The protective role of inflammation in the lactating breast: activation of milk microbiome, somatic cells, and fever

The mammary immune system responds to and aims to downregulate physiological stress

From a complex systems perspective, when the mammary gland immune system is stressed by areas of alveoli rupture, due to high back pressures in the alveoli, a wound-healing inflammatory response ensues. Multiple feedback loops within the breast stroma, the microbiome, and cells of the milk are activated to re-assert homeostasis or equilibrium.

From an evolutionary perspective, activation of the milk microbiome, milk cells, milk metabolome, and other aspects of the mammary gland immune system are intended to successfully suppress positive feedback loops and protect the host.

The breast stroma responds to and aims to downregulate physiological stress

A very active wound-healing or inflammatory response needs to occur in the breast stroma surrounding the alveolar glands and ducts before the breast stroma inflammation presents clinically. Inflammation of the breast stroma aims to downregulate the physiological stress of tightly stretched tight junctions between the alveoli, and ruptured alvoli and basement membranes. You can find out about this here. Breast stroma contains a low-count microbiome of bacteria, which will also alter as part of the inflammatory or wound-healing response.

The milk microbiome responds to and aims to downregulate physiological stress

The milk microbiome participates in the activation of myriad immune feedback loops within multiple complex systems (for example, micro-organisms interact together, with the milk metabolome, with milk oligosaccharides, with milk leukocytes, and many other factors) to maintain physiological integrity and health.9

Although it’s not clear yet why counts of some bacteria increase in milk during an episode of breast inflammation, this does not necessarily signal a pathogenic process which requires antimicrobial intervention. For example, toxins and degrading enzymes secreted by specific bacteria promote the wound-healing environment required for rapid degradation of involuted alveoli and cell debris.

Bacterial communities are highly dynamic. For example

• Antimicrobial-induced disturbance of milk microbiota is quickly reversed.

• During an episode of breast inflammation, total bacterial counts climb, with decreased diversity of species, and higher counts of those species identified, often including Staphylococcus.

Applying a complex systems lens, these perturbations characterise an ecosystem adapting under stress, acting to restore equilibrium through upregulation of some feedback loops and downregulation of others.

Leukocytes in human milk respond to and aims to downregulate physiological stress

Human milk leukocyctes form a complex system, operating within the many complex adaptive systems of mammary gland immunity.

• During the clinical presentation of lactation-related breast inflammation typically diagnosed as mastitis, leukocyctes increase to comprise 95% of human milk cells (also known as somatic cells).

• Antimicrobial proteins, granulysin, perforin, and other granzymes released by leukocyctes in human milk are also elevated.

• Leukocyte concentrations return to normal with resolution of clinical symptoms.

Milder lactation-related inflammatory conditions such as painful nipples or blocked ducts show less dramatic but measurable leukocyte count increases in milk.

Leukocytes pass through lactocyte or mammary epithelial cell tight junctions into milk, in response to mechanical strain or rupture of tight junctions. They are recruited to downregulate inflammation in the ensuing wound-healing environment.

The NDC mechanobiological model of breast inflammation proposes that high leukocyte counts are associated with decreased bacterial diversity because leukocytes phagocytose bacteria and secrete antimicrobial factors.

Certain bacteria, for example, Staphyloccus aureus, are well-adapted in human environments and more resilient despite high leukocycte counts, and are more likely to survive as the leukocyte counts increase.

Fever is part of the mammary immune system's response to stress and aims to downregulate physiological stress

In 2007, Kvist et al conducted a study of 154 lactating women presenting to a midwifery clinic with breast inflammation, who had been symptomatic for between 1-7 days prior to presentation. Although 52% had an elevated temperature at their initial visit, no association was found between fever at presentation and antibiotic use or outcomes.12 In a 2010 analysis, Kvist points out that the high levels of leukocyctes and c-reactive protein associated with mastitis indicate inflammation, not bacterial load.13 Kvist et al’s findings are supported by recent work on the immune homeostatic role of fever.

Fever may be activated either by pathogenic micro-organisms or by internal cell and tissue damage. Applying the mechanobiological model of breast inflammation, when alveolar breakdown is identified either by mammary epithelial cells, milk microbiota, or stromal leukocyctes, signaling networks are activated and pro-inflammatory cytokines released. When a critical mass of alveolar collapse has occurred, clinical inflammation along a spectrum of signs emerges, developing into hyperemia, pain, and fever.

Higher body temperatures are known to drive the activity of proteins which switch on genes responsible for further recruitment of the body’s cellular immune response, in particular neutrophils, which phagocytose cell debris.14 Overly aggressive use of anti-pyrectics may interfere with the homeostatic role of fever in the human immune system, and this is likely to be the case in the mammary immune system too.

Selected references

Hassiotou F, Geddes DT. Immune cell-mediated protection of the mammary gland and the infant during breastfeeding. Advances in Nutrition. 2015;6:265-75.

Twigger aJ, Kuffer GK, Geddes DT, Filgueria L. Expression of granulisyn, perforin and granzymes in human milk over lactation and in the case of maternal infection. Nutrients. 2018;10:1230.

Hassiotou F, Hepworth AR, Metzger P. Maternal and infant infections stimulate a rapid leukocyte response in breastmilk. Clin Transl Immunology. 2013;2:e3.

Fernandez L, Pannaraj PS, Rautava S, Rodriguez JM. The microbiota of the human mammary ecosystem. Frontiers in cellular and infection microbiology. 2020;10:Article 5866667.

Mediano P, Fernandez L, Jimenez E. Microbial diversity in milk of women with mastitis: potential role of coagulase-negative staphylococci, viridans group streptococci, and corynebacteria. Journal of Human Lactation. Arroyo, Rebeca;33(2):309-18.

Sakwinska O, Bosco N. Host microbe interactions in the lactating mammary gland. Frontiers in Microbiology. 2019;10:doi:10.3389/fmicb.2019.01863.

Kvist L. Diagnostic methods for mastitis in cows are not appropriate for use in humans: commentary. International Breastfeeding Journal. 2016;11(2):doi 10.1186/s13006-016-0061-1.

Ingman WV, Glynn DJ, Hutchinson MR. Inflammatory mediators in mastitis and lactation insufficiency. Journal of Mammary Gland Biology and Neoplasia. 2014;19:161-7.

Kvist L, Larsson BW, Hall-Lord ML, Steen A, Schalen C. The role of bacteria in lactational mastitis and some considerations of the use of antibiotic treatment. International Breastfeeding Journal. 2008;3(6):doi:10.1186/746-4358-3-6.

Kvist LJ. Toward a clarfication of the concept of mastitis as used in empirical studies of breast inflammation during lactation. Journal of Human Lactation. 2010;26(1):doi:10.1177/0890334409349806.

Harper CV, Woodcock DJ, Lam C. Temperature regulates NF-kB dynamics and function through timing of A20 transcription. The Proceedings of the National Academy of Sciences. 2018;115(22):E5243-E9.

Evans SS, Repasky EA, Fisher DT. Fever and the thermal regulation of immunity: the immune system feels the heat. Nat Rev Immunol. 2015;15(6):335-49.