Milk is Alive with Mom’s Cells

  • Breast feeding protects babies from disease.
  • Several types of mom’s cells are present in milk.
  • Fresh breast milk contains a new class of immune cells called innate lymphoid cells (ILCs).
  • ILCs may take up temporary residence in a baby’s gut tissues where they potentially aid protection of the baby from infections and gut inflammation, help train the baby’s developing immune system, and regulate the establishment of the microbiome in the gut.
  • ILCs in milk may protect the mother from infection in her baby and signal the need to change milk composition to aid fighting the infection.

 

Surprises upturn accepted routines and demonstrate how little we really know. A new class of immune cell type, innate lymphoid cells (ILCs), was recently and unexpectedly discovered in fresh breast milk [1], and it promises to radically alter scientists’ understanding of how milk protects babies from infections, and possibly much more. The ground-breaking scientific paper [1] describing this discovery was recently published in the prestigious Journal of the American Medical Association – Paediatrics by Babak Baban and three colleagues from Augusta University. The paper has the modest but revealing title “Presence and Profile of Innate Lymphoid Cells in Human Breast Milk.”

Breast Feeding Helps Protect Babies from Infections

Numbers talk, sometimes loudly. More than 80 years ago, Grulee and colleagues undertook a large study of 20,000 mother-infant pairs and demonstrated that breast-fed infants compared with non-breast-fed infants had strikingly higher chances of survival from various infectious diseases [2]. Investigators in many subsequent studies confirmed these results and concluded that something in fresh breast milk protects babies and infants from infections [3-6]. This advantage of breast feeding is important as babies are burdened by increased risk of infectious diseases due to their poorly developed immune defense system. But how does milk protect the very young from disease? A number of big surprises are now emerging!

Milk is well recognized for its nutritional benefits to babies. Moreover, there is substantial evidence that milk’s molecular components help to protect babies from infectious diseases [3,7]. The latter characteristic of milk is a consensus view that has withstood the test of time, but it largely ignores the role played by maternal cells in milk.

Milk Contains Large Numbers of Different Cell Types

Many investigators over the last 60 years reported that fresh milk contains maternal cells, including immune cells (leukocytes), stem cells (cells that can give rise to multiple cell types), and mammary cells shed from breast tissue [7]. The leukocytes include the usual well-known suspects in the immune defense system i.e. neutrophils, macrophages and lymphocytes. Each has a different functional role, like the army, navy, and air force, but they act together to fight infections. Babak Baban and colleagues reported that newborn babies ingest about 100 million maternal cells in milk every day; most of these cells are leukocytes [1]. In the past, scientists assumed milk cells must have little biological importance in the baby because it was thought that these cells could not survive in the acidic environment in the infant’s stomach and upper region of the small intestine. These ideas are now being challenged by Baban and colleagues [1] and Cabinian and colleagues [8].

The high abundance of leukocytes in milk, about a million cells in a milliliter, is a strong clue that their presence in milk is biologically important [3]; nature usually does not condone waste. Cabinian and colleagues, using a mouse model, demonstrated that milk leukocytes unexpectedly survived in the guts of mouse pups for several days [8]. This was the first big surprise. The second surprise was that some of the ingested maternal leukocytes were localized in the pups to small tissue masses in the wall of the intestine called Peyer’s patches. Peyer’s patches are specialized immune tissues that monitor and regulate bacterial populations in the intestine and prevent growth of disease-causing bacteria and parasites [9]. The survival of the ingested maternal leukocytes may be due to the less acidic gut of the nursing pup compared with the adult gut and the ready acceptance of these maternal cells by the immature Peyer’s patches [3]. Something similar could also occur to human breast-fed babies. This is startling news as it indicates that a baby may acquire some functional maternal leukocytes at a very early stage in life.

