Milk-Derived Extracellular Vesicles: A Drug and Drug Carrier

Within the past 5 years, extracellular vesicles (EVs) have emerged as an exciting potential nanotherapy for various gastrointestinal and inflammatory disorders. New research has focused on the role of these particles, which are secreted by cells and involved in regulating complex biological processes in nearly all living organisms. EVs were found to have a particularly central role in regulating the intestinal barrier and immune responses related to the gut. Given their close relationship with immune and metabolic health, EVs have become a new therapeutic target with the potential to revolutionize the treatment of a wide range of diseases.

Importance of the Intestinal Barrier

The gastrointestinal tract is constantly exposed to outside pathogens. As a result, a method of filtering what is transported into the bloodstream is vital to both maintaining nutrition and preventing infection. The intestinal barrier accomplishes this critical function. It does so by allowing for the passage of nutrients to the bloodstream while also preventing the entry of toxic substances. Without this barrier, harmful entities could potentially enter the circulation. 

The mucus layer is a specific part of the intestinal barrier known for its defense function. Mucus, a gel-like substance secreted from the GI epithelium, protects the cells covering the GI tract from harmful exposures such as gut bacteria, high acid levels, and food-associated toxins. A defective mucus layer can lead to loss of protective function and subsequent epithelial damage, which can have serious consequences. 

Located directly beneath the mucus layer is another part of the intestinal barrier- epithelial cells linked together by tight junctions. These cells are the main site of communication between the gut microbiome and the underlying gastrointestinal-associated lymphoid tissue, which functions in immune response. There is a very close association between the intestinal barrier and immune function, which explains the connection between gut health and inflammatory diseases. Evidently, maintaining an effective intestinal barrier is vital to overall health. As a result, the intestinal barrier has become a highly studied therapeutic target. 

Intestinal Barrier Damage: Risk Factors and Disease Associations

A wide variety of risk factors and diseases are associated with intestinal barrier damage. Major risk factors include:

• Chronic alcohol use
• Smoking
• Obesity 
• Overuse of NSAIDS, such as ibuprofen or aspirin
• Food allergies, which can lead to repeated inflammation
• Diet high in fats and sugars, which can cause dysbiosis of the gut microbiome

The major diseases tied to intestinal barrier damage are most commonly GI conditions but can include disorders outside of the GI tract. Some key examples are:

• Celiac disease, which induces an immune response to gluten
• Inflammatory bowel disease, including Crohn’s disease and ulcerative colitis
• Colon carcinoma
• Chronic liver disease
• Diabetes, particularly Type I
• Infections, such as sepsis
• Malnutrition
• Rheumatoid arthritis, an inflammatory disease that affects the joints

All of these diseases have a similar proposed mechanism in which there is uncontrolled “leakage” of toxic substances across the damaged intestinal barrier, leading to an immune response. This immune response may affect the GI tract but also can have a detrimental impact on distant organs. 

What Are EVs and mEVs?

On a positive note, all of the aforementioned diseases have the potential to be treated with EVs. EVs are small nanoparticles released by nearly all cells in the body. It is hypothesized that they serve as a method of intercellular communication. They do so by carrying proteins and microRNA, a signaling molecule that can initiate a vast range of biological processes when it is released in a target molecule. EVs can travel to reach their target molecules by various methods, one of which is transport through breast milk. Specific EVs that travel through milk are referred to as milk-derived extracellular vesicles, or mEVs. 

Potential Utility of mEVs in Disease Treatment

mEVs have recently been found to have revolutionary protective and restorative effects on the intestinal barrier. However, the research regarding their function and mechanisms of action is relatively new and therefore has mostly been done on mouse models. Nevertheless, the findings show promise for future treatment of human disease. 

More specifically, it has been shown that mEVs promote integrity of the gut barrier by increasing mucus secretion, improving tight junctions between epithelial cells, and regulating inflammatory responses. This not only has a protective effect on the gut itself, but can also affect other organ systems through its mediation of immune responses. mEVs have been shown to have both protective and suppressive effects on the immune system, suggesting a dual regulatory role for these nanomolecules. Recent evidence has shown that, through these mechanisms, mEVs have a therapeutic effect in several diseases, including liver disease and acute malnutrition. They have also been proposed as a potential drug delivery mechanism.

Milk-derived extracellular vesicles protect intestinal barrier integrity in the gut-liver axis

Liver Disease
In a 2023 study, oral administration of mEVs improved both colitis and non-alcoholic fatty liver disease, its root cause, in mouse models. Local inflammation of the colon caused by the liver pathology was ameliorated. Interestingly, inflammation and scarring in the liver were markedly decreased after mEV ingestion as well, suggesting a systemic effect of the nanoparticles.

Severe Acute Malnutrition (SAM)
A 2021 article discussed the impact of mEVs on a mouse model of severe acute malnutrition, a disease that causes atrophy of the intestinal epithelium and disrupts its barrier function. Results showed that mEVs induced restoration of the villous architecture of the small bowel epithelium and improved intestinal barrier function to normal levels. 

Drug Delivery
Since mEVs can survive the harsh environment of the gut, they have also been proposed as a drug delivery mechanism. The mEVs themselves do not cause an immune response and are generally better tolerated than traditional mechanisms of drug delivery, such as liposomes. Their lipid bilayer effectively protects drugs, and their efficient uptake into target cells provides an optimal route of administration.

Summary

mEVs are a promising therapeutic method for various gastrointestinal and inflammatory disorders. The intricate relationship between these nanomolecules and the intestinal barrier underlies their potential to revolutionize disease treatment. Exciting research findings have demonstrated the therapeutic potential of mEVs in conditions such as liver disease and severe acute malnutrition. Additionally, the prospect of utilizing mEVs as a drug delivery mechanism has advantages over traditional methods. As investigations into the function and applications of mEVs continue to evolve, they hold promise as a transformative tool in GI and inflammatory disease management.