Nevertheless, it is unknown whether the concentrations of sialyllactose present in cows milk alters the microbiota in vivo. Indeed, non-heat-sensitive cows milk components may also contribute to the induction of a regulatory phenotype (37). Christodoulopoulos P, Cameron L, Durham S, Hamid Q. Molecular pathology of allergic disease: II: upper airway disease, Multifunctional strands in tight junctions. Therefore, in this review we discuss potential mechanisms by which dietary components, using cows milk as an example, can protect against airway inflammation. RN is an employee of FrieslandCampina and MS received research funding from FrieslandCampina. Ex vivo cultures of mesenteric lymph node (MLN) DC showed direct TLR4 activation by 3SL (116). Sozaska B, Pearce N, Dudek K, Cullinan P. Consumption of unpasteurized milk and its effects on atopy and asthma in children and adult inhabitants in rural Poland. As reviewed by Tan et al., SCFAs reduce paracellular permeability and induces the expression of TJ genes and MUC2 expression, thus strengthening the epithelial barrier (91) that may subsequently protect the host against infections (92). Interestingly, human RA-primed CD103+ DCs were also shown to induce differentiation of naive T cells into IL-10-producing T cells expressing gut homing markers in vitro (122). Mora JR, Iwata M, Eksteen B, Song S-Y, Junt T, Senman B, et al. The immune complexes can bind to FcRII on antigen-presenting cells (APCs), leading to phagocytosis and clearance of the pathogensas well as antigen presentation to (regulatory) T cells. Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of -catenin signaling. For further reading about TJ proteins, we would like to refer to other excellent reviews specifically about occludins (75), claudins (73), or the function and morphology of TJs in general (72, 77). Cytosolic scavenger proteins (e.g., ZO-1) link the actin cytoskeleton to paracellular located proteins: the claudins and occludins. PMC legacy view Thus, several components present in cows milk promote epithelial barrier functioning (Figure (Figure11). These vitamin D3 DCs are less sensitive to TLR ligands and develop a semi-mature phenotype upon stimulation. Zabel BA, Agace WW, Campbell JJ, Heath HM, Parent D, Roberts AI, et al. congenital lung disease Indeed, several B. longum strains were capable of converting 3SL and 6SL, which are abundantly present in bovine milk, into SCFA in vitro (55). We thank J. Geurts and L. Ulfman for critically reviewing the manuscript. The role of milk oligosaccharides in the induction of oral tolerance remains inconclusive. This protective effect was shown to be mediated by acetate produced by the microbiota.

