Much like actual infants, infant immune systems are short on experience. They need to be taught how to differentiate friend from foe, when to fight and when to make peace. These early lessons can have long-term implications for an infant’s immune system, microbiome and general health.
In honor of Mother’s Day, we spoke with Dr. Meghan Koch, who uses mice to study how specialized immune proteins passed to infants during breastfeeding can “imprint” the infant’s immune system. Koch hopes her insights into what factors in breast milk set infants up for optimal health translate into improved formula composition and support for parents who do breastfeed.
It was a little bit of serendipity. During my postdoctoral fellowship, I was trying to understand specialized immune responses to different types of microbes in the gut and how these responses are regulated. I started to look at the levels of antibodies [specialized immune proteins that can protect against infection] and when these responses originated.
When I looked at that, I found that these antibody responses to microbiota [the microbes in a specific environment] were really high in early life. And then they dipped, and then they came up again. Which led to the question, well, is the response in early life generated by the infant (mouse, in this case) or is there potentially a contribution from the mother?
I tested this and found that it was maternal antibodies present in breast milk that contributed to the antibody response early in life. So then I wondered, is this some sort of immune instruction?
The immune system early in life is basically a blank slate. We know that certain types of immune responses to, for example, pathogens versus commensal [friendly] microbes are important for promoting health. You need to have an antagonistic response to a pathogen to act and clear that pathogen. At the same time, you need to tolerate the commensal microbiota. We know that there are lots of immune mechanisms and immune cell types that help shape this process and to make these decisions, pro or con, depending on the microbe.
These bacterial species look, for all intents and purposes, very similar. And so that got me thinking about a mechanism that might be present in early life but doesn't really need to be present later.
Infant formula and breast milk are nutritionally matched: The carbohydrates [sugars and starches] and the lipids [fats] and such are present in formula, and that promotes weight gain of human infants. And that's very important for their health. However, breast milk has evolved to have all these other bioactive components. And there’s likely a reason for that; even if they’re not essential for health, they could promote health.
In recent years, there have been meta-analyses comparing infants fed breast milk or formula, or different combinations of formula with breast milk. And by and large, kids fed formula are just fine. But there are some long-term consequences that seem to result from being fed only formula. Breast milk is protective against development of cardiovascular disease and type 2 diabetes and might have some implications for neurocognitive function, although that’s tricky to interpret.
So it could be context-dependent. Say you have an underlying predisposition for inflammatory bowel disease, maybe breast milk is protective in that context. Maybe it’s protective in the context of obesity, but only if you eat too much food.
The idea is, we can tweak formula with the bioactive components from breast milk to promote robust health in a variety of contexts, but we need to know what those components are first.
We’re trying to understand how to best reap the benefits of breastfeeding while also protecting the lives and mental health of mothers. We want to try to understand how breastfeeding promotes health, to understand the components of breast milk that are important for this process, to understand the processes that they regulate and to see if there are ways to improve formula so it better provides the health benefits of breastfeeding.
My work suggests that antibodies in breast milk help shape offspring’s immune responses later, and that the window in which this happens is short. So providing these antibodies [in formula] or promoting breastfeeding in really early life might be advantageous, and it doesn't necessarily need to extend [for a long time].
My group is trying to understand how maternal-offspring interactions influence infant health. We’re primarily focused on understanding immune responses in the gut mucosa [the mucus membranes of the intestines] and really understanding infant immunity.
My work suggests that maternal antibodies have dual roles. We’ve known for a while that antibodies transmitted via breast milk help protect the offspring from pathogens. And we have some other antibodies that are helping to restrict inflammatory responses to microbiota and promote health and growth. So one of the major goals of my research program is to try to understand the basis for these distinct functions.
We also want to understand how immune responses in early life are affecting long-term health. And what the windows of opportunity, or windows of susceptibility, are.
We’ve shown that antibodies via breast milk are important for shaping immune responses during the weaning transition, when mice go off breast milk and are introduced to solid food. This is a hugely important transition for babies and mice, because they’re being introduced to new antigens [structures that antibodies and immune cells can recognize] that their immune system can react to. And the new food will grow new beneficial bacteria, and it can be a source of potential infection as well.
If mice don’t get maternal antibodies through breast milk at just the right stage, their immune systems react differently to the weaning transition. It’s the same in mice that don’t receive any breastmilk antibodies at all. I think the implication of that discovery was that those early-life experiences, which happen to be mediated by these antibodies, can qualitatively change the immune response later in life. The infant immune systems imprint. There’s some kind of instruction going on.
We’re trying to identify the receptors and the cell types [in the infant] that are important for receiving that signal from the maternal antibodies. And to better understand the immune dysregulation that occurs during the weaning transition [in mice that haven’t ingested breast milk antibodies during the correct time period] and trying to understand the cell types contributing to that.
These antibodies — which we think have to be able to bind to the microbiota — somehow are engaging with the neonatal immune system and providing some sort of instruction for how the immune system will behave during this transition. The changes we see suggest that mice that don’t get these antibodies could be at higher risk for inflammation or allergenic responses, like food allergies — but that still needs to be explored.
Our work also suggests a new role for a specific type of antibody, known as immunoglobulin gamma, or IgG. These antibodies are well known for their defensive properties: telling the immune system, “Hey, we have an intruder here, we need to react, we need to respond, we need to get rid of this pathogen.” But in the context of a beneficial member of the microbiota, you don't want the immune system to be on high alert and to generate an inflammatory response.
We found IgG could also be helping the immune system learn to tolerate beneficial bacteria. This is basically a new function for IgG: Instead of only promoting antagonistic responses to pathogens it can also promote beneficial responses to the [friendly] microbiota.
So those are the two main areas we’re currently exploring: how antibodies facilitate immune imprinting, and how IgG functions in this process. We hope this research will advance our ability to ensure infant health by promoting immunity in early life.
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a Ph.D. in immunology from the University of Washington, an M.A. in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at firstname.lastname@example.org.
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