In mice, RA production by mucosal CD103+ DCs (143, 144) or stromal cells in the MLN (145) is essential for efficient differentiation of naive T cells into FoxP3+ Tregs that express the gut homing markers 47 and CCR9 in the MLN. Caco-2 cells express enzymes that are expressed in the fetal intestine and are biochemically and morphologically similar to ileal enterocytes (83). Similarly, moDC differentiated in the presence of bovine lactoferrin showed inhibited cytokine responses and surface marker expression upon stimulation with TLR ligands (106). All authors contributed to the writing process, prepared the manuscript, and approved the final version. After swallowing milk components, allergens, or pathogens, they pass through the GI tract and are exposed to different pH levels and proteases, varying from pancreatic, gastric, or peptidases on the enterocytic brush border. When the allergen or virus is not neutralized, it will encounter the epithelial cell layer of mucosal tissues. Interestingly, breastfed infants showed a higher prevalence of Dolosigranulum that was negatively associated with respiratory tract infections (59). Verhasselt V, Milcent V, Cazareth J, Kanda A, Fleury S, Dombrowicz D, et al. Generation of Gut-Homing IgA-secreting B cells by intestinal dendritic cells. milk dairy diet disease respiratory modalities sleep Milk fatty acids were traced by carbon isotope analysis on Middle Eastern pottery, showing that cows milk was already processed since 6500 BC (154). The binding of bovine IgG to RSV also directly neutralizes RSV, as shown by protection of Hep2 cells from infection with RSV in vitro (64). Hence, we can only speculate about the mechanisms by which cows milk through sialylated oligosaccharides and vitamin A and D could affect microbiota composition or homing of lymphocytes, respectively. It was hypothesized that breast-fed infants developed less otitis caused by viral infections (e.g., RSV and influenza) due to the decoy receptor activity of milk oligosaccharides (29). In colostrum, the concentrations of sialylated oligosaccharides range between 0.231.5 and 13.3g/L in cows and humans, respectively (30). 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). Khoo A-L, Koenen HJPM, Michels M, Ooms S, Bosch M, Netea MG, et al. 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. Another link between airway immunity and the gut microbiota is the release of SCFAs. Martn-Sosa S, Martn M-J, Garca-Pardo L-A, Hueso P. Sialyloligosaccharides in human and bovine milk and in infant formulas: variations with the progression of lactation, Vitamin effects on the immune system: vitamins A and D take centre stage, Prevention of rickets and vitamin D deficiency in infants, children, and adolescents, Vitamin D and its metabolites in human and bovine milk, Farm living: effects on childhood asthma and allergy. Brand-Miller JC, McVeagh P, McNeil Y, Messer M. Digestion of human milk oligosaccharides by healthy infants evaluated by the lactulose hydrogen breath test. In Europe, rapid evolutionary changes are found in the lactase persistance gene suggesting health benefits of cows milk consumption to humans (Box 1). 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). Viruses use lectin-like structures to adhere and infect host cells. However, it is unknown whether dietary vitamin A contributes in the upper airways to induce antigen-specific Tregs. Cows milk contains vitamin A, vitamin D3, and 1,25-hydroxyvitamin D3. Viral infections during this critical period also impact health later in life. Emerging pathogenic links between microbiota and the gutlung axis. Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N, Ngom-Bru C, et al. Antigen-specific IgG in breast milk was shown to protect against OVA-induced asthma in a mouse model by inducing regulatory responses. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Human neonatal Fc receptor mediates transport of IgG into luminal secretions for delivery of antigens to mucosal dendritic cells. B. longum is abundantly present in breast-fed neonates and is thought to confer various health benefits (e.g., enhanced barrier functioning and anti-inflammatory effects) to the host (56). DCs with low CD86/CD80 expression in the presence of TGF or IL-10 are known to polarize naive T cells into FoxP3+ T cells (105). TLR signaling by microbiota in the gut results in improved airway immunity although the exact mechanism in this gutlung axis is unknown. Which aspects of the farming lifestyle explain the inverse association with childhood allergy? In summary, the direct immunomodulatory effect of sialylated oligosaccharides remains inconclusive. This study showed that the thermosensitive milk fraction (i.e., proteins) induced the expression of immune-related pathways and thereby indirectly barrier functioning. Sigurs N, Aljassim F, Kjellman B, Robinson PD, Sigurbergsson F, Bjarnason R, et al. Interestingly, RA also induces CCR10 expression in human B cells and acts even synergistically with 1,25-dihydroxyvitamin D3 (153). Bacterial microbiota of the upper respiratory tract and childhood asthma. obstructive lung slideshow diet disease respiratory modalities sleep Careers, Edited by: Philip Calder, University of Southampton, United Kingdom, Reviewed by: Linette Willemsen, Utrecht University, Netherlands; Dayong Wu, Tufts University, United States. Bovine lactoferrin counteracts toll-like receptor mediated activation signals in antigen presenting cells, SMAD regulatory networks construct a balanced immune system, Dendritic cells in intestinal immune regulation. National Library of Medicine It is now well established that children growing up on a farm less often develop allergies and asthma (35). Effect of bovine lactoferrin from iron-fortified formulas on diarrhea and respiratory tract infections of weaned infants in a randomized controlled