Lactulose synergizes with CpG-ODN to modulate epithelial and immune cells cross talk

Mukherjee, Reshmi; Kaa, Melanie van de; Garssen, Johan; Pieters, Roland J.; Kraneveld, Aletta D.; Willemsen, Linette E. M.

doi:10.1039/c8fo02376j

Cited by 8 publications

(6 citation statements)

References 20 publications

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“…Previous studies using this well-established in vitro IEC/PBMC co-culture model reported regulatory-type Th1 responses upon exposure to NDO in association with bacterial DNA or synthetic CpG oligodeoxynucleotides, known to be TLR9 ligands. The immunomodulatory effects observed upon exposure to NDO and CpG in the IEC/PBMC model could support mucosal immune development and were shown to be mediated by epithelial-derived galectin-9, which was found to be a key mediator contributing to the effects observed in vitro [29][30][31]34,35]. These studies also showed that the immunomodulatory properties of CpG and NDO occurred only when the PBMC underlying the IEC were activated, mimicking inflammatory conditions [29].…”

Section: Introductionmentioning

confidence: 74%

“…Within the DP2 fraction, various NDO structures have been characterized also including lactose residues [14]. Previous studies did not observe immunomodulatory effects upon exposure to lactose in the IEC/PBMC co-culture model [35]. However, due to the presence of lactose and the inability to separate this from other possible active NDO within the DP2 fraction, this study focused on analyzing GOS fractions with size of DP3 and longer fractions, namely DP4-7, DP3-7, and DP3-5 fractions, which were isolated by size-exclusion chromatography.…”

Section: Discussionmentioning

confidence: 99%

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Modulation of the Epithelial-Immune Cell Crosstalk and Related Galectin Secretion by DP3-5 Galacto-Oligosaccharides and β-3′Galactosyllactose

et al. 2022

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Prebiotic galacto-oligosaccharides (GOS) were shown to support mucosal immune development by enhancing regulatory-type Th1 immune polarization induced by synthetic CpG oligodeoxynucleotides (TLR9 agonist mimicking a bacterial DNA trigger). Epithelial-derived galectin-9 was associated with these immunomodulatory effects. We aimed to identify the most active fractions within GOS based on the degree of polymerization (DP), and to study the immunomodulatory capacities of DP3-sized β-3′galactosyllactose (β-3′GL) using a transwell co-culture model of human intestinal epithelial cells (IEC) and activated peripheral blood mononuclear cells (PBMC). IEC were apically exposed to different DP fractions of GOS or β-3′GL in the presence of CpG, and basolaterally co-cultured with αCD3/CD28-activated PBMC, washed, and incubated in fresh medium for IEC-derived galectin analysis. Only DP3-5 in the presence of CpG enhanced galectin-9 secretion. DP3-sized β-3′GL promoted a regulatory-type Th1 response by increasing IFNγ and IL-10 or galectin-9 concentrations as compared to CpG alone. In addition, IEC-derived galectin-3, -4, and -9 secretion was increased by β-3′GL when combined with CpG. Therefore, the GOS DP3-5 and most effectively DP3-sized β-3′GL supported the immunomodulatory properties induced by CpG by enhancing epithelial-derived galectin secretion, which, in turn, could support mucosal immunity.

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Section: Introductionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Modulation of the Epithelial-Immune Cell Crosstalk and Related Galectin Secretion by DP3-5 Galacto-Oligosaccharides and β-3′Galactosyllactose

et al. 2022

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“…These differences could not be ascribed to differences in endotoxin contaminations in enzymatic or bacterial produced HMOS (presented in Table 1). The endotoxin contamination level of all used HMOS is low and not in a range to expect to significantly contribute to the immunological responses [33,65]. In the presence of CpG, enzymatic 2 FL further enhanced regulatory and Th1 type cytokine release from PBMCs and galectin-9 secretion from IEC, while also diminishing Th2 cell development.…”