It is now well established that children growing up on a farm less often develop allergies and asthma (35). lung obstructive diet disease slideshow fish modalities respiratory sleep In the lamina propria, RA may induce expression of gut homing markers CCR9 and 47 on T cells and CCR9 on B cells directly or prime DC to induce the expression of these markers in the mesenteric lymph node (MLN). Furthermore, germ-free mice showed increased susceptibility to pulmonary infection with K. pneumoniae, which could be restored by i.p. In breastfed infants, the genus Bifidobacterium is commonly present, which comprises mainly Bifidobacterium bifidum, Bifidobacterium longum subsp. Interestingly, maternal RSV-specific antibodies in amniotic fluid were recently shown to protect mouse pups from RSV infection for at least 1week after birth (61). DCs metabolize sunlight-induced vitamin D3 to program T cell attraction to the epidermal chemokine CCL27. The activation of this exogenous latent TGF can be triggered by multiple factors such as macrophages membrane-bound receptor TSP-1, v-3/5/6 and v8 integrins, ROS, low pH during passage of the stomach, and proteases (49, 50). These studies demonstrate that microbial metabolites produced in the intestines can have an effect on immune function in the airways. histamine) upon secondary exposure to the allergen that cause immediate type I allergic symptoms. Interestingly, it has been shown that the microbial community in the upper respiratory tract can be differentially modulated by breast milk compared to formula-fed children (59). Thus, different cell types are responsible for Th2-mediated diseases such as allergies. 6SL was shown to alleviate OVA-induced food allergic symptoms by promoting IL-10-producing T cells (115). The new PMC design is here! Immunosuppressive cytokines such as IL-10 and TGF in milk are important in maintaining immune homeostasis and the suppression of type I interferon production. We briefly describe several immunomodulatory components in cows milk that are used in this review to illustrate potential mechanisms by which cows milk may affect respiratory health. Roche JK, Martins CAP, Cosme R, Fayer R, Guerrant RL. The proposed mechanism involves binding of IgG to neonatal Fc receptor (FcRn), which resulted in the expansion of antigen-specific Tregs. The mechanisms underlying this protective effect of raw cows milk remains speculative. TGF1 induces the expression of claudin-4 and protein kinase C expression in vitro, both strengthening the barrier (87, 88). McCarthy RJ, Ross RP, Fitzgerald GF, Stanton C. The immunological consequences of pasteurisation: comparison of the response of human intestinally-derived cells to raw versus pasteurised milk, Mechanisms and modulation of intestinal epithelial repair, Claudins, dietary milk proteins, and intestinal barrier regulation. Kalliomki M, Ouwehand A, Arvilommi H, Kero P, Isolauri E. Transforming growth factor-beta in breast milk: a potential regulator of atopic disease at an early age. and transmitted securely. This indicates that the farming environment might protect the children from the detrimental effects of Moraxella. TLR stimulation in the gut could activate DCs leading to the activation of lymphocytes in the mediastinal lymph node. den Hartog G, van Altena C, Savelkoul HFJ, van Neerven RJJ. 1,25-hydroxyvitamin D3 may induce the expression of homing marker CCR10 on T and B cells directly or indirectly via vitamin D3-primed DC (VitD3 DC). Lymphoid tissues in the upper airways are the lingual tonsils, tubal tonsils, palatine tonsils, and adenoids, together forming the Waldeyers ring (98). Viral infections during this critical period also impact health later in life. Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N, Ngom-Bru C, et al. TJs consists of a ziplock-like structure of multiple protein strands that are connected to the cytoskeleton, allowing selective transport across the barrier (72). Currently, there is no in vivo evidence on effects of cows milk on epithelial barrier functioning.

Brand-Miller JC, McVeagh P, McNeil Y, Messer M. Digestion of human milk oligosaccharides by healthy infants evaluated by the lactulose hydrogen breath test. For instance, the protease activity of one of the major HDM allergens, Der p 1, was shown to disrupt the cleavage site in the extracellular loops of claudins and occludins (79). This review focuses on potential mechanisms via which cows milk or its components can influence immune function in the intestine and the upper respiratory tract. Bodammer P, Kerkhoff C, Maletzki C, Lamprecht G. Bovine colostrum increases pore-forming claudin-2 protein expression but paradoxically not ion permeability possibly by a change of the intestinal cytokine milieu. Less is known about the effect of vitamin A on barrier functioning. Similarly, infants of 46months of age receiving infant formula supplemented with lactoferrin showed fewer respiratory illness (42, 43). TH2, allergy and group 2 innate lymphoid cells, Barrier epithelial cells and the control of type 2 immunity, Childhood risk factors for atopy and the importance of early intervention. It is suggested that this regulatory milieu induced to breast milk components favors tolerance inductions towards other harmless antigens such as allergens (102). The Moreover, pups of mothers that were exposed to antigen aerosols during lactation resulted in a regulatory immune response that protected them from developing asthma (112). Milk: an exosomal microRNA transmitter promoting thymic regulatory T cell maturation preventing the development of atopy? Of the three, B. longum infantis has the right machinery to ferment sialylated oligosaccharides directly (52, 53) and is unique in its ability to import and degrade low-molecular-weight oligosaccharides (54). Anti-inflammatory mechanisms of bioactive milk proteins in the intestine of newborns. Vitamin A can be obtained from different dietary sources and can be converted to its active metabolite retinoic acid (RA) by epithelial cells and DCs in the gut (32). In the oropharynx, raw cows milk components can contribute to immune homeostasis via different mechanisms. Human milk glycobiome and its impact on the infant gastrointestinal microbiota, Utilization of major fucosylated and sialylated human milk oligosaccharides by isolated human gut microbes. This type of tolerance induction is known as oral tolerance.