trial. Indeed, several B. longum strains were capable of converting 3SL and 6SL, which are abundantly present in bovine milk, into SCFA in vitro (55). This epithelial cell layer is the first line of defense in mucosal tissues. Miner-Williams WM, Stevens BR, Moughan PJ. Several recent studies have shown that immune responses triggered in the GI tract can influence immunity in the respiratory tract. Th2 responses are now known to be enhanced by the production of type 2 cytokines (e.g., TSLP, IL-25, IL-33) secreted by group 2 innate lymphoid cells and epithelial cells (5, 6). The claudin family consists of transmembrane proteins, which via the interaction of claudin strands, are connected to each other by extracellular loops (73). lung obstructive diet disease slideshow fish modalities respiratory sleep Further, the expression of tight junction proteins can be enhanced by several milk components, thus strengthening the mucosal barrier against breaching by allergens and pathogens. will also be available for a limited time. Both acetate and propionate bind via GPR41, which is expressed on various tissues and cells including enteroendocrine cells and PBMCs (134). Mosconi E, Rekima A, Seitz-Polski B, Kanda A, Fleury S, Tissandie E, et al. The integrity of the epithelial barrier in the upper airways (67) and intestine (68) is regulated by tight junctions (TJs). Closure of the barrier occurs only after a few weeks in humans, while in mice, this is a more gradual process that develops during weaning (48, 82). With the discovery of additional T cell subsets such as Th17 cells and regulatory T cells (Tregs), this paradigm had to be revised. Many allergens have protease activity that could breach barrier functioning (78). 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). Bovine IgG shows some affinity for human FcRn (113) and is specific for human allergens (65), and it is therefore possible that the uptake of bovine IgGallergen complexes induces FoxP3+ T cells (Figure (Figure1).1). Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway. In this review, the role of dairy components on epithelial barrier function in terms of epithelial proliferation, differentiation, and TJ regulation is addressed. 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). Immunosuppressive cytokines such as IL-10 and TGF in milk are important in maintaining immune homeostasis and the suppression of type I interferon production. One type of non-digestible fibers are sialylated oligosaccharides present in cows milk. 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). Moreover, RA and TGF1 induce IgA class switching (147). Bakdash G, Vogelpoel LT, van Capel TM, Kapsenberg ML, de Jong EC. Castillo-Courtade L, Han S, Lee S, Mian FM, Buck R, Forsythe P. Attenuation of food allergy symptoms following treatment with human milk oligosaccharides in a mouse model. Interestingly, the production of endogenous TGF1 by epithelial cells is regulated through a positive feedback loop by other milk proteins like lactoferrin that triggers an intracellular cascade that results in the production of TGF1. These studies demonstrate that microbial metabolites produced in the intestines can have an effect on immune function in the airways. lung congenital disease Rezaee F, DeSando SA, Ivanov AI, Chapman TJ, Knowlden SA, Beck LA, et al. Retinoic acid imprints gut-homing specificity on T cells. We here address several potential cows milk components that might promote these regulatory responses. However, the majority of vitamin D3 is taken up into the systemic and converted into its active form in the kidneys. Rudloff S, Pohlentz G, Borsch C, Lentze MJ, Kunz C. Ruhaak LR, Stroble C, Underwood MA, Lebrilla CB. Nevertheless, atopy and viral infections in early life are risk factors for asthma development. ten Bruggencate SJM, Bovee-Oudenhoven IMJ, Feitsma AL, van Hoffen E, Schoterman MHC. Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier, All-trans retinoic acid enhances differentiation and influences permeability of intestinal Caco-2 cells under serum-free conditions. Thus, bovine IgG can neutralize RSV infection in vitro and might also play a role in preventing sensitization by binding allergens and supporting barrier functioning by preventing binding of TLR ligands to the epithelium. Mucosal immune development in early life: setting the stage. Requirement for runx proteins in IgA class switching acting downstream of TGF-1 and retinoic acid signaling. Perdijk O, van Neerven RJ, Meijer B, Savelkoul HF, Brugman S. Induction of human tolerogenic dendritic cells by 3-sialyllactose via TLR4 is explained by LPS contamination. Less is known about the effect of vitamin A on barrier functioning. Bovine milk, including pasteurised milk, contains antibodies directed against allergens of clinical importance to man. Thus, it is evident that vitamin D3 contributes to epithelial barrier function by regulating TJ protein expression. Breast milkmediated transfer of an antigen induces tolerance and protection from allergic asthma. Riedler J, Braun-Fahrlnder C, Eder W, Schreuer M, Waser M, Maisch S, et al. 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. In addition, soluble CRP levels were lower in the infants that received raw cows milk. Retinoic acid induces homing of protective T and B cells to the gut after subcutaneous immunization in mice, Vitamin A and retinoic acid in the regulation of B-cell development and antibody production. To date, it is unknown whether raw cows milk alters the nasopharyngeal microbiota composition and if this influences susceptibility toward upper respiratory tract infections or allergies. In addition, sialylated milk oligosaccharides were shown to alter the microbiota composition and growth in infants (118). lungs healthy human surely tips help Neonates receiving infant formulas were shown to have a higher gut permeability compared to breast-fed neonates. Upon activation, these lymphocytes can migrate to the lung and potentially to the gut. SCFAs bind to metabolite-sensing G protein-coupled receptors, and signaling influences gene expression via induction of histone deacetylases (133). Another homing marker that could be important in migration between gut and lung is CCR6 as its ligand CCL20, which are expressed in both tissues (141). A high-fiber diet was prevented against allergic airway disease (AAD) in mice (132, 133). 