Section: Discussionmentioning

confidence: 99%

Specific Human Milk Oligosaccharides Differentially Promote Th1 and Regulatory Responses in a CpG-Activated Epithelial/Immune Cell Coculture

et al. 2023

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Proper early life immune development creates a basis for a healthy and resilient immune system, which balances immune tolerance and activation. Deviations in neonatal immune maturation can have life-long effects, such as development of allergic diseases. Evidence suggests that human milk oligosaccharides (HMOS) possess immunomodulatory properties essential for neonatal immune maturation. To understand the immunomodulatory properties of enzymatic or bacterial produced HMOS, the effects of five HMOS (2′FL, 3FL, 3′SL, 6′SL and LNnT), present in human milk have been studied. A PBMC immune model, the IEC barrier model and IEC/PBMC transwell coculture models were used, representing critical steps in mucosal immune development. HMOS were applied to IEC cocultured with activated PBMC. In the presence of CpG, 2′FL and 3FL enhanced IFNγ (p < 0.01), IL10 (p < 0.0001) and galectin-9 (p < 0.001) secretion when added to IEC; 2′FL and 3FL decreased Th2 cell development while 3FL enhanced Treg polarization (p < 0.05). IEC were required for this 3FL mediated Treg polarization, which was not explained by epithelial-derived galectin-9, TGFβ nor retinoic acid secretion. The most pronounced immunomodulatory effects, linking to enhanced type 1 and regulatory mediator secretion, were observed for 2′FL and 3FL. Future studies are needed to further understand the complex interplay between HMO and early life mucosal immune development.

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“…However, this was not seen in rats receiving longer-sized fructo-oligosaccharides, suggesting that shorter NDO might be absorbed by enterocytes and thereby be able to promote immunomodulation as opposed to longer DP-sized NDO. Similar to the rat study, also a 9:1 mixture of short chain and long chain FOS as well as lactulose enhanced IFNg and IL-10 secretion on top of the effect of CpG in a similar co-culture model used to study GOS DP [85,86]. All these studies suggest that NDO like GOS/lcFOS, GOS or FOS/lcFOS may generate direct immunomodulatory effects mainly via interaction of their short-chain NDO with epithelial and/or immune cells.…”

Section: Ndo As Immunomodulatory Agentssupporting

confidence: 69%

Shaping mucosal and systemic immunity by non-digestible oligosaccharides and postbiotics

Muruzabal¹

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Besides NDO, the use of postbiotics is being considered as a dietary strategy to support immune development in early life. Although the microorganisms are inactivated during the fermentation process, the presence of inactivated bacteria and their structural fragments which serve as PRR ligands as well as the derived metabolites, are thought to provide benefits for the host [46, 47]. In Chapter 7, the immunomodulatory effects of postbiotics were studied using an in vitro IEC/PBMC co-culture model. Furthermore, the ability of specific fermentation products containing postbiotics in supporting systemic immunity was studied in vivo. Therefore, a dietary intervention with specific fermentation products was studies using a murine influenza vaccination model and was shown to improve the influenza-specific DTH response, a primary marker measuring vaccination responsiveness.The findings of this thesis are summarized and discussed in Chapter 8 in respect to the current knowledge, and opportunities for future research are outlined. 18 19 General introduction Chapter 1

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Lactulose synergizes with CpG-ODN to modulate epithelial and immune cells cross talk

Abstract: Apart from being a prebiotic and laxative, lactulose has direct immunomodulatory effects.

Cited by 8 publications

References 20 publications

Modulation of the Epithelial-Immune Cell Crosstalk and Related Galectin Secretion by DP3-5 Galacto-Oligosaccharides and β-3′Galactosyllactose

Modulation of the Epithelial-Immune Cell Crosstalk and Related Galectin Secretion by DP3-5 Galacto-Oligosaccharides and β-3′Galactosyllactose

Specific Human Milk Oligosaccharides Differentially Promote Th1 and Regulatory Responses in a CpG-Activated Epithelial/Immune Cell Coculture

Shaping mucosal and systemic immunity by non-digestible oligosaccharides and postbiotics

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