Riedler J, Braun-Fahrlnder C, Eder W, Schreuer M, Waser M, Maisch S, et al. Lactose digestion and the evolutionary genetics of lactase persistence. Nevertheless, these studies show that the thermosensitive fraction of the milk (i.e., proteins, most likely whey fraction) is an important driver of the protection against not only allergies and asthma but also viral infections, fever, and inflammatory conditions in the upper airways. Bovine milk, including pasteurised milk, contains antibodies directed against allergens of clinical importance to man. Vitamins A and D are potent inhibitors of cutaneous lymphocyte-associated antigen expression. However, it should be noted that the concentrations of vitamin A and vitamin D3 are relatively low in cows and breast milk.

In Europe, rapid evolutionary changes are found in the lactase persistance gene suggesting health benefits of cows milk consumption to humans (Box 1). Evidence for the existence of this so-called gutlung axis is increasing, although the exact mechanisms involved are not yet completely understood (125128). The anti-inflammatory properties of milk components on the epithelium are reviewed by Chatterton et al. Several studies indicate that SCFAs play an important role in the gutlung axis by regulating immune activation in the lung (132, 133) (Figure (Figure2).2). Gregori S, Tomasoni D, Pacciani V, Scirpoli M, Battaglia M, Magnani CF, et al. However, for ethical reasons, it is not possible to conduct controlled studies with raw cows milk in infants, so formal proof is lacking to date.

Hammerschmidt SI, Friedrichsen M, Boelter J, Lyszkiewicz M, Kremmer E, Pabst O, et al. Since both vitamins are present in milk, we speculate that raw milk may influence homing of lymphocytes to the upper respiratory tract. These DCs had a more immature phenotype (lower levels of MHCII and CD40) and therefore a reduced capacity of activating Th2 cells (132). In comparison to ultra-heat-treated milk, raw milk consumption in the first year of life was inversely associated with the occurrence of rhinitis, otitis, and respiratory tract infections at 12months of age. Detection of milk oligosaccharides in plasma of infants. Yoshida M, Claypool SM, Wagner JS, Mizoguchi E, Mizoguchi A, Roopenian DC, et al. This study showed that raw cows milk consumption in the first year of life is inversely associated with atopic sensitization and asthma independently of the farming environment. Moreover, increased demethylation of the FOXP3 gene and increased FoxP3+ T cell numbers were detected in PBMC cultures of children who were exposed to farm milk, suggesting that farm milk consumption induces an immunoregulatory phenotype. For instance, 10% of the orally fed bovine IgG (bIgG) can be found in stool of infants, compared to <0.1% in adults (47). Moreover, in low concentrations, lactoferrin induces differentiation of epithelial cells, whereas lactoferrin stimulates proliferation in higher concentrations (26). showed that the protective effect of cows milk on asthma and hay fever incidence was only noted in children who consumed raw milk and not in children who consumed high heat-treated shop milk (>85C). In contrast, RSV disrupts barrier functioning by remodeling the actin cytoskeleton and interfering with cytosolic scavenger proteins (80). This makes it appealing to speculate that this mutation confers health benefits to the host by consuming cows milk. A follow-up study investigated the association between raw, boiled, or commercially available cows milk consumption and the occurrence of common infections in infants (212months of age). Lymphocytes expressing CCR9 have a homing capacity toward the small intestine, while lymphocytes expressing CCR10 have a homing potential toward the colon and respiratory tract, providing a potential mechanism of the gutlung axis. In contrast, pups fed milk that contained 3SL had more severe induced colitis compared to pups fed milk devoid of 3SL.

