Table 2.
Overview of studies included in this review, which describe effects of non-digestible oligosaccharides (NDO) on immune function.
| References | Model | NDO | Main effect of intervention |
|---|---|---|---|
| In vitro | |||
| Gnoth et al. (42) | Caco-2 cells | Isolated HMOS | Neutral HMOS are transported across intestinal epithelia via receptor-mediated transcytosis as well as by paracellular flux, while acidic HMOS are translocated solely via paracellular pathways |
| Eiwegger et al. (161) | cord blood T cells | Isolated HMOS | Acidic HMOS increased the percentage of IFN? and IL-13 producing T cells as well as CD25+ T cells. IgE and IgG1 production was unaffected |
| Coppa et al. (101) | Caco-2 cells | Isolated HMOS | Acidic HMOS showed anti-adhesive effects on all 3 intestinal pathogens. Neutral HMOS showed anti-adhesive effects on 2 out of 3 tested pathogens |
| He et al. (49) | Fetal small intestinal samples | Isolated HMOS | HMOS from colostrum samples were able to attenuate mucosal response to surface inflammatory stimuli, and enhanced maturation of intestinal mucosa |
| Xiao et al. (140) | human moDCs | Isolated HMOS | HMOs limited LPS maturation of moDCs. HMOS-conditioned moDCs promoted Treg generation |
| Newburg et al. (50) | T84 cells, H4 cells, NCM-460 | Isolated HMOS and GOS | HMOS attenuated surface inflammatory stimuli. HMOS and GOS attenuated NF-κB signaling |
| Eiwegger et al. (162) | Caco-2 cells | Isolated HMOS and scGOS + lcFOS and AOS | Acidic HMOS increased IFN? and IL-10 secretion and suppressed TH2 cytokine production in T cells from peanut allergic patients |
| He et al. (16) | T84 cells, H4 cells | Isolated HMOS, 2'FL3, LNFP-I3, 3'SL3 and 6'SL3 | HMOS and 2'FL inhibited LPS-TLR4 signaling via suppressed CD14 expression. No significant results for any of the other tested NDOs |
| Holscher et al. (75) | Caco-2Bbe cells, HT-29 cells | Isolated HMOS, 2'FL1, 3'SL2 and 6'SL1 | Single HMOS and isolated HMOS decreased proliferation in pre-confluent cells, but increased cell differentiation. isolated HMOS decreased apoptosis and necrosis |
| Akbari et al. (124) | Caco-2 cells | GOS | GOS improved tight junction assembly and DON induced loss of transepithelial resistance was prevented |
| De Kivit et al. (154) | T84 cells, HT-29 cells | scGOS + lcFOS | scGOS + lcFOS in combination with B. breve M-16V increased epithelial expression and secretion of galectin-9, and enhanced TH1 and Treg polarization |
| Hayen et al. (157) | HT-29 cells | scGOS + lcFOS and scFOS + lcFOS | Both mixtures induced enhanced IFN? and IL-10, but suppressed IL-13 and TNFα secretion. scFOS + lcFOS enhanced TH1 and Treg response in a peanut-specific co-culture (HT-29/PBMC) model |
| Zenhom et al. (126) | Caco-2 cells | FOS and 3'SL3 | Both decreased levels of inflammation, as IL-12 secretion and mRNA expression of IL-12p35, IL-8, and TNFα was reduced in a dose- and time-dependent manner |
| Perdijk et al. (163) | human moDCs | GOS, 2'FL1 and 6'SL1 | None of the oligosaccharides influenced DC differentiation and LPS-induced maturation |
| Yu et al. (17) | Hep-2 cells, HT-29 cells | 2'FL2 | 2'FL attenuated C. jejuni invasion in both cell lines |
| Perdijk et al. (159) | human moDCs | 3'SL1 | 3'SL mediated NF-κB activation via TLR4 induction was explained by LPS contamination |
| Zehra et al. (38) | T84 cells, HT-29 cells | 2'FL2 and 6'SL2 | 2'FL inhibited CCL20 secretion from epithelium upon antigen-antibody complex stimulation. 6'SL inhibited IL-8 and CCL20 secretion from epithelium upon antigen-antibody complex stimulation |
| Holscher et al. (74) | Caco-2Bbe cells, HT-29 cells | LNnT3, 2'FL3 and 6'SL3 | All HMOS inhibited cell proliferation in undifferentiated cell cultures. 2'FL increased alkaline phosphatase and sucrase activity. LNnT increased transepithelial resistance |
