Nourish Immunity: How Breast Milk’s Vital Gifts Shape Lifelong Defenses

The significance of trans-vaccenic acid (TVA), the predominant trans fatty acid present in human breast milk, for fostering immune system maturation and exerting enduring benefits on immune health has been demonstrated in a novel investigation conducted by researchers affiliated with the University of Chicago.

Published this week in the prestigious journal Science, the study’s findings revealed that lactating female mice sustained on a diet fortified with TVA effectively transferred this crucial nutrient to their offspring. This nutritional support stimulated an augmented proliferation of immune cells during the critical early stages of development. Furthermore, genomic analyses elucidated that prenatal exposure to TVA via breastfeeding initiated a reprogramming of immune cells, enhancing their capacity to combat infectious agents. Mice that received TVA-enriched milk exhibited a more rapid and robust response to viral and common bacterial infections, with these protective effects persisting well into adulthood.

While the importance of breastfeeding for neonatal immune development and general well-being is widely acknowledged, the intricate composition of breast milk makes it challenging to conceive that a solitary molecule could profoundly alter a baby’s immune maturation. Consequently, it was exceptionally surprising to observe that a single nutrient, derived from the maternal diet and delivered through breastfeeding, could exert such a substantial influence during this pivotal developmental window.

Jing Chen, PhD, the Janet Davison Rowley Distinguished Service Professor of Medicine at UChicago and a senior author of the recent study

Sustained Immune Imprinting

Trans-vaccenic acid is a long-chain fatty acid indigenous to animal products from grazing livestock, such as beef and dairy. The human and murine metabolisms are incapable of synthesizing TVA intrinsically, necessitating its dietary acquisition. In a prior investigation from 2023, Chen and his associates ascertained that TVA enhances the migratory capacity of CD8+ T cells towards tumors and their efficacy in eradicating cancerous cells in adult mice. Given TVA’s prevalence in human breast milk, the research team sought to investigate its potential role in modulating immune development during early life.

Through a series of meticulously designed mouse experiments, the research cohort administered a TVA-supplemented diet to lactating mothers. The nutrient was subsequently transferred to their pups via breast milk, where it played a pivotal role in cultivating a more diverse and effective repertoire of immune cells, with a particular emphasis on CD4+ T cells, which are indispensable for adaptive immunity.

In collaboration with Chuan He, PhD, the John T. Wilson Distinguished Service Professor of Chemistry and a co-senior author of the study, the investigators performed comprehensive genetic analyses. These revealed the mechanisms by which elevated TVA levels facilitated the reprogramming of CD4+ T cells in the murine subjects, recalibrating their immunological responses to prioritize the neutralization of microbial threats and other pathogens over the recognition of extraneous antigens. Subsequent experimental trials demonstrated that mice nourished with TVA-enriched breast milk exhibited accelerated recovery and improved survival rates when challenged with influenza virus or Salmonella, compared to their control counterparts.

Intriguingly, this protective advantage was contingent upon TVA exposure exclusively during the breastfeeding period. Offspring exposed to TVA through their mothers’ dietary intake during gestation, but subsequently nursed by foster mothers not adhering to a TVA-rich regimen, did not benefit from these enhanced anti-infective responses.

“Our findings indicate that only postnatal exposure to TVA through breastfeeding is instrumental in the education of neonatal T cells, yielding enduring imprinting effects,” stated Chen. “Even as adults, when challenged with influenza, the mice that experienced higher TVA levels during their nursing period demonstrated superior resilience in combating the infection.”

Chen also joined forces with Erika Claud, MD, the Stephen Family Professor of Pediatrics and Director of the UChicago Center for the Science of Early Trajectories (SET), whose research focuses on the long-term health and well-being implications of early-life developmental biology. Dr. Claud’s work within the SET Center harmonizes with Chen’s long-standing commitment to understanding the influence of nutrition on immune system development and health outcomes. The research consortium leveraged the expertise of the Metabolomics Platform at the UChicago Comprehensive Cancer Center, under the direction of Hardik Shah, to meticulously quantify TVA concentrations in breast milk and blood samples obtained from human nursing mothers and their infants, meticulously collected from a biorepository managed by the SET Center.

Their analysis revealed a strong correlation between elevated TVA levels in maternal breast milk and corresponding increases in infant blood TVA concentrations. In the context of preterm infants, circulating TVA levels were observed to correlate with discernible alterations in immune responses mirroring those identified in the murine models. Furthermore, higher TVA concentrations in human breast milk were associated with a diminished risk of bronchopulmonary dysplasia, a chronic inflammatory pulmonary condition that disproportionately affects premature infants with incompletely developed lungs and heightened vulnerability to respiratory infections.

A Question of Profound Health Significance

Chen emphasized that the successful execution of this study was significantly facilitated by the collaborative efforts of partners such as He, with his extensive experience in RNA sequencing and epigenetic analysis, and Claud, with her profound expertise in early infant development. “This was a quintessential example of ‘team science,’ reflecting the exceptional collaborative ethos prevalent at UChicago,” he remarked. “Our collective strength, with contributions from three distinct departments, enabled us to address a question of considerable health impact.”

In light of mounting evidence substantiating the immunological advantages of TVA, particularly during the crucial early-life period, Chen expressed a hopeful outlook for increased research into the potential of TVA supplementation during pregnancy and lactation, as well as its incorporation into infant formulas. The research team is also keen on exploring the benefits of other fatty acids and nutrients found in breast milk.

“Breast milk contains approximately 40 distinct fatty acids, in addition to hundreds of other constituents,” Chen elaborated. “Therefore, it is reasonable to posit that additional fatty acids and nutrients may possess comparable beneficial properties.”

The pivotal study, titled “Maternal trans-vaccenic acid shapes neonatal T cell development and early-life immune imprinting,” received financial support from 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 contributors to this research 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, all 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.