Extracellular Vesicles (mEVs) from Milk May Support Gut Health

 Written by: Alice Callahan, PhD | SPLASH! Issue # 115 | 2023

Researchers probed the gut-healing properties of extracellular vesicles isolated from both cow and human milk [1]. These tiny packages, called milk-derived extracellular vesicles (mEVs), are secreted from mammary cells and carry a cargo of lipids, proteins, and nucleic acids. The new research revealed promising effects of mEVs on the cells lining the gastrointestinal tract, indicating a potential therapy for the “leaky” gut barrier found in many gastrointestinal and metabolic diseases [1].

The GI tract is teeming with partially digested food, microbes, digestive enzymes, and toxins, and one of the main jobs of the intestinal lining is to be a selective barrier between that messy gut environment and the bloodstream. When the gut lining is working properly, it facilitates the absorption of vital nutrients but blocks less savory elements from entering. But when the gut lining is “leaky,” or overly permeable, it can expose the body’s cells to harmful molecules and allow bacteria and toxins to invade the bloodstream. A more permeable gut lining has been associated with a range of diseases, including inflammatory bowel disease, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis [2].

Because they can be orally administered and have been reported to survive the harsh environment of the digestive tract, mEVs have attracted attention as potential therapeutics. In a recent study published in April 2023 in the journal Science Advances, researchers from National University of Singapore and Ocean University of China set out to investigate how mEVs affect the gut barrier [1], adding to previous promising research by their group and others on both cow and human mEVs [3-4].

The research team reported results from a series of intricate experiments on mEVs. First, they isolated mEVs from both cow and human milk and studied their contents, finding that both types were rich in proteins and small nucleic acids known to be related to gut barrier function and inflammation. They looked at how mEVs affected intestinal cells—both isolated cells and those arranged in a single layer as a model of the intestinal lining—and found that mEVs decreased inflammation and increased the expression of proteins involved in intestinal barrier function. They also tested how well mEVs survived conditions that mimicked a trip through the digestive tract, awash in saliva and stomach, pancreatic, and bile juices. “We confirmed that mEVs remained intact after passage through oral-gastrointestinal digestive conditions,” the researchers wrote, referring to mEVs from both cow and human milk.

In the next series of experiments, cow mEVs were administered to mice and were found to reach both the small intestine and the colon, where they were absorbed by epithelial cells. Most importantly, in mouse models of colon inflammation and nonalcoholic steatohepatitis, oral mEV administration reduced intestinal inflammation, repaired the gut barrier, and even suppressed inflammation in the liver—indicating that mEVs have effects beyond the digestive tract.

Because gut inflammation and hyperpermeability are common features of so many diseases, these findings could have exciting implications, wrote Dr. Jiong-Wei Wang, an assistant professor of surgery and physiology at the National University of Singapore and a lead author on the paper, in an email interview with the SPLASH! editorial team. Wang added, “Our findings suggest that mEVs may be used for the treatment of a broad range of diseases instead of one single disease type.”

The milk we buy at the store contains mEVs, but to mimic the dose given to the mice in the study, you’d need to drink one liter, or about four cups, of milk per day, the researchers estimated in their paper. That’s more than is recommended in the Dietary Guidelines for Americans; plus, lactose is difficult to digest for about two-thirds of the world’s population [5). But the good news is that mEVs themselves, once extracted from milk, have very little lactose, wrote Wang. “They may be an alternative milk product for lactose-intolerant people,” he added.

Though the results are promising, more research is needed before mEVs can be promoted as a therapy for preventing or healing gut disorders. Currently, Wang and his colleagues “are trying to uncover the exact mechanism underlying the therapeutic effects of mEVs.” His team is also preparing to conduct clinical trials in humans, which will be necessary to see if the anti-inflammatory and gut-healing properties of mEVs observed in isolated cells and mice also occur in humans. And even though mEVs are found in cow milk, which has been consumed by humans for thousands of years, concentrated mEV therapeutics will need to be studied to determine appropriate dosing, whether they are safe, and if they cause side effects, Wang wrote in the interview with the SPLASH! editorial team.

That’s the incremental nature of scientific research, but the current study [1] paves the way for those future explorations of mEVs.

References

1. Tong L, Zhang S, Liu Q, Huang C, Hao H, Tan MS, Yu X, Lou CKL, Huang R, Zhang Z, Liu T, Gong P, Ng CH, Muthiah M, Pastorin G, Wacker MG, Chen X, Storm G, Lee CN, Zhang L, Xi H, Wang JW. Milk-derived extracellular vesicles protect intestinal barrier integrity in the gut-liver axis. Science Advances. 2023 Apr 9:eade5041.
2. Di Tommaso N, Gasbarrini A, Ponziani FR. Intestinal barrier in human health and disease. International Journal of Environmental Research and Public Health. 2021;18(23):1-23.
3. Tong L, Hao H, Zhang Z, Lv Y, Liang X, Liu Q, Liu T, Gong P, Zhang L, Cao F, Pastorin G, Lee CN, Chen X, Wang JW, Yi H.  Milk-derived extracellular vesicles alleviate ulcerative colitis by regulating the gut immunity and reshaping the gut microbiota. Theranostics. 2021 Jul 11:8570–86.
4. Zonneveld MI, van Herwijnen MJC, Fernandez-Gutierrez MM, Giovanazzi A, de Groot AM, Kleinjan M, van Capel TMM, Sijts AJAM, Taams LS, Garssen J, de Jong EC, Kleerebezem M, Nolte-‘t Hoen ENM, Redegeld FA, Wauben MHM. Human milk extracellular vesicles target nodes in interconnected signalling pathways that enhance oral epithelial barrier function and dampen immune responses. Journal of Extracellular Vesicles. 2021 Mar 10:e12071.
5. Storhaug CL, Fosse SK, Fadnes LT. Country, regional, and global estimates for lactose malabsorption in adults: a systematic review and meta-analysis. Lancet Gastroenterology and Hepatology. 2017 Oct 2:738–46.