| Varasteh et al. (125) | Caco-2 cells | 3'GL3, 4'GL3 and 6'GL3 | 3'GL prevented loss of transepithelial resistance upon DON exposure, 4'GL and 6'GL had no effect |
| Pre-clinical | |||
| Xiao et al. (133) | Mice | Isolated HMOS | HMOS intervention delayed and suppressed type 1 diabetes development and reduced development of severe pancreatic insulitis in NOD-mice |
| Wu et al. (123) | Mice | Isolated HMOS | HMOS increased mucin expression, whereas intestinal permeability was decreased |
| Jantscher-Krenn et al. (129) | Mice | Isolated HMOS and GOS | HMOS reduced NEC pathology scores, the effects were attributed to DSLNT in the HMOS mixture |
| Yu et al. (131) | Rats | Isolated HMOS, GOS and synthetic disialylated-GOS | HMOS and sialylated-GOS reduced NEC pathology scores. GOS had no effect on NEC development |
| Autran et al. (130) | Rats | Isolated HMOS, GOS and synthetic disialylated-GOS | HMOS and sialylated-GOS reduced NEC pathology scores. GOS had no effect on NEC development |
| Comstock et al. (164) | Pigs | Isolated HMOS, 2'FL3, 3FL3, 3'SL3, 6'SL3, LNFP-III3 and LNnT3 | HMOS stimulation IL-10 production by PBMCs. Fucosylated HMOS decreased proliferation of HMOS. Sialylated HMOS increased PBMC proliferation, although less CD4+ cells were observed |
| Akbari et al. (124) | Mice | GOS | GOS treatment stabilized villus height upon DON exposure |
| Verheijden et al. (30) | Mice | GOS | GOS prevented induction of airway eosinophilia and TH2 related cytokine concentrations in lung, similar to budesonide treatment in house-dust mite allergy |
| Verheijden et al. (135) | Mice | GOS | GOS decreased IL-33 secretion and expression in HDM-induced asthma |
| Verheijden et al. (165) | Mice | GOS | GOS decreased CCL5 and IL-13 concentration in lung tissue from HDM-induced allergic asthma mice, similar to budesonide treatment |
| Djouzi and Andlueux (23) | Rats | GOS and FOS | GOS and FOS decreased pH in caecum, increased total SCFA concentration |
| Verheijden et al. (31) | Mice | scFOS + lcFOS | scFOS + lcFOS in combination with B. breve M-16V prevented house-dust mite induced airway inflammation |
| De Kivit et al. (137) | Mice | scGOS + lcFOS | scGOS + lcFOS in combination with B. breve M-16V induced reduced acute allergic skin response, and higher concentrations of galectin-9, which was associated with allergy prevention |
| De Kivit et al. (166) | Mice | scGOS + lcFOS | scGOS + lcFOS in combination with B. breve M-16V in an ovalbumin allergic mouse model, reduced allergic symptoms and increased galectin-9 serum levels. DC activation and TH2 frequency were normalized in allergic mice |
| Schouten et al. (134) | Mice | scGOS + lcFOS + AOS | Prebiotic mixtures enhanced percentages of TH1 cells and decreased Th2 cell percentages were observed. Strong reduction in allergic skin reaction. CD25+ Treg cells were involved in the tolerance induction effect |
| Kerperien et al. (29) | Mice | scGOS + lcFOS and AOS | Only NDO mixtures reduced allergic skin response, whey-IgG1 levels, TH2 and TH17 mRNA expression, and increased Foxp3+ cells |
| Kerperien et al. (136) | Mice | scGOS + lcFOS + AOS | Prebiotic mixtures increased mRNA expression of IL10, TGFβ and Foxp3, and acute allergic skin response was 50% lower in whey allergic mice when fed the prebiotic mixture. These protective effect were depended on IL10 and TGFβ |
| Xiao et al. (127) | Mice | scGOS + lcFOS + 2'FL2 | NDOs enhanced influenza vaccine response, higher levels of IgG1, IgG2a, and activated B cells were observed |
| van den Elsen et al. (128) | Mice | scGOS + lcFOS + 2'FL2 | NDOs improved vaccine-specific antibody response and modulated gut microbiota composition |
| Yu et al. (17) | Mice | 2'FL2 | 2'FL attenuated C. jejuni colonization, weight loss and inflammatory cytokines |