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). The conversion locally by epithelial cells of dietary inactive vitamin D3 into the active form can create a microenvironment containing active vitamin D3. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. In line with these findings, controlled studies in infants with milk components such as lactoferrin, milk fat globule membrane, and colostrum IgG have shown to reduce respiratory infections. HHS Vulnerability Disclosure, Help The mucosal immune system is capable of distinguishing between harmful and harmless compounds resulting in inflammation or tolerance, respectively. B. longum infantis has been shown to ferment sialylated oligosaccharides directly (52, 53). lung infection course Saad K, Abo-elela MGM, El-baseer KAA, Diab M, Khair A, Abdel-salam AM, et al. 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. Thus, in infants, a significant fraction of milk proteins reaches the small intestine intact and may interact with intestinal immune cells (e.g., epithelial cells and sampling DC). However, the concentration or presence of several specific components (e.g., -lactoglobulin specific for cows milk) may differ. DC) and immunoregulatory T cells (Tregs). Overgaard CE, Daugherty BL, Mitchell LA, Koval M. Claudins: control of barrier function and regulation in response to oxidant stress, Regulation of intestinal epithelial permeability by tight junctions, Occludin: structure, function and regulation, Tight junctions and the regulation of gene expression. One mechanism by which food components could modulate immunity in the (upper) respiratory tract is by preventing contact between pathogens or allergens and the host immune system. A similar association of raw cows milk consumption with respiratory tract infections is recently found. RN is an employee of FrieslandCampina and MS received research funding from FrieslandCampina. This introduction of processed ruminant milk might explain why it was adopted so quickly, despite lactose intolerance. A role for CCL28-CCR3 in T-cell homing to the human upper airway mucosa. In contrast, RA also decreased the expression of claudin-2, resulting in a decrease in permeability of the Caco-2 model (97). Direct oral administration of acetate resulted in higher Treg numbers in the lung and protection against HDM-induced AAD (133). These RA DCs expressed CD103 and were capable of polarizing naive T cells into Tregs (121) or FoxP3 IL-10-producing T cells (122). For example, respiratory syncytial virus (RSV) infection in early life was shown to increase the risk of wheezing up to 11years of age (9) and allergic sensitization and development of asthma into adulthood (1012). infection rhinitis disease opsic den Hartog G, Savelkoul HFJ, Schoemaker R, Tijhaar E, Westphal AH, de Ruiter T, et al. Anti-inflammatory mechanisms of bioactive milk proteins in the intestine of newborns. Cows milk and colostrum contain several immunoregulatory cytokines such as TGF and IL-10. plague arsenic pneumonic poison biology breathing droplets person creative showing breath looks who compared the composition of breast milk to cows milk (18). 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. As mentioned earlier, milk oligosaccharides are fermented in the colon into SCFAs (51). Vitamins A and D are potent inhibitors of cutaneous lymphocyte-associated antigen expression. about navigating our updated article layout. Indeed, the thermosensitive whey proteins BSA, -lactalbumin, and -lactoglobulin were associated with the protective effects. Intrarectal administration of TLR agonists could restore immune responses to influenza infection in this model. Well-studied homing marker interactions in humans are among others, CCR9 binding to locally produced CCL25 in the small intestine (136, 137) and CCR10 binding to CCL28 produced in the airways and colon (138). van Neerven RJJ, Knol EF, Heck JML, Savelkoul HFJ. Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma, Viral infections and atopy in asthma pathogenesis: new rationales for asthma prevention and treatment, The role of FcRI expressed in dendritic cells and monocytes. disease obstructive lung chronic pulmonary respiratory copd teeth slideshow diet lungs brushing diseases effects brush happen foods mineral vitamin energy Clusterin in human gut-associated lymphoid tissue, tonsils, and adenoids: localization to M cells and follicular dendritic cells. TGF is an unique pleiotropic cytokine that is produced by leukocytes and epithelial cells (107). 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. To clear the influenza infection, commensal bacteria or TLR agonists were needed to induce inflammasome-dependent cytokine release (IL-1 and IL-18). Sialylated milk oligosaccharides promote microbiota-dependent growth in models of infant undernutrition. Peptidase allergens, occludin and claudins. Second, sialylated oligosaccharides may function as decoy receptors for viruses in the lumen of the oropharynx, preventing viral adhesion. Enhanced mucosal antibody production and protection against respiratory infections following an orally administered bacterial extract. calf replacers Bovine immunoglobulin/protein isolate binds pro-inflammatory bacterial compounds and prevents immune activation in an intestinal co-culture model.