Studies Redefine Lactation Biology Through Computational Multi-Omics and Mammary Metabolic Modeling

A study led by researchers at NYU Grossman School of Medicine identified shared molecular patterns in human milk that link maternal nutrition, mammary gland biology, and infant growth.

Researchers analyzed thousands of molecular measurements from human milk collected across three geographically and nutritionally diverse populations of mothers. They identified shared patterns in milk composition associated with both maternal nutritional status and infant growth, and asked whether these patterns could also provide insight into the mammary gland functional state.

Published online October 8 in the journal Science, the study examined this state, which involves three interconnected aspects of mammary gland function: milk synthesis and secretion, epithelial barrier and tissue remodeling, and immune and repair activity. Milk synthesis and secretion describe how mammary cells produce the components of milk and release them into milk; barrier and tissue-remodeling functions regulate what passes between the bloodstream and milk while reshaping the milk-producing tissue; and immune and repair activity helps protect the gland and restore tissue after stress or injury. 

By mapping molecular patterns in milk onto these biological processes, the researchers asked not only what is present in milk, but also what its composition may reveal about the function of the mammary gland that produces it.

"Human milk gives us a rare, non-invasive window into the biology of the lactating mammary gland," said Liat Shenhav, PhD, senior author of the study and an assistant professor at NYU Grossman School of Medicine, with appointments in the Institute for Systems Genetics, the Department of Microbiology, and the Department of Obstetrics and Gynecology.

By looking at molecular patterns across diverse populations, we can begin to identify shared features of mammary function and understand how maternal nutritional and metabolic state relates to milk composition and infant growth."

Liat Shenhav, PhD, Study Senior Author and Assistant Professor, NYU Grossman School of Medicine

Despite its central role, how the functional state of the gland shapes milk composition-and how that variation relates to infant growth-remains poorly understood. Human milk contains thousands of nutrients, metabolites, proteins, immune factors, and other molecules, but research has often examined these components one at a time rather than as an integrated biological system. 

Across 1,543 human milk samples from three cohorts in Canada, Pakistan and Burkina Faso, the researchers combined multiple molecular layers-including metabolites, proteins, micronutrients (e.g., vitamins), macronutrients (e.g., carbohydrates), and human milk oligosaccharides - with growth data and computational approaches including machine learning, a form of artificial intelligence. 

In two randomized nutritional trials, maternal supplementation promoted recovery or stability among infants at higher risk for poor growth. Multi-omic analyses – which integrate information across several molecule types, such as proteins and metabolites, to provide a complete picture of a biological system - also revealed a shared pattern of milk composition associated with both maternal supplementation and infant growth.

The researchers then examined which molecules most consistently contributed to these shared nutrition-growth patterns. Their analysis identified seven candidate biomarkers linked to maternal nutritional status, infant growth and biological programs related to mammary gland function. Together, these markers captured aspects of mammary biology that extend beyond established measures of blood-milk barrier permeability.

Four of the markers-C2, C3, C4 and C5-were short-chain acylcarnitines, molecules that help cells process nutrients for energy. The remaining three were lysine, an amino acid; 6′ sialyllactose, a human milk oligosaccharide; and selenium, a mineral. Together, the seven biomarkers captured complementary aspects of mammary biology, including milk synthesis, tissue remodeling, and immune response activity.

Short-chain acylcarnitines showed the strongest links across mammary functional domains, with C5 emerging as a particularly prominent signal. Higher C5 levels were associated with reduced milk synthesis signatures and with biological patterns related to tissue remodeling and immune activity.

Because C5 emerged as a central metabolic signal, the researchers examined nutritional factors that might help explain variation in acylcarnitine levels. Acylcarnitine metabolism depends on coenzyme A (CoA), a central molecule in energy and lipid metabolism synthesized from pantothenic acid, or vitamin B5. Drawing on associations across cohorts and established metabolic biology, the researchers propose that low vitamin B5 availability may constrain CoA-dependent metabolism and contribute to altered acylcarnitine profiles, including accumulation of C5.

"Our findings demonstrate the intimate link between maternal nutrition, metabolic health and mammary function, highlighting the importance of an integrative approach to supporting maternal and infant health," said first author Dr. April Jauhal of the Shenhav lab at NYU Grossman School of Medicine. "One plausible route linking maternal nutrition to mammary metabolism in our data is via the pantothenic-CoA-C5 metabolic pathway, and we are currently investigating the functional role of this pathway in mammary biology and lactation."

Because human milk can be collected repeatedly, it provides a non-invasive way to study mammary gland biology over time. Viewing milk as a window into mammary gland biology also places lactation within a broader continuum of maternal physiology that begins during pregnancy. During gestation, the mammary gland undergoes extensive hormonal differentiation, tissue and immune remodeling, and metabolic programming, while its major functional phenotype-lactation-becomes apparent only after delivery.

In this sense, the mammary gland can be viewed as a postnatal maternal-infant interface: an organ programmed during pregnancy that subsequently connects maternal biology and nutrition with the developing infant. Like the placenta during pregnancy, it sits at a critical interface between mother and child-but human milk provides a way to study that interface repeatedly and non-invasively after delivery.

Building on this work, the Shenhav Lab is now developing an integrated computational and experimental framework to test potential nutritional bottlenecks that may constrain mammary metabolism and milk production, including the vitamin B5–coenzyme A–C5 pathway. The lab is also studying colostrum and transitional milk to understand how mammary functional states emerge during the transition from pregnancy to mature lactation, and whether early molecular changes in milk reflect the emergence of mammary metabolic, barrier, and secretory function.

The study is one of two complementary papers published in Science arising from the International Milk Composition (IMiC) Consortium, an international research effort conducted in collaboration with Meghan Azad of the University of Manitoba and funded by the Gates Foundation.

IMiC brought together more than 1,000 mother-infant pairs and profiled more than 25,000 molecular features in human milk. While the NYU Grossman School of Medicine-led study asked what milk composition can reveal about mammary gland function and its relationship with infant growth, the companion study asked a complementary question: Which components of human milk can be changed through maternal nutrition?

The companion study found that supplementation during lactation increased several B vitamins in milk, while many other milk components remained comparatively stable. Together, these studies aim to determine how maternal nutritional and metabolic state during pregnancy and postpartum shapes mammary function, how that state is reflected in human milk, and how these processes relate to infant development.

"The studies show that human milk is neither fixed nor simply a reflection of what a mother eats," said Dr. Shenhav. "Some components respond to maternal nutrition, while others remain stable or appear to reflect broader biological states within the mammary gland. Understanding that distinction is essential if we want to design interventions that meaningfully support maternal and infant health."

"Ultimately, we want to understand milk in the context of the biology that produces it," said Dr. Shenhav. "The mammary gland sits at a critical interface between maternal physiology and the developing infant. By understanding how maternal metabolism influences mammary function and milk composition, we can begin to uncover the biological pathways linking maternal nutritional status with infant growth."