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Human Milk Sugars Help Reduce Infections That Cause Preterm Births

    sleeping baby, blue blankets, human milk sugars (HMOs), preterm births, infection

    Written by: Sandeep Ravindran, Ph.D. | Issue # 118 | 2024

    • Group B Streptococcus (GBS) infections are a major cause of preterm births.
    • Sugars found in human milk, called human milk oligosaccharides (HMOs), were found to inhibit GBS infection and reduce inflammation in mice and human tissues.
    • HMOs could thus have potential therapeutic applications against GBS infections in humans and could help reduce preterm births.

    Preterm births are a major global problem, affecting approximately 11.1% of all pregnancies worldwide and nearly 10% of all pregnancies in the United States (1). Microbial infections are a major cause of preterm births, and are responsible for 40% of preterm births in the United States. Bacterial infections can lead to an inflammatory response that can then cause premature onset of labor. Streptococcus agalactiae or Group B Streptococcus (GBS) is one of the most common pathogens responsible for such infections.

    GBS is a commensal bacterium often found in the human gastrointestinal and reproductive tracts. It can cause opportunistic infections that lead to adverse pregnancy outcomes such as preterm birth and stillbirth, making it a leading cause of infant morbidity and mortality (2-6). “I wanted to know the drivers of preterm birth, and one of the biggest ones when you look at the bacterial pathogens that cause preterm birth is Group B Strep,” says Jennifer Gaddy, Associate Professor of medicine at Vanderbilt University Medical Center.

    A recent study led by Gaddy and Steve Townsend, Professor of Chemistry at Vanderbilt University, found that sugars found in human milk, known as human milk oligosaccharides (HMOs), can inhibit GBS infection and reduce inflammation in mice and human tissues (7). HMOs could thus have potential therapeutic applications against GBS infections and could help reduce preterm births.

    From chemistry to biology

    Townsend has long been working on studying and synthesizing HMOs, and reached out to Gaddy to investigate their biology. “That launched an almost 10-year collaboration now where he’s done the chemistry and I’ve done the biology,” says Gaddy. “Breast milk has all these wonderful molecules in it, and I was really interested in what molecules have antimicrobial or immunomodulatory activity, so this paper is really a culmination of almost a decade of work,” she says.

    Pregnant women are routinely screened for GBS and given antibiotics if they are found to have the bacteria. “But this does not prevent preterm birth or preterm rupture of membranes, because usually the mother is not screened until late in the third trimester, so we were really looking at being able to prevent or clear these earlier infections,” says Rebecca Moore, first author of the new paper (7) (see previous article). Moore conducted the work as a postdoctoral student with Gaddy and was previously a PhD student with Townsend. The researchers decided to test whether HMOs could serve as an alternative way to control GBS infections.

    HMOs are a group of sugars present only in human milk, and have been shown to function as prebiotics, anti-adhesive antimicrobials, and immunomodulators in the infant gut (8-11) (see previou article) “HMOs act as anti-adhesives, so they help prevent the adhesion of bacteria, and they can act as prebiotics, so they help increase the good bacteria,” says Moore. GBS pathogenesis depends on the bacteria’s ability to adhere to and colonize the host tissues, so the researchers tested how HMOs affected this ability.

    The researchers investigated the effects of a heterogeneous mixture of HMOs isolated from human milk on GBS infection in a pregnant mouse model. “We can take a pregnant mouse, and then just pipette bacteria into the vagina, and those bacteria ascend through the cervix up into the uterus, they cross the placenta, they infect the fetus, we get rupture of membranes, we get inflammation, we get preterm birth, we get fetal demise, we even get maternal demise, just like you get in the clinical model, so this is a really powerful model,” says Gaddy. “We’re marching towards trying to get closer to modeling what happens in a human being,” she says. 

    Examining HMOs in human tissues and mice

    The researchers’ mouse experiments involved a lot of hard work, with multiple people working 11-hour days. “It’s all hands on deck,” says Gaddy. But the hard work paid off.

    “Very excitingly, we found that when we fed the mice HMOs orally or gave them HMOs vaginally, they were able to significantly reduce the bacterial burden of Group B Strep in all of the reproductive organs,” says Moore. HMOs also reduced inflammation in the reproductive tissues and fetal compartments of GBS-infected mice compared with infected mice not given HMOs.

    The orally-delivered HMOs did not reduce bacterial burden as much as when they were delivered vaginally, but the fact that they had an effect at all came as a surprise. Gaddy says Moore was the one who suggested trying the HMOs orally in order to test whether they could eventually be given as orally-ingested pills to humans. “I said, ‘I don’t think it’ll work, but let’s do it’, and I was really shocked that it actually was very efficacious orally, and we are now in the process of trying to figure out how that works by tagging the HMOs and following them when we deliver them in vivo,” says Gaddy. She suggests that one of the ways HMOs might be working when delivered orally is through their effects on the immune system.

    In addition to seeing whether HMOs could reduce bacterial burden, the researchers also examined their effects on preventing preterm births in the pregnant mouse model. Pregnant mice infected with GBS experience both preterm birth and maternal death, as well as elevated levels of inflammatory cytokines. “We saw no instances of maternal death or preterm birth when the mice were given the HMOs, so that was exciting,” says Moore. “We also saw that immunologically HMOs also reduced the cytokines that are related to preterm birth in the mouse model,” she says.

    In addition to the mouse model, the researchers also used gestational membranes from a human placenta and a human vaginal organoid tissue model. “We’re always trying to use these complementary techniques because although the mouse immune system is very similar to ours, there are salient differences between the mouse and human reproductive tract and placenta,” says Gaddy. 

