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HMOs  as promising Antimicrobials and Antivirals

It is widely accepted that breast milk provides the best nutrition for newborns.1. Beyond an optimal combination of all essential nutrients, which babies need for their healthy growth and development, breast milk offers various health benefits including protection against infections.2-5 In the mix of many different components in breast milk, human milk oligosaccharides (HMOs) are the third most common solid components, but have virtually no nutritive benefits.6-8 Various clinical observational studies showed that HMOs provide protection against pathogenic infections at a time when infants are most vulnerable.8-10

Many viruses, bacterial pathogens or toxins need to adhere to receptors on mucosal surfaces, such as in the gut, to colonise or invade infants and cause diseases.11 Since some HMOs, especially fucosylated HMOs, are structurally similar to these receptors, they can bind to pathogens and serve as decoy receptors to prevent pathogen binding and enhance pathogen clearance.8,12 This unique pathogen-binding capacity of HMOs is highly dependent on their structure.12,13

Growing evidence from various experimental and preclinical research shows that HMOs directly interact with various pathogenic bacteria and viruses and reduce their growth and infectivity.12,14-19
As such, fucosylated HMOs, such as 2′-fucosyllactose (2′FL) have shown to reduce the infectivity of Campylobacter jejuni, one of the major causes of bacterial diarrhoea, worldwide.14 In line with these preclinical findings, Campylobacter-induced diarrhoea occurred less often in breastfed infants whose mothers were secretors with typically high levels of 2′FL in breast milk.9

HMOs demonstrated antimicrobial16,17 and antibiofilm16 activity against different strains of Group B Streptococcus (GBS) that are leading causes of neonatal infections. Further growth and biofilm assays with other pathogenic bacteria showed that HMOs possess antibiofilm activity against methicillin-resistant, pathogenic Staphylococcus aureusand antimicrobial activity against Acinetobacter baumannii.18

Furthermore, HMOs are able to bind to several noroviruses 12 that can cause a sudden onset of severe vomiting and diarrhoea; noroviruses belong to the group of caliciviruses.20 Especially, 2′FL has shown to bind to relatively conserved regions of the viral capsids, which contribute to the antiviral activity of this HMO.12 Consistently with these preclinical findings, high levels of 2′-linked fucosylated HMOs in breast milk are related to a reduced risk of calicivirus-associated diarrhoea in infants.9Similarly, there is emerging evidence that certain HMOs may protect against rotavirus infection, one of the most common causes of severe diarrhoea in infants and young children.12 HMOs, such as lacto-N-tetraose (LNT), are able to bind to rotaviruses; 2′FL and some sialylated HMOs reduced the infectivity of certain rotavirus strains by directly interacting with the virus.12,19 Additionally, a mixture of neutral and acidic HMOs reduced rotavirus-induced diarrhoea in an animal model.12

These findings collectively imply that some HMOs could be potent antimicrobials against certain pathogenic bacteria, as well as antivirals against norovirus or rotavirus infections.12,14-19

Professor Clemens Kunz, University Giessen, Germany

The potential of HMOs to protect against viral (e.g. rotavirus, norovirus) or bacterial (Campylobacter jejuni, Staphylococcus aureus, etc.) infections provides an interesting and possible alternative to current strategies using drugs, as they target the vital steps of bacterial adhesion and viral invasion. Intriguingly, many fucosylated or sialylated HMOs contain specific epitopes, which are able to recognise multiple pathogenic bacteria or viruses. This pathogen recognising function seems to be specific to the individual HMO structure. The potency of these HMOs to prevent infections is worth exploring in systematic and clinical studies. The fundamental knowledge obtained by these studies can then be translated into preventive or therapeutic applications.


References

1.Agostoni C, Braegger C, Decsi T, et al. Breast-feeding: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2009;49(1):112-125.
2.Horta BL, Victora CG. Short-term effects of breastfeeding: a systematic review on the benefits of breastfeeding on diarrhoea and pneumonia mortality. 2013;   https://apps.who.int/iris/bitstream/handle/10665/95585/9789241506120_eng.pdf;jsessionid=
126665DF3E351CFC9AA740FED9820757?sequence=1
.
Accessed July 29, 2019.
3.Bachrach VR, Schwarz E, Bachrach LR. Breastfeeding and the risk of hospitalization for respiratory disease in infancy: a meta-analysis. Arch Pediatr Adolesc Med. 2003;157(3):237-243.
4.Kramer MS, Kakuma R. Optimal duration of exclusive breastfeeding. Cochrane Database Syst Rev. 2012(8):CD003517.
5.Duijts L, Jaddoe VW, Hofman A, Moll HA. Prolonged and exclusive breastfeeding reduces the risk of infectious diseases in infancy. Pediatrics. 2010;126(1):e18-25.
6.Zivkovic AM, German JB, Lebrilla CB, Mills DA. Human milk glycobiome and its impact on the infant gastrointestinal microbiota. Proc Natl Acad Sci USA. 2011;108 (Suppl 1):4653-4658.
7.Austin S, De Castro CA, Benet T, et al. Temporal change of the content of 10 oligosaccharides in the milk of Chinese urban mothers. Nutrients. 2016;8(6).
8.Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012;22(9):1147-1162.
9.Morrow AL, Ruiz-Palacios GM, Altaye M, et al. Human milk oligosaccharides are associated with protection against diarrhea in breast-fed infants. J Pediatr. 2004;145(3):297-303.
10.Stepans MB, Wilhelm SL, Hertzog M, et al. Early consumption of human milk oligosaccharides is inversely related to subsequent risk of respiratory and enteric disease in infants. Breastfeed Med. 2006;1(4):207-215.
11.Vandenplas Y, Berger B, Carnielli VP, et al. Human milk oligosaccharides: 2'-fucosyllactose (2'-FL) and lacto-N-neotetraose (LNnT) in infant formula. Nutrients. 2018;10(9):1161.
12.Morozov V, Hansman G, Hanisch FG, Schroten H, Kunz C. Human milk oligosaccharides as promising antivirals. Mol Nutr Food Res. 2018;62(6):e1700679.
13.Bode L, Jantscher-Krenn E. Structure-function relationships of human milk oligosaccharides. Adv Nutr. 2012;3(3):383S-391S.
14.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(16):14112-14120.
15.Townsend SD. Human milk oligosaccharides: defense against pathogens. Breastfeed Med. 2019;14(S1):S5-S6.
16.Craft KM, Townsend SD. Mother knows best: deciphering the antibacterial properties of human milk oligosaccharides. Acc Chem Res. 2019;52(3):760-768.
17.Lin AE, Autran CA, Szyszka A, et al. Human milk oligosaccharides inhibit growth of group B Streptococcus. J Biol Chem. 2017;292(27):11243-11249.
18.Ackerman DL, Craft KM, Doster RS, et al. Antimicrobial and Antibiofilm Activity of Human Milk Oligosaccharides against Streptococcus agalactiae, Staphylococcus aureus, and Acinetobacter baumannii. ACS Infect Dis. 2018;4(3):315-324.
19.Donovan SM. Human milk oligosaccharides: potent weapons in the battle against rotavirus infection. J Nutr. 2017;147(9):1605-1606.
20.Clinic M. Norovirus infection. https://www.mayoclinic.org/diseases-conditions/norovirus/symptoms-causes/syc-20355296. Accessed July 26, 2019.

 

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