Don’t throw the baby out with the breast milk
Mechanistic studies on ‘maternal-offspring immune crosstalk’ show we know little about consequences of not breastfeeding
This is the third guest post from Dr. Bienen—a veterinarian whose research focuses on zoonotic disease and associated policies. She recently left the OHSU-Portland State University School of Public Health in Portland, Oregon to work in her biomedical editing and writing business, C3 Science. I learned a lot from this discussion. JMM
Many discussions about the importance of breastfeeding suffer from 1) overlooking the most interesting and rigorous research on breast milk and breastfeeding and 2) a variation of ‘cherry picking’ that lumps all research on breastfeeding into the weak/confounded category.
Yes, badly confounded studies exist and are promoted by media or organizations pushing the ‘breast is best’ mantra. But there are also good studies focusing on mechanistic immunology.
I highlight a few here, but there are many more. This field is expanding rapidly due to novel sequencing, high-powered visualization, and metabolomic tools.
There are also studies that over-conclude in the other direction, purporting to show no differences between formula and breastmilk.
This newly published study in JAMA Network Open found that donated (i.e., not from the babies’ mothers) breastmilk was not better than formula for several measured parameters in preterm infants. The study measured a narrow set of outcomes over 22 months.
I have several concerns about this study. One is that the people who agreed to enroll fragile preterm infants are likely quite atypical. Recruitment of eligible babies was 24% (483/1965), meaning 75% of parents/guardians refused to participate—a problem for generalizability. The main outcome was neurodevelopmental measures as scored by the Bayley Scales of Infant and Toddler Development (BSID), and no immunological outcomes were measured other than indirectly via rates of necrotizing enterocolitis (NE). The study therefore potentially missed many subtle differences in immune status, though, interestingly, NE was twice as common in the formula group but deaths were similar.
Evidence is beginning to accumulate that lactation plays a complex and long-lasting role in creating offspring immunity, but it will take years to generate a substantial body of data. I predict this evidence will revolutionize our understanding of immune development and related disorders, and that when the molecular bases of maternal-offspring immune cross talk (a term coined by Prof. Ai Ing Lim, an immunological molecular biologist) are better worked out, formula likely will look very different and more closely approximate breastmilk.
Right now, however, we must acknowledge that we do not understand the long-term effects of not breastfeeding. We know that formula is not killing babies immediately and can be lifesaving. Yet, we understand very little about the long-term implications of foregoing the immune education of infants that happens through breastfeeding. There are also few-to-no downsides to breastfeeding if mother and family can make it work. Therefore, the preponderance of evidence argues for making a strong effort to do so (unless you live somewhere, for example, with radiation or heavy metal contamination).
Lim’s pioneering studies on maternal-offspring immune crosstalk look at the transfer of immune cells, and regulation of those cells by factors in breast milk, in mouse models and in humans. She, and many others, have found that immunity transfer from skin contact—presumably breastfeeding is a major source of this contact--from breast milk, and placentally are all important.
Much interesting mechanistic work on immune transfer is being done through cross-fostering studies on rodents. Darby et al., looked at “maternal immune imprinting of offspring nursed by mothers who had a pre-conception helminth infection. Nursing of pups by helminth-exposed mothers transferred protective cellular immunity to these offspring against helminth infection.” Interestingly, immune enhancement was not dependent on maternal antibodies, but derived from transferring maternally derived TH2-competent CD4 T cells via nursing. Lactation-acquired immunity was maintained into adulthood.
Many other cross fostering studies are finding support for what Lim calls her 'maternal-driven immune education' hypothesis, which she defines as maternal encounters that occur during critical developmental windows that drive optimal immune fitness—lactation being one such critical window. Many cross-fostering studies show that effects of nursing on offspring immunity can be lifelong, affecting susceptibility to both infection and inflammation. Researchers are just starting to learn how this happens.
This review (Nat. Rev. Gastroenterol Hepatol) reported:
“Breast milk contains microorganisms…which influence the developing infant and shape the intestinal microbiota. Therefore, breastfeeding is a unique mechanism of immune–microorganism transference to the neonate. Specific bacteria present in precolostrum…have also been found in the oral microbiota of neonates, which suggests a key role for maternal–neonatal microbial transfer in oral microbial assembly. Furthermore, breast milk microorganisms contribute to infant gut microbial colonization and stimulate the activation and differentiation of T cells and IgA-producing B cells in the newborn immune system. Human milk oligosaccharides can exert immune effects towards specific receptors in the intestine (for example, glycan receptors and TLRs) and immune cells (dendritic cells), modulating the adaptive immune response (via the T helper cell response), stimulating Treg cells and regulatory B cells, and having an effect on cellular and inflammatory gene regulation. [Note: citations removed for ease of reading.]
