Human milk oligosaccharide secretion dynamics during breastfeeding and its antimicrobial role: A systematic review

Table 5 Studies of the role of human milk oligosaccharides against viral infections

Ref.	Virus investigated	Type of HMOs	Mechanisms of action	Key findings	Patient population
Patil et al[112]	Human Norovirus (HuNoV)	2'-FL	Acts as decoy receptors, blocking binding to HBGAs	Significant inhibition of Norovirus GII.4 Sydney [P16] replication in adult and pediatric HIEs. Less effective in infant HIEs due to low HBGA expression	Adults and pediatric intestinal organoids
Koromyslova et al[87]	GI.1 and GII.17 Noroviruses	2'-FL	Inhibits binding to HBGAs by mimicking natural attachment sites	Broad inhibition of GI.1 and GII.17 norovirus binding across genogroups. Demonstrated dose-dependent inhibition with 2'-FL in vitro	Not specified (laboratory models)
Hanisch et al[88]	Norovirus GII.4 (Sydney 2012) and GII.10 (Vietnam 026)	High-molecular mass HMOs rich in fucose	Multivalent fucose presentation enhances steric and valency effects for strong virus binding inhibition	High-mass HMOs with terminal blood group H1 or Lewis-b antigens showed potent binding to GII.4; distinct preferences observed for GII.10	Not specified (laboratory models)
Weichert et al[89]	Norovirus (not strain-specific)	2'-FL and 3-FL	Structurally mimic HBGAs and block norovirus binding to surrogate HBGA samples	2'-FL and 3-FL bind to HBGA pockets on the capsid, acting as naturally occurring decoys to inhibit norovirus attachment	Not specified (laboratory models)
Derya et al[90]	Norovirus GII.17 and GII.4	LNFP I and simpler fucosylated HMOs	Structurally similar to HBGAs; block binding to natural receptors	Simple fucosylated HMOs were more effective than complex ones (e.g., LNFP I) in inhibiting GII.17 and GII.4 binding to human gastric mucins	Not specified (laboratory models)
Hester et al[91]	RV OSU and Wa strains	SA-containing HMOs (e.g., 3'-SL, 6'-SL), neutral HMOs (e.g., LNnT)	Blocks viral binding and decreases infectivity through decoy receptor mechanisms.	SA-containing HMOs inhibited RV OSU infectivity in vitro. Both neutral and SA-containing HMOs reduced viral replication during acute infection in situ	In vitro and 21-day-old piglets
Comstock et al[92]	Rotavirus OSU strain	2'-FL, LNnT, 6'-SL, 3'-SL, and free SA	Modulates systemic and gastrointestinal immune cells to alter infection susceptibility	HMO-fed pigs showed increased NK and memory T cells and reduced immune cell populations linked to infection compared to formula-fed pigs	Colostrum-deprived neonatal piglets
Li et al[93]	Rotavirus OSU strain	4 g/L HMOs (2'-FL, LNnT, 6'-SL, 3'-SL)	Modulates immune response and alters colonic microbiota to reduce diarrhea duration	HMO-fed piglets had shorter diarrhea duration, enhanced anti-inflammatory and Th1 cytokine expression, altered colonic microbiota, and increased pH	Formula-fed newborn piglets
Laucirica et al[94]	Human Rotavirus G1P[8] and G2P[4]	2'-FL, 3'-SL, 6'-SL, galacto-oligosaccharides	Acts as soluble decoy receptors, directly affecting the virus to block binding	All oligosaccharides reduced infectivity in vitro. Maximum reduction for G1P[8] (62%) with 2'-FL and for G2P[4] (73%) with 3'-SL + 6'-SL mixture	African green monkey kidney epithelial cells (MA104)
Gozalbo-Rovira et al[113]	Rotavirus P[8] genotype	LNB, precursor of H1 antigen	LNB binds to the VP8* domain of the P[8] VP4 spike protein, inhibiting viral attachment	LNB binds with reduced affinity but induces conformational changes that inhibit rotavirus infection. Differences in ligand affinity explain variability in susceptibility among secretor and non-secretor phenotypes	Not specified (laboratory models)
Xiao et al[95]	Influenza virus	2'-FL	Enhances both innate and adaptive immune responses to vaccination	2'-FL improved vaccine-specific humoral and cellular immune responses, including CD4+ and CD8+ T-cell proliferation, dendritic cell maturation, and antigen presentation	6-week-old female C57Bl/6JOlaHsd mice
Mahaboob Ali et al[96]	Influenza virus, respiratory syncytial virus, human metapneumovirus, SARS-CoV-2	Multiple HMOs (e.g., 2'-FL, LNnT)	Mimic host cell receptors to inhibit viral entry by binding to viral surface proteins	In silico studies identified HMOs with high binding affinities to viral proteins, suggesting their potential as viral entry inhibitors and antiviral agents	Computational in silico modeling
Pandey et al[97]	Avian Influenza (H9N2 and other subtypes)	3'-SL, 6'-SL	Bind hemagglutinin and block viral attachment to host cells	3'-SL showed broad-spectrum activity against avian influenza in vitro. In vivo, 3'-SL eliminated H9N2 in chickens and improved clinical symptoms	Pathogen-free chickens
Duska-McEwen et al[98]	RSV, Influenza	2'-FL, 6'-SL, 3'-SL, LNnT	Enhance innate immunity by reducing viral load, cytokines, and inflammation	2'-FL reduced RSV viral load and cytokines. LNnT and 6'-SL decreased Influenza viral load. 6'-SL reduced IP-10 and TNF-α in RSV-infected PBMCs	In vitro respiratory epithelial cells and PBMCs
Schijf et al[114]	RSV	scGOS, lcFOS, pAOS	Modulates Th1/Th2 immune responses and enhances RSV-specific CD4+ and CD8+ T cells	Increased RSV clearance, enhanced Th1 response, reduced Th2 cytokines, and lower airway eosinophilia in RSV-infected mice	RSV-infected C57BL/6 mice
Guo et al[115]	Influenza virus	3'-SL	Synergistically reduces viral load and inflammation when combined with OPN	3'-SL and OPN reduced viral load by 75%, suppressed cytokine levels (TNF-α, IL-6), and exhibited anti-inflammatory effects	Human laryngeal carcinoma cell line (HEP-2)

2'-FL: 2'-Fucosyllactose; 3-FL: 3-Fucosyllactose; 3'-SL: 3'-Sialyllactose; 6'-SL: 6'-Sialyllactose; CD4: Cluster of differentiation 4+; CD8: cluster of differentiation 8+; HBGAs: Histo-blood group antigens; HIEs: Human intestinal enteroids; HMOs: Human milk oligosaccharides; LNnT: Lacto-N-neotetraose; NK: Natural Killer; OPN: Osteopontin; PBMCs: Peripheral blood mononuclear cells; RSV: Respiratory syncytial virus; RV: Rota virus; SA: Sialic acid; Th1: T helper 1; Th2: T helper 2; LNDFHI: Lacto-N-difucohexaose I; NLB: Lacto-N-biose; scGOS: Short-chain galactooligosaccharides; lcFOS: Long-chain fructooligosaccharides; pAOS: Pectin-derived acidic oligosaccharides.