Analysis of the lactose back-defusion theory of hyperlactation

Currently, the dominant hypothesis concerning hyperlactation (Eglash 2023) claims that hyperlactation causes

• Decreased organisation of the tight junctions between lactocytes

  • Which allows lactose to pass back through lactocyte tight junctions to attach to base of the lactocyte and inhibit milk secretion (in addition to the action of bioactive factors such as serotonin which are proposed to signal back to the lactocyte and inhibit milk secretion)

  • Which allows lactose to pass back through lactocyte tight junctions into the stroma to increase interstitial fluid volume, resulting in 'oedema'

• This lactose-triggered 'oedema' causes

  • Blood vessels near the lactocytes to narrow, which reduces nutrients going to the lactocytes

  • Compression on the lactiferous ducts, resulting in blocked ducts

  • Raised stromal pressure which compresses the lactiferous ducts, resulting in clinical presentations of 'blocked ducts'.

I propose that this theory, which is wrongly presented as fact, lacks biological plausibility. It fails to address the following questions.

1. Why does lactose pass back through 'weakened' tight junctions? The proponents of the lactose back-defusion theory cite two research papers, both of which demonstrate that cytokines or inflammatory factors are associated with weakened tight junctions between lactocytes. They appear to be claiming that idiopathic inflammation (unknown origin) weakens the tight junctions, which then let lactose through.

2. How does lactose attach to lactocyte base to inhibit milk production? It is widely accepted that high total loads of lactose in the alveoli result in decreased milk production. But there is no evidence supporting the theory that lactose acts directly on the base of the lactocytes to downregulate supply.

3. Why do the myoepithelial cells and also the basement membrane, which are known to jointly constitute a 'fence' or barrier, let nanoparticles of lactose through, contrary to the physiological flow of solute defusion?

I apply the principle of Occam's razor to propose that when lactocyte tight junctions are mechanically stretched, high levels of inflammatory factors will be measurable in the vicinity of the tight junctions due to tight junction mechanosensing and mechanotransduction.

Inflammatory factors further weaken the tight junctions, due to the effects of the inflammatory cascade. Alveoli disintegration may result, with mechanical and inflammatory breaching of the basement membrane. This will be accompanied by lactose spreading into the extracellular miatrix, and is followed by cell apoptosis. The ongoing inflammatory cascade may result in the clinical presentation of breast inflammation.

The two research studies used to cite support of the lactose back-defusion theory don't actually support this theory

There are two research studies which proponents of the lactose back-defusion theory use to support the theory (Eglash 2023). Neither corroborate the lactose back-defusion theory - but both, when read closely, corroborate the NDC mechanobiological model.

• Kobayashi et al 2021, in their study of mice mammary gland tissue extracts in laboratory cultures, showed that tight junctions (claudin and occluding proteins) deteriorate when preparations of inflammatory cytokines are added to the culture.

• Stelwagen & Singh 2014 conducted a review of the research (predominantly dairy cattle) concerning the role of tight junctions (claudin and occludin) in mammary gland function. They found that tight junction integrity is compromised during mammary involution and also with mammary inflammation. They noted that tight junctions prevent the paracellular transport of ions and small molecules between the blood and milk compartments. Loss of tight junction integrity is linked to reduced milk secretion and mammary function and increased paracellular transport of blood components into milk and vice versa. The interlactocyte tight junction is linked to an active role in intracellular signalling, since tight junction proteins are linked by scaffolding proteins to the cell's cytoskeleton.

Selected references

Eglash A. Academy of Breastfeeding Medicine Webinar on Breast Inflammation. 2 August 2023.

Shams A. Re-evaluation of the myoepithelial cells role in the breast cancer progression. Cancer Cell International. 2022;22(403):https://doi.org/10.1186/s12935-12022-02829-y.

Chang J, Chaudhuri O. Beyond proteases: basement membrane mechanics and cancer invasion. Journal of Cell Biology. 2019;2018(8):2456–2469.

Kobayashi K, Matsunaga K, Tsugami Y. IL-1β is a key inflammatory cytokine that weakens lactation-specific tight junctions of mammary epithelial cells. Experimental Cell Research. 2022;409(2):112938.

Fiore A, Yu G, Northey JJ. Live imaging of the extracellular matrix with a glycan-binding fluorophore. Nature Methods. 2024:https://doi.org/10.1038/s41592-41024-02590-41592.

Stelwagen K, Singh K. The role of tight junctions in mammary gland function. Journal of Mammary Gland Biology and Neoplasia. 2014;19:131-138.