| Cilieborg et al. (132) | Pigs | 2'FL3 | 2'FL intervention did not result in observed differences in bacterial colonization, intestinal function and NEC pathology |
| Xiao et al. (18) | Mice | 2'FL2 | 2'FL improved humoral and cellular immune response to influenza vaccination |
| Azagra-Boronat et al. (19) | Rats | 2'FL3 | 2'FL increased plasma IgE and IgA levels. Increased intestinal villus height. Higher Lactobacillus proportion in cecum |
| Weiss and Hennet (103) | Mice | 3'SL3 | 3'SL induced higher degree of resistance to dextran sulfate sodium-induced colitis |
| Kurakevich et al. (15) | Mice | 3'SL3 | 3'SL increased colitis, via TLR4 signaling |
| Castillo-Courtade et al. (39) | Mice | 2'FL2 and 6'SL2 | 2'FL and 6'SL attenuated ovalbumin induced allergic symptoms like diarrhea, hypothermia, mast cell number in the intestine, and increased induction of IL-10 producing Treg cells |
| Clinical | |||
| Newburg et al. (32) | Infants | HMOS in human milk | Higher 2'FL and LNF-I to 3FL and LNF-II ratios in human milk correlated with more protection against diarrhea in infants |
| Sjögren et al. (35) | Infants | HMOS in human milk | Neutral HMOS concentration in human milk is not related to maternal allergy status nor allergy development in children |
| Bode et al. (33) | Infants | HMOS in human milk | Higher concentrations of HMOS in human milk were correlated to decreased risk of HIV transmission from mother to child. However, higher concentrations of 3'SL were found in HIV transmitting woman |
| Wang et al. (88) | Infants | HMOS in human milk | Breastfed infants had relative higher abundances of Bacteroides, and lower proportions of Clostridium, Streptococcus, Enterococcus and Veillonella than infants fed formula milk |
| Kuhn et al. (34) | Infants | HMOS in human milk | Higher concentrations of 2'FL and LNF-I were found in human milk from HIV non-transmitting woman |
| Sprenger et al. (36) | Infants | HMOS in human milk | FUT-2 associated oligosaccharides in human milk in infants at high risk of allergy development, and born via C-section are associated with lower risk of IgE-associated eczema |
| Seppo et al. (37) | Infants | HMOS in human milk | Low LNFP-III concentrations in human milk was related to an increased likelihood to develop cow's milk allergy, compared high concentrations of LNFP-III in infants |
| Grüber et al. (44) | Infants | Neutral oligosaccharides + AOS | Prebiotic supplemented formula resulted in a significant lower rate of atopic dermatitis compared normal formula in infants. Incidence of atopic dermatitis in prebiotic supplemented infants was in a similar range compared to breast fed infants |
| Moro et al. (27) | Infants | GOS and FOS | GOS and FOS dose-dependently increased in Bifidobacteria and Lactobacilli, in infants receiving prebiotic supplemented formula compared to non-supplemented formula |
| Arslanoglu et al. (28) | Infants | scGOS + lcFOS | Infants receiving scGOS + lcFOS had a lower incidence of allergic manifestations, in addition, fewer physician-diagnosed respiratory tract infections, fever episodes, and antibiotic prescriptions were recorded |
| De Kivit et al. (137) | Infants | scGOS + lcFOS | scGOS + lcFOS in combination with B. breve M-16V induced higher serum galectin-9 levels, which is associated with allergy prevention |
| Goehring et al. (167) | Infants | GOS + 2'FL3 | GOS + 2'FL supplemented formula fed infants had similar plasma inflammatory cytokine concentrations compared to breast fed infants. Infants fed with the GOS diet had significantly increased levels of inflammatory cytokines present in plasma |
As HMOS has different origin which may influence the immunological outcome, when possible the origin of the used HMOS was noted. Biological isolated HMOS1, chemically synthesized2, bacterial fermentation/synthesis3 or source unknown. Studies are sorted based on model subgroup (e.g., in vivo), NDO and year of publication.