a tremendous effect.”

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 diet. In a 2023 study, Chen and his 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 influence immune development early in life.

In a series of mouse experiments, the team fed nursing mothers a diet enriched with TVA. The nutrient was passed on to their pups through breast milk, where it promoted the development of a broader and more effective immune cell population, particularly 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 analyses that revealed how increased TVA helped reprogram CD4+ T cells in the mice in a way that shifted their natural immune responses to favor fighting off microbes and other pathogens, instead of responding to antigens. Later experiments showed that when mice raised on TVA-enriched breast milk were exposed to the flu virus or Salmonella, they responded more quickly and had better survival rates than controls.

Interestingly, this advantage appeared only when mice were exposed to TVA during breastfeeding. Pups that were exposed to TVA via the mothers’ diet during pregnancy but were then nursed by a foster mother who was not on a TVA-rich diet did not have these improved responses to infection.

“We saw that only postnatal exposure to TVA through breastfeeding is important to train the neonatal T cells, and this can have long-lasting imprinting effects,” Chen said. “Even in adulthood, when we challenged the mice with influenza, the ones that were exposed to higher TVA levels during breastfeeding responded better when battling the infection.”

Chen also partnered 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-life development on long-term health and wellbeing. Claud’s work with the SET Center complements Chen’s longstanding interest in the impact of nutrition on immune system development and health outcomes. The research team worked with the Metabolomics Platform at the UChicago Comprehensive 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 linked to higher TVA levels in infants’ blood. In preterm infants, levels of circulating TVA correlated with similar shifts in immune responses to those the researchers saw in mice. Higher TVA levels in human breast milk were also associated with 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 that has huge health impact’

Chen said working with partners like He, with his extensive experience with RNA sequencing and epigenetic analysis, and Claud, with her expertise on early infant development, was crucial to the success of this study. “This was truly ‘team science.’ It definitely reflects the great collaborative environment here at UChicago,” he said. “That's our strong suit, with three different departments working together to address a question that has huge health impact.”

With multiple studies now showing the immune benefits of TVA, particularly in the early-life period, Chen said he hopes there will be more research on the possibilities for 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 close to 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 believe there could be additional fatty acids and nutrients that can do something similar.”

The study, “Maternal trans-vaccenic acid shapes 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 McNeely, Candace Cham, Robert B. Hamanaka, Gökhan 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 from Weill Cornell Medicine; Brian T. Layden from the University of Illinois Chicago; and Hongbo Chi from St. Jude Children's Research Hospital.