A Human Milk Oligosaccharide Protects Against Intestinal Infection and Inflammation

  • Campylobacter jejuni is a major cause of intestinal inflammation and diarrhea worldwide.
  • Sugars found in human milk, called human milk oligosaccharides (HMOs), have been shown to protect against intestinal infections.
  • Studies have found that an HMO called 2’-fucosyllactose (2’-FL) can inhibit C. jejuni binding to intestinal cells.
  • A new study finds that 2’-FL inhibits C. jejuni infection and associated inflammation in vitro in human cells and in vivo in a mouse model.
  • 2’-FL was protective when given to mice before C. jejuni infection, which suggests that it also acts as a prebiotic to restore healthy gut microbiota.
  • Once the results are replicated in clinical trials, 2’-FL could potentially be used to prevent or treat C. jejuni and other intestinal infections in humans.

 

Sugars found in human milk, called human milk oligosaccharides (HMOs), have various protective effects against intestinal infections [1–4]. A new study finds that the HMO 2’-fucosyllactose (2’-FL) protects against infection and inflammation caused by the pathogen Campylobacter jejuni [5].

Campylobacter is a major cause of infant diarrhea in many parts of the world, and that was what got us interested early on,” says David Newburg, who conducted the new study at Boston College. “We wanted to be able to help young children globally,” he says.

Previous work showed that breast milk with higher levels of 2’-FL was associated with a lower risk of C. jejuni-caused diarrhea in infants [6, 7]. “What we found was that pure 2’-FL was sufficient to fight this disease,” says Newburg. “It seems as though this molecule found in human milk is very well designed to protect infants from disease,” he says.

Newburg has long been interested in studying the protective effects of HMOs against Campylobacter. “Back in 1985, when we were investigating the effects of the HMOs in terms of any protective potential, Campylobacter was one of the pathogens that was inhibited by HMOs, and we localized that effect to 2’-FL,” he says.

bigstock-medical-bacteria-illustration-95919002But Newburg ran into a problem when trying to test the effects of purified 2’-FL. “At the time we didn’t have enough 2’-FL to do any more than in vitro tests,” he says. “It was only when we got enough 2’-FL to be able to feed to animals that we were able to test its actual effects in vivo in an animal model,” says Newburg. “This was not economically feasible until Glycosyn, our company, put together a method to have bacteria make 2’-FL, and to do that in such amounts that it became possible to do these experiments with mice,” he says.

Before Newburg could test the purified 2’-FL in mice, he and his team first developed a suitable mouse model for human C. jejuni infection. “Usually mice cannot be effectively infected by human Campylobacter,” he says. “To get a human clinical strain to attack the mice and colonize it in a meaningful way, we treated with antibiotics ahead of time, and that caused the mice to have disrupted gut microbiota, and made the gut much more vulnerable to growth by the human pathogen,” he says.

When the researchers treated human cells with 2’-FL, it greatly reduced C. jejuni invasion and associated inflammation. Similarly, when mice ingested 2’-FL, they experienced less C. jejuni colonization and reduced intestinal inflammation. When the researchers gave 2’-FL to mice three days before C. jejuni infection, they found that it was protective against inflammation and intestinal damage.

C. jejuni needs to bind to host sugars to infect intestinal cells, and previous work found that HMOs, and particularly 2’-FL, can block this binding [4,8,9]. Newburg and his team found that 2’-FL also had a couple of additional tricks up its sleeve. Not only did 2’-FL block C. jejuni binding and infection in intestinal cells, but it also inhibited the release of pro-inflammatory signals, and acted as a prebiotic to help restore normal healthy gut microbiota. “It’s fascinating that this one molecule can have these three very different effects,” says Newburg.

The results suggest that adding 2’-FL to food could help protect against intestinal infections. “It could be formula, it could be a supplement for a mother who’s breast feeding, it could be a supplement for a kid, or it could be added to the diet for a child who’s weaned, in all cases it looks like 2’-FL will protect against Campylobacter,” says Newburg.

But there is more work to be done before 2’-FL can be used therapeutically in humans. “I think there are two directions to go in; one is to move towards clinical trials, and the other is to do further research on mechanisms of this protection,” says Newburg.

By including other HMOs besides 2’-FL, the researchers could eventually target a broader range of pathogens. “We’re hoping that with a cocktail of HMOs we’ll have something that’s more universal,” says Newburg. “I think it’s very, very hopeful.”

 

1. Newburg DS, Walker WA. Protection of the neonate by the innate immune system of developing gut and of human milk. Pediatr Res 2007;61:2–8.
2. Morrow AL, Rangel JM. Human milk protection against infectious diarrhea: implications for prevention and clinical care. Semin Pediatr Infect Dis 2004;15:221–8.
3. Newburg DS, Ruiz-Palacios GM, Morrow AL. Human milk glycans protect infants against enteric pathogens. Annu Rev Nutr 2005;25:37–58.
4. Morrow AL, Ruiz-Palacios GM, Jiang X, Newburg DS. Human-milk glycans that inhibit pathogen binding protect breast-feeding infants against infectious diarrhea. J Nutr 2005;135:1304–7.
5. Yu ZT, Nanthakumar NN, Newburg DS. The human milk oligosaccharide 2′-fucosyllactose quenches Campylobacter jejuni-Induced inflammation in human epithelial cells HEp-2 and HT-29 and in mouse intestinal mucosa. J Nutr. 2016;146:1980-1990.
6. Newburg DS, Ruiz-Palacios GM, Altaye M, Chaturvedi P, Meinzen- Derr J, Guerrero Mde L, Morrow AL. Innate protection conferred by fucosylated oligosaccharides of human milk against diarrhea in breastfed infants. Glycobiology 2004;14:253–63.
7. Morrow AL, Ruiz-Palacios GM, Altaye M, Jiang X, Guerrero ML, Meinzen-Derr JK, Farkas T, Chaturvedi P, Pickering LK, Newburg DS. Human milk oligosaccharides are associated with protection against diarrhea in breast-fed infants. J Pediatr 2004;145:297–303.
8. Day CJ, Tiralongo J, Hartnell RD, Logue CA, Wilson JC, von Itzstein M, Korolik V. Differential carbohydrate recognition by Campylobacter jejuni strain 11168: influences of temperature and growth conditions. PLoS One 2009;4:e4927.
9. Ruiz-Palacios GM, Cervantes LE, Ramos P, Chavez-Munguia B, Newburg DS. Campylobacter jejuni binds intestinal H(O) antigen (Fuc alpha 1, 2Gal beta 1, 4GlcNAc), and fucosyloligosaccharides of human milk inhibit its binding and infection. J Biol Chem 2003;278:14112–20.

 

Contributed by
Dr. Sandeep Ravindran
Freelance Science Writer
Sandeepr.com