Human milk immune activity may both lower and increase infants’ infectious disease risk

By Dr. Liji Thomas, MDReviewed by Benedette Cuffari, M.Sc.Jul 7 2022

The human immune system is complex and carefully regulates itself to optimize its protective effects while preventing unwanted inflammatory responses to arise due to misdirected immune activity.

Study: Tradeoffs in Milk Immunity Affect Infant Infectious Disease Risk. Image Credit: Rohappy / Shutterstock.com

Introduction

Breastfeeding has been recognized and recommended by the medical community as the best possible source of nutrition and immunological protection for the newborn and early infancy period. Moreover, breastfeeding has been proven to reduce the rates of respiratory infections and other infectious diseases as compared to formula-fed infants.

These protective effects of breast milk are primarily mediated by the immune system of milk (ISOM). The ISOM includes white cells, antibodies, cytokines, which are signaling molecules produced by immune cells, and antimicrobial factors such as lysozyme.

Taken together, these molecules can target many infective agents in the gut and help elicit an immune response by the body in combination with the gut-associated lymphoid tissue (GALT) in the infant.

The ISOM also contributes white cells to the thymus of the infant. The thymus is the source of T-cells, which are key to humoral and cellular adaptive immunity.

Within the thymus, T-cells from the ISOM ensure long-term immunological memory of infectious agents encountered by the infant. Thus, the ISOM protects infants from infectious diseases.

The composition of the ISOM varies between breastfeeding women. The level of secretory immunoglobulin A (sIgA), a primary component of mucosal immunity that neutralizes many pathogens upon their entrance into the mucosa of the respiratory, gut, and urinary systems, is one such variable.

Prior research has shown that anti-Campylobacter, anti-Shigella, and anti-Giardia sIgA reduced the risk for these diseases among infants, while higher total sIgA was associated with lower diarrheal disease risk. A higher level of anti-inflammatory factors in milk was linked to greater length-for-age in infants as well.

Taken together, the higher the activity of the ISOM, the greater the protection for the infant. However, the immune response can occasionally be hyperactive in certain body sites, thereby causing tissue damage while attacking pathogens.

A hyper-inflammatory response can cause widespread tissue injury and endanger life. An aberrant immune response to a non-harmful agent produces allergic and autoimmune reactions.

In these situations, the immune system may target beneficial microorganisms present within the body, thus predisposing the affected individual to certain chronic diseases. This presents a central challenge of immune system evolution, in which the multifactorial costs and benefits of immune activity must be balanced.

The breadth of impact of various immune response pathways is responsible for this unintended harm. This is coupled with the high cost to the body in terms of nutrient consumption and energy expenditure of immune reactions.

During infancy, the need to protect the immature organism from long-term or fatal harm may cause the ISOM to provide more intensive protection against infections; however, this may also cause more adverse effects. Over time, the ISOM modulates the immune system to achieve a balance between these effects, thereby helping to establish a healthy microbiome in the gut and reducing the risk of autoimmune or other immunological disease mechanisms.

About the study

The current Evolution, Medicine, & Public Health study discusses the short-term effects of the ISOM on infant health. Using four parameters including sIgA and the cytokines interleukin-6 (IL-6), IL-10, and interferon-γ (IFN-γ), the scientists assess the immune activity in breast milk in response to Salmonella enterica and Escherichia coli, both of which are common enteric bacterial species.

Both sIgA and IL-6 reflect immune antibody response and pro-inflammatory activity, respectively. Comparatively, IL-10 and IFN-γ are anti-inflammatory and T-helper type 1 cell (Th1) promoting in nature, respectively.

The researchers were primarily interested in determining whether higher levels of these ISOM biomarkers against S. enterica would result in greater protection of infants against infection when exposed to this pathogen. The current study also sought to ascertain whether higher ISOM activity against non-pathogenic bacteria would cause collateral damage that could ultimately impact infant health.

Study: 3D illustration of Salmonella Bacteria. Image Credit: urfin / Shutterstock

Study findings

Using breast milk samples from 85 mothers, a wide range of measurements in sIgA and IL-6 were identified. More specifically, IL-6 was found to vary both at baseline and after exposure to the two bacterial species, Nevertheless, this cytokine exhibited a robust response against these microbes.

Comparatively, IL-10 and IFN-γ did not vary significantly in their response to both bacteria. Thus, these levels were not measured further.

While there were approximately two cases of respiratory infection per 100 children per day, higher sIgA and IL-6 responses to S. enterica were associated with lower respiratory infection rates. The response of IL-6 to E. coli showed an inverse association with respiratory infection but a positive association with gut infections.

Overall, the IL-6 responses to these microbes predicted infectious disease risk among infants. However, the response to S. enterica appeared independent of that to E. coli but not vice versa.

If the response of IL-6 to S. enterica was assessed as a Yes/No variable in terms of any increase or not, it was found to be protective against infectious disease, while the response to E. coli did not show a significant association. If used as a spectrum of responses, the IL-6 response to these two microbes showed opposing effects.

That is, IL-6 responses to S. enterica reduced the risk of respiratory infections and pneumonia by 32%, as well as upper respiratory infections by 30%. When IL-6 levels doubled, the respiratory infection risk declined by 23%.

However, IL-6 levels in response to E. coli stimulation increased the risk of gut infection by 44%. With each doubling of the response, the risk increased by 29%.

Overall, the doubling of the IL-6 response to S. enterica reduced the risk of any infection by 17%. However, with E. coli, IL-6 response doubling was associated with a 20% increase in infectious disease risk.

Other infant characteristics such as age, sex, weight-for-length, and preterm birth did not appear to affect the ISOM activity. The IL-6 responses to these bacteria were analyzed by binary models to discern any relationship to age. To this end, IL-6 levels, when exposed to E. coli, were less strongly associated with respiratory infection risk, or any infectious disease risk, as the infant grew older.

Implications

When exposed to the pathogenic bacterium S. enterica, the ISOM response showed appropriate pro-inflammatory activity that significantly reduced the risk that the infant would develop any infectious disease of the respiratory tract. Although this microorganism is primarily found in the gut, no protection was provided against gut infection.

Thus, the pro-inflammatory activity of the ISOM appeared to reinforce the systemic immune responses of the infant, rather than acting in the gut against bacterial invaders.

Conversely, the response to the relatively benign E. coli could stimulate unwanted pro-inflammatory activity elsewhere. Indeed, this response was associated with higher gut infection risk, but only at higher levels of IL-6.

This exclusive increased risk of gut infection alone appears to indicate that it is caused by inappropriate ISOM activity in the infant gut. This response could therefore perturb the developing microbiome and allow pathogens to infect the infant's gut.

This points to the existence of ‘tradeoffs’ in the ISOM. For example, during a situation where the infant is exposed to greater infection risk, an enhanced immune response may be activated, thus reducing the growth rate. However, during periods of rapid growth, immunity may be low.

Our findings make clear that, as elsewhere in the immune system, ISOM proinflammatory activity has both benefits and costs, and caution against simple interpretations of milk immune content or activity as exclusively beneficial to infants.”

Further studies will be needed to validate the findings of this in vitro study and compare ISOM activity in multiple settings.