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Rhesus monkey mom and baby at the UC Davis, the California National Primate Research Center (CNPRC). Overall, the microbiota in breast-fed macaques was more diverse than in the bottle-fed group.

Breast versus bottle feeding

Infant rhesus monkeys receiving different diets after birth develop distinct immune systems. As we are also primates, these results relate to humans as well.

Infant rhesus monkeys receiving different diets early in life develop distinct immune systems that persist months after moms wean their babies. The study was conducted by researchers from UC Davis, the California National Primate Research Center (CNPRC) at UC Davis and UC San Francisco.

The study, which compares breast and bottle-fed infants, appears in Science Translational Medicine.

While the researchers expected different diets would promote different intestinal bacteria (microbiota), they were surprised at how dramatically these microbes shaped immunologic development. Specifically, breast-fed macaques had more "memory" T cells and T helper 17 (TH17) cells, which are known to fight Salmonella and other pathogens.

These differences persisted for months after the macaques had been weaned and placed on identical diets, indicating that variations in early diet may have long-lasting effects.

"We saw two different immune systems develop: one in animals fed mother's milk and another in those fed formula.

"But what's most startling is the durability of these differences. Infant microbes would leave a long-lasting imprint on immune function."

Dennis Hartigan-O'Connor, CNPRC scientist, Infectious Diseases Unit, and Reproductive Sciences and Regenerative Medicine Unit, assistant professor, Department of Medical Microbiology and Immunology, UC Davis.

Previous research has highlighted the relationship between breast milk, microbiota and the developing immune system. For example, sugars in breast milk help grow specific bacteria, which in turn support certain immune cells. This new study is an important step towards understanding how these separate pieces link together and how they might influence the immune systems response to infections or vaccinations.

Macaques are born with virtually no TH17 cells, and must develop them during the first 18 months of life. Hartigan-O'Connor and other researchers have noted that some macaques develop large TH17 cell populations, while others have few.

This could profoundly affect an animals' ability to fight infection, particularly SIV, the simian strain of HIV.

To understand this variability, the investigators followed six breast- and six bottle-fed rhesus macaques from age five months to 12 months. At six months, they found significant differences in the two groups' microbiota.

Specifically, the breast-fed macaques had larger numbers of the bacteria Prevotella and Ruminococcus, while the bottle-fed group had a greater abundance of Clostridium. Overall, the microbiota in breast-fed macaques was more diverse than in the bottle-fed group.

The big surprise came when examining their immune systems. By 12 months, the two groups showed significant contrasts, with the differences centered on T cell development. The breast-fed group had a much larger percentage of experienced memory T cells, which are better equipped to secrete immune defense chemicals called cytokines, including TH17 and interferon-producing cells.

"This is the first time researchers have shown that these immunologic characteristics may be imprinted in the first new months of life.

"Our study suggests that the gut microbiota present in early life may leave a durable imprint on the shape and capacity of the immune system, a programming of the system if you will."

Amir Ardeshir, study first author.

Further investigation may have identified chemicals that drive these differences. For example, arachidonic acid, which stimulates the production of TH17 cells and is found in macaque breast milk, was tightly linked to TH17 cell development. Previous studies have suggested it can influence T cell development. The researchers caution that these chemicals must be tested in larger studies to understand their effects.

While this research provides a fascinating window into immune cell development in macaques, Hartigan-O'Connor cautions that it doesn't prove the same mechanisms exist in people. The lab is planning similar studies in humans to test that hypothesis. In addition, this study does not prove a link between breastfeeding and better health.

"There's a developmental shape to the immune system that we don't often consider," Hartigan-O'Connor said. "It's dramatic how that came out in this study. There's a lot of variability in how both people and monkeys handle infections, in their tendency to develop autoimmune disease, and in how they respond to vaccines. This work is a good first step towards explaining those differences."

Abstract
Diet has a strong influence on the intestinal microbiota in both humans and animal models. It is well established that microbial colonization is required for normal development of the immune system and that specific microbial constituents prompt the differentiation or expansion of certain immune cell subsets. Nonetheless, it has been unclear how profoundly diet might shape the primate immune system or how durable the influence might be. We show that breast-fed and bottle-fed infant rhesus macaques develop markedly different immune systems, which remain different 6 months after weaning when the animals begin receiving identical diets. In particular, breast-fed infants develop robust populations of memory T cells as well as T helper 17 (TH17) cells within the memory pool, whereas bottle-fed infants do not. These findings may partly explain the variation in human susceptibility to conditions with an immune basis, as well as the variable protection against certain infectious diseases.

Other authors include: Nicole Narayan, Gema Mendez-Lagares, Ding Lu, and Koen K. A. Van Rompay, Marcus Rauch, Susan V. Lynch and Yong Huang at UC San Francisco.

This research was supported by grants from the National Institute of Allergy and Infectious Diseases (K23AI081540), the Bill and Melinda Gates Foundation under a Grand Challenges Exploration award (#52094) and by Office of the Director of NIH (P51-OD011107).

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