Other studies show that transfer of IgA, IgM, and IgE occur throughout lactation. IgA induces tolerance to antigens, in addition to providing barrier immunity at the mucosal level, and is completely absent from formula. Little is known about transfer of other Igs such as IgD. The Ig composition of breastmilk changes daily, even hourly, and varies by individual, and is so complex the term ‘immunoglobulinome’ has been coined to describe it. This high variability of breastmilk composition also makes it difficult to meaningfully compare breastmilk to formula. The composition of breastmilk is altered by the mother’s exposure to pathogens in her environment, her sleep, diet, microbiome, by the baby’s growth and caloric needs, and other factors.
IgA transferred via breastmilk is known to have tissue-specific activation in the gut, the tissue most likely to encounter pathogens in the neonate. These and other studies raise questions about how these maternal immune cells survive in the newborn gut and suggest that vaccination of breastfeeding mothers can be an efficient method to provide immunity to infants. Breastfeeding is also able to transfer Igs that protect the newborn from specific pathogens such as influenza, as shown in elegant studies by Chronopoulos et al., in which pregnant mothers infected with influenza virus transfer IAV-specific IgG1 to their offspring via both the placenta and breastmilk.
In an important study on immune inheritance, Ramanan et al. found that IgA helped establish a set point for ROR-gt+ Tregs (a specialized subpopulation of T cells that act to suppress immune responses, thereby helping tamp down inflammation and/or autoimmune attacks.) Their findings suggest that maternal IgA/ROR-gt+ Tregs transferred during breastfeeding prepare offspring for microbial encounters, while avoiding auto-inflammation and susceptibility to NE. In addition, amazingly, the effect persisted over multiple generations, in what the authors refer to as “transgenerational immune inheritance".
“Strain-specific maternal transfer of IgA levels via milk in early life leads to differential coating of microbes in the postnatal intestine, which modifies their stimulatory properties and their ability to induce RORγ+ Tregs… Finally, when the female mouse becomes pregnant herself, the low or high IgA traits are passed on via milk IgA, which repeats the cycle and ensures multi-generational transmission.”
Last, a promising area of research is studying effects of breastmilk on offspring weight gain, type 2 diabetes, and other chronic diseases. These mechanistic studies focus primarily on connections between breastfeeding and the baby’s microbiome, and the fact that bioavailability of many nutrients is different in formula than in breastmilk.
Researchers are studying the “bioactive components of milk, such as human milk oligosaccharides, lactoferrin, and secretory immunoglobulins” that modify neonatal microbiota and help seed the baby’s microbiome. Microbiome studies are a hot topic in metabolic disorder research, and we have little-to-no idea of whether disturbing the infant’s initial seeding of its microbiome--of which breastfeeding is a component, as well as through vaginal birth and skin contact—has lifelong consequences on weight, metabolism, gut health, and even depression/mental health.
These studies, and the fascinating mechanisms they are unraveling, reveal how little we know about the critical immune education window encompassed by lactation. We also know little about whether these effects are duplicated by other immune mechanisms acting through other pathways.
Of course, women should not be browbeaten to breastfeed. We need stronger policies that support women to nurse, not more guilt for women who do not or cannot. All or nothing solutions are not helpful. Mixing formula and breastmilk (what most women to do to some extent and for some period of time) probably helps women sustain nursing longer, for example, by giving formula during the day but nursing at night after work (the majority of American mothers go to work.)
Maybe… instead of using guilt or shame to promote breastfeeding, we can spread the word about research shining a light on the complex waltz between the mother’s and baby’s immune system, a dance that clearly extends beyond gestation and has far reaching, profound, and long-lasting effects on offspring immunity.
Leslie Bienen is a veterinarian whose research and writing focuses on zoonotic disease and associated policies. She recently left the OHSU-Portland State University School of Public Health in Portland, Oregon to do consulting work.
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This topic and Dr Bienen’s training as a veterinarian make me think of my hobby for the past 35 years, breeding and showing dogs.
We are instructed by our veterinarians that we are not to start immunizing our puppies until the mother’s protective immunity has waned after the weaning process. The first DHPP vaccine is typically given at 8, 12 and 16 weeks so that we can be sure to “hit” a good window of opportunity to create maximum protective effect for the growing dog, and to allow time for the immune system to mature adequately so the vaccine can be effective.
This is certainly different than the recommendations for human babies, breastfed or not. I look forward to following this research as it continues.
Investigating the effects of breastmilk on the development of the infant/child's immune system and the intestinal microbiome is a fascinating and important field.
One of the research questions that is so important is to what degree any beneficial immunoregulation and microbiome development conferred by breastfeeding can withstand subsequent hits to the microbiome, such as repeated antibiotics, overuse of chronic acid suppressant medications in infants and children, and high intake of high sugar, ultraprocessed foods with multiple additives which can adversely modify the microbiome later in life.