    “Looking at the vaginal organoids, we wanted to see if HMOs were able to inhibit adherence to this tissue, because if we’re able to inhibit that initial adherence we can prevent the ascending infection to the baby,” says Moore. “We found that the HMOs were able to prevent bacterial adherence to these tissues as well,” she says. They also prevented the bacteria from forming biofilms.

    HMOs also played a role in decreasing inflammation. “These compounds were really potent anti-inflammatory compounds,” says Gaddy. She suggests that HMOs could be useful against a variety of infections and inflammatory diseases. “I think that these molecules might have really potent, broad, anti-inflammatory applications,” she says.

    Fulfilling HMOs’ potential to prevent preterm births

    The study concludes that HMOs reduce GBS infection in a mouse model, reduce GBS adherence in an organoid model, and decrease reproductive tissue inflammation and the production of proinflammatory cytokines (7). “If you can deploy a molecule that has both antimicrobial activity and anti-inflammatory activity, there are some potent applications for that,” says Gaddy.

    The researchers suggest that their findings highlight the potential of HMOs to reduce GBS infection and thus prevent preterm births. “The thought process is that HMOs could be given to the mother almost like a vitamin that she would take during pregnancy,” says Moore.

    As antibiotic resistance becomes more of a problem, HMOs might serve as a safe alternative to antibiotics. “Most people get exposed to these molecules at least once in their life, and that should underscore their safety and their efficacy,” says Gaddy.

    “These are natural products that are present in human milk, which is a source of nutrition that 70% of people have had in their lifetime, so they have utility because of the public trust in them,” she says. 

    However, more studies are needed before HMOs could be used in humans. The current study used a heterogeneous mixture of HMOs, and Gaddy says the next step is to narrow down the specific properties of different sugars or combinations of sugars. “We’re trying to ascertain from the 11 dominant sugars that we’re seeing in the HMO cocktail, which ones are doing the antimicrobial activity, which ones are doing the anti-biofilm activity, which ones are expanding commensals, which ones are modulating the immune system, and we’re in the process right now of teasing that out,” says Gaddy.

    The researchers are aiming to synthesize individual HMO molecules and then test their effects in their existing models. “I think we’ll probably spend the next five years doing that, and then after we know which molecules do what, it’ll be easier for us to move into a human clinical trial,” says Gaddy.

    But finding the right sugars or combination of sugars will take some effort, highlighting the complexity of human milk. “One of the first steps is being able to synthetically produce these HMOs in the right combination, and we haven’t found a combination that works as well as the combination that is found naturally in breast milk,” says Moore. “There are over 200 HMOs, so it’s a matter of finding that sweet spot,” she says.

    References

    1. Blencowe H, Cousens S, Chou D, Oestergaard M, Say L, Moller AB, Kinney M, Lawn J; Born Too Soon Preterm Birth Action Group. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health. 2013;10 Suppl 1(Suppl 1):S2.
    2. Dai, W.; Zhang, Y.; Xu, Y.; Zhu, M.; Rong, X.; Zhong, Q. The effect of group B Streptococcus on maternal and infants’ prognosis in Guizhou, China. Biosci. Rep. 2019, 39 (12).
    3. Bianchi-Jassir F, Seale AC, Kohli-Lynch M, Lawn JE, Baker CJ, Bartlett L, Cutland C, Gravett MG, Heath PT, Ip M, Le Doare K, Madhi SA, Saha SK, Schrag S, Sobanjo-Ter Meulen A, Vekemans J, Rubens CE. Preterm birth associated with group B Streptococcus maternal colonization worldwide: Systematic review and meta-analyses. Clin Infect Dis. 2017 Nov 6;65(suppl_2):S133-42.
    4. Nan C, Dangor Z, Cutland CL, Edwards MS, Madhi SA, Cunnington MC. Maternal group B Streptococcus-related stillbirth: a systematic review. BJOG. 2015 Oct;122(11):1437-45.
    5. Sass L. Group B streptococcal infections. Pediatr Rev. 2012 May;33(5):219-24.
    6. Verani JR, McGee L, Schrag SJ; Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC). Prevention of perinatal group B streptococcal disease–revised guidelines from CDC, 2010. MMWR Recomm Rep. 2010 Nov 19;59(RR-10):1-36.
    7. Moore RE, Spicer SK, Lu J, Chambers SA, Noble KN, Lochner J, Christofferson RC, Vasco KA, Manning SD, Townsend SD, Gaddy JA. The utility of human milk oligosaccharides against Group B Streptococcus infections of reproductive tissues and cognate adverse pregnancy outcomes. ACS Cent Sci. 2023 Aug 9;9(9):1737-49.
    8. 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 May;135(5):1304-7.
    9. Chichlowski M, De Lartigue G, German JB, Raybould HE, Mills DA. Bifidobacteria isolated from infants and cultured on human milk oligosaccharides affect intestinal epithelial function. J Pediatr Gastroenterol Nutr. 2012 Sep;55(3):321-7.
    10. Zivkovic AM, German JB, Lebrilla CB, Mills DA. Human milk glycobiome and its impact on the infant gastrointestinal microbiota. Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1(Suppl 1):4653-8. 
    11. Newburg DS, Grave G. Recent advances in human milk glycobiology. Pediatr Res. 2014 May;75(5):675-9.

     

    Contributed by

    Dr. Sandeep Ravindran

    Freelance Science Writer

    Sandeepr.com