In addition, the active metabolites of these vitamins can be endogenously produced (e.g., by stromal cells) in the secondary lymphoid tissues. Mosconi E, Rekima A, Seitz-Polski B, Kanda A, Fleury S, Tissandie E, et al. However, no differences were observed in permeability, which was proposed to be counteracted by the milk-induced increase of endogenous TGF expression. The dual role of TGF was shown in a recent review, which showed that TGF-induced SMAD proteins are key in balancing immunity (108). These studies indicate that there is cross-talk between the commensal microbiota and immunity in the respiratory tract via TLR signaling (Figure (Figure22). 8600 Rockville Pike This introduction of processed ruminant milk might explain why it was adopted so quickly, despite lactose intolerance. Effect of bovine lactoferrin from iron-fortified formulas on diarrhea and respiratory tract infections of weaned infants in a randomized controlled trial.

The consumption of farm milk is associated with higher regulatory FoxP3+ T cell numbers, which were negatively associated with doctors-diagnosed asthma and IgE levels (37). Puddu P, Latorre D, Carollo M, Catizone A, Ricci G, Valenti P, et al. These RA DCs expressed CD103 and were capable of polarizing naive T cells into Tregs (121) or FoxP3 IL-10-producing T cells (122). Careers, Edited by: Philip Calder, University of Southampton, United Kingdom, Reviewed by: Linette Willemsen, Utrecht University, Netherlands; Dayong Wu, Tufts University, United States. Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway. The .gov means its official. It was suggested that the milk fat globule membrane contributes to this negative association between boiled milk consumption and respiratory tract infections (19). The bacterial extract also boosted specific polyclonal antibodies against Klebsiella pneumoniae and Streptococcus pneumoniae, which protected the mice against these airway pathogens (130). Although articles report different concentrations of TGF in breast and cows milk, there is a consensus that TGF2 is several fold more abundant compared to TGF1 (21, 24). These findings were confirmed in vitro in humans by differentiating moDC in the presence of RA. The exact mechanism by which allergy and viral infection in the upper airways results in the development of asthma is not yet elucidated. Watanabe K, Sugai M, Nambu Y, Osato M, Hayashi T, Kawaguchi M, et al. Similarly, moDC differentiated in the presence of bovine lactoferrin showed inhibited cytokine responses and surface marker expression upon stimulation with TLR ligands (106). When the allergen or virus is not neutralized, it will encounter the epithelial cell layer of mucosal tissues. One of the proteins in cows milk that is important for epithelial barrier functioning is TGF. Earliest date for milk use in the Near East and southeastern Europe linked to cattle herding. Licona-Limn P, Kim LK, Palm NW, Flavell RA. In contrast, T cells express CCR10 to bind CCL28 produced in the lower respiratory tract and salivary glands (16, 139), while T cells express CCR3 to bind CCL28 in the nasal mucosal (140). This finding is in line with in vitro studies showing that vitamin D3 induces CCR10 expression on human B and T cells (149, 151, 153). Uptake of antigens by the tonsils occurs via M-like cells in specialized induction sites, which are composed of follicles containing both myeloid and lymphoid cells (99). However, as stated in the review by ten Bruggencate et al., it is to date uncertain which sialylated oligosaccharides can serve as a decoy receptor for human respiratory infecting viruses (30). Strikingly, the active forms of TGF1 and TGF2 are identical between cow and human (23). Nevertheless, both studies show that either raw cows milk or farm milk is associated with lower total serum IgE levels and allergic diseases (37, 39). Thus, TGF can be activated by binding integrins in the upper airways or by activation in the stomach and small intestine. Children with asthma show a lower nasal microbiota composition and higher abundance of Moraxella (60). The active form of vitamin D3, 1,25(OH)2D3, halts the differentiation of monocytes into moDC in vitro and does not affect pDCs (124). Loss et al. Recent evidence suggests that it can also be modified by dietary components. Cross-reactive antibodies to other human pathogens have also been demonstrated in bovine milk and colostrum.

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