Cabinian and colleagues concluded that some milk leukocytes may directly protect the mother’s breast from infection while also supplementing the baby’s immature immune defense capability and possibly regulating the developing immune system of the baby [1,8]. The latter function is particularly important as the immature immune system of a baby is confronted by an onslaught of microbes colonizing its gastrointestinal tract. Therefore, the baby’s immune defense system must very quickly learn to tolerate good gut microbes and eliminate others that are a disease threat but without generating too much inflammation. A little help from mom’s leukocytes in the training of the baby’s immune system in the gut could be very handy at this time. Notably, once the pups ceased being nursed by the mother, there was rapid loss of the maternal leukocytes from the pup’s Peyer’s patches. Mom’s additional cellular help did not persist in her absence.

A New Class of Immune Cells is Present in Milk

Baban and colleagues analyzed the different types of leukocytes present in fresh breast milk. They used a machine that sorts individual cells based on fluorescent antibodies that bind to specific proteins on the surface of cells [1]. Leukocytes contain specific cell surface proteins that can be used for their detection and separation from non-leukocytes. The well-known classes of leukocytes were then easy to spot as each has additional and characteristic protein markers on their cell surfaces. The recently discovered class of leukocytes called innate lymphoid cells (ILCs) are much harder to find and isolate because they do not carry any known cell surface markers that are characteristic of only ILCs. Baban and colleagues used the absence of cell surface markers characteristic of all of the well-known leukocyte classes to isolate ILCs away from other leukocytes using samples of fresh breast milk. This was the third big surprise for this area of research; a new class of leukocytes was present in milk. Moreover, all three subtypes of ILCs were present in fresh breast milk. The ILC subtypes were identified by their differing abilities to produce specific proteins that communicate with other leukocyte classes. Scientists have started to document some of the functions of ILCs, but it is early days yet.

All defensive forces require a general who efficiently coordinates the army, navy, and air force to ensure a rapid and effective response to an invasion. ILCs, unlike the other classes of leukocytes, usually do not get directly involved in the battle against disease, but they stay in the background and coordinate the defense, just like a general. Their job is to sense injured cells in infected tissue and then send out protein signals to rapidly attract the business end of the immune defense system, the macrophages, lymphocytes, and neutrophils. These three are deadly to microbes, but they need to be carefully controlled by ILCs to prevent too much inflammation at the site of the infection, which can cause collateral damage to cells. Milk ILCs have not been formally shown to take up residence in the intestine of the baby, but this is likely as the leukocytes (mainly cytotoxic T cells) shown to be present in the intestinal tissue require command and control signals to keep them in line.

ILCs have an impressive resumé of specialized biological roles, including resistance to infectious microbes and parasites, regulation of inflammation, involvement in tissue remodeling, surveillance of the body for tumors, and the maintenance of energy balance in the body [10-12]. This diverse expertise of ILCs and their ability to direct the activities of other immune cells makes them very useful. Conversely, dysfunction of ILCs can lead to infections, allergies, asthma, autoimmune diseases, and obesity [10-12].

One of the functions of the ILC3 subclass is the ability to modulate the intestinal microbiome [13, 14]. Baban and colleagues suggest that maternal ILCs in milk could regulate the baby’s innate immune system and shape the establishment of the intestinal microbiome, which is essential to initiate the digestive functions of the rapidly developing infant. Some investigators also argue that the microbiome is important for prevention of various diseases [15]. Baban and colleagues additionally speculated that ILCs may somehow signal to the mother that a baby has an infection, thereby triggering a change in the composition of her milk to better fight the infection and protect the mother—milk is certainly dynamic. This is biological finesse at its best.

Implications

Baban and colleagues indicated that ILCs in milk do not survive refrigeration [1]. This observation may help explain why breast-fed infants have a lower risk of infections. The many functions of ILCs in the context of maternal ILCs in ingested milk that potentially take up residence in a baby’s intestinal Peyer’s patches may be fertile ground for future scientific explorations. The growing realization by scientists that there is often an early life origin of many adult diseases of increasing incidence in modern populations emphasizes the urgent need for these explorations.

 

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15. Tuddenham S, Sears CL. The intestinal microbiome and health. Curr Opin Infect Dis. 2015;28(5):464-470.

 

Contributed by
Dr. Ross Tellam (AM)
Research Scientist
Brisbane, Australia