Analyzed the data: MP, AV. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer, MS, and handling editor declared their shared affiliation, and the handling editor states that the process nevertheless met the standards of a fair and objective review.
We thank Nelsy Scheleef for histological slides and Pilar Crespo for flow cytometry support. A Kovacs Nolan J, Mine Y. Egg yolk antibodies for passive immunity. Annu Rev Food Sci Technol — Rediscovering the importance of mucosal immune system MIS in poultry. Acad J Biotechnol 4 3 —5. Redvet 15 1 :1—8. Google Scholar. Anti ETEC IgY administered by pH sensitive-hydrogels carbon nanotubes nanocomposites to prevent neonatal diarrhea in experimentally challenged piglets.
Vaccine —7. Reflection of serum immunoglobulin isotypes in the egg yolk of laying hens immunized with enterotoxigenic Escherichia coli. Vet World 7 9 — Production of egg yolk immunoglobulin against Escherichia coli from white leghorn and lohmann chickens. J Anim Vet Adv 10 18 — Characterization of egg yolk immunoglobulin IgY against enterotoxigenic Escherichia coli and evaluation of its effects on bovine intestinal cells.
Afr J Microbiol Res 7 5 — Effects of dietary egg yolk antibody powder on growth performance, intestinal Escherichia coli colonization, and immunocompetence of challenged broiler chicks.
Poult Sci 89 Chicken egg yolk antibody Ig Y powder against Escherichia coli K J Anim Vet Adv 9 2 — The mucosal immune system for vaccine development. Vaccine — Reciprocal interactions of the intestinal microbiota and immune system. Nature — Honda K, Takeda K.
Regulatory mechanisms of immune responses to intestinal bacteria. Mucosal Immunol 2 3 — Kogut M. The gut microbiota and host innate immunity: regulators of host metabolism and metabolic diseases in poultry. J Appl Poult Res — Kohl K. Diversity and function of the avian gut microbiota. J Comp Physiol B — Guide to the Care and Use of Experimental Animals. Ottawa: Canadian Council on Animal Care Immunophenotyping of chicken peripheral blood lymphocyte subpopulations: individual variability and repeatability.
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Trends Immunol 23 4 — Adjuvants and delivery systems in veterinary vaccinology: current state and future developments. Arch Virol — Immunity, vaccination and tract gastrointestinal aviar.
Dev Comp Inmunol — Mucosal delivery of vaccines in domestic animals. Vet Res — Locations of gut associated lymphoid tissue in the 3-month old chicken: a review. Avian Pathol 39 3 — Smith A, Beal R. The avian enteric immune system in health and disease. Avian Immunology. Academy Press Ratcliffe M.
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Successive immunoglobulin and cytokine expression in the small intestine of juvenile chicken. Dev Comp Immunol — Iseri V, Klasing K.
GSH is essential to maintaining the thiol redox state, which is vital to adequate functioning of enterocytes and immune cells Table 1 [ 6 ]. Glutamate has a very low capacity to cross biological membranes, and enterocytes contain glutamate transporters in the plasma membrane[ 54 ] making them one of the few cells that can rapidly transport and metabolize exogenous glutamate[ 55 ].
Dietary glutamate, as both a carbon and nitrogen donor, is the precursor of the conditionally essential amino acid, arginine[ 55 ]. Maintaining endogenous arginine synthesis in piglet enterocytes has been demonstrated to be essential for optimal growth[ 31 ]. In vitro and in vivo studies have reported that providing glutamate can modulate the intestinal epithelium Table 1.
Although the immune functions of the intestine were not specifically measured in these studies, these changes would be consistent with improved intestinal immune function. However, Tsuchioka et al. Although immune cells produce considerable amounts of glutamate when provided glutamine[ 4 ], investigations into the effects of glutamate on immune cells are limited.
It has been recently reported that T-cells, B-cells, dendritic cells and macrophages express glutamate receptors[ 59 , 60 ], suggesting that glutamate likely has an important role in immune cell function. In support, Sturgill et al. In T-cells, glutamate may function as an immunotransmitter, akin to its role as a neurotransmitter, as extracellular concentrations of glutamate have been shown to regulate T-cell responses Table 1.
Pacheco et al. During the early stages of dendritic cell-T-cell interaction, glutamate binds to the constitutively expressed mGlu5R on T-cells to inhibit proliferation and cytokine production; however, later in the interaction glutamate binds to mGlu1R to induce T-cell proliferation and Th1 and proinflammatory cytokine production[ 61 ].
This study demonstrates that glutamate plays an essential role in regulating antigen-specific T-cell activation and suggests that the high concentrations of glutamate in the intestine may play an important role in T-cell regulation in the gut. Despite glutamate being present in high concentrations in the intestinal lumen and immune cells having unique glutamate receptors, there have not been dietary studies that have directly assessed the effect on GALT. Due to the high oxidation rate of glutamate by enterocytes and immune cells, and its role as a precursor for GSH and other amino acids[ 62 ] it is reasonable to postulate that changes in the availability of glutamate modulates aspects of GALT Table 1.
We recently reviewed the evidence and presented a hypothesis for a novel role of glutamate receptors on immune cells as the means by which changes in glutamate availability modulates specific immune functions[ 6 ].
In that review, we proposed that due to its immunosuppressive effects at concentrations above plasma levels, glutamate may have a key role in the development and maintenance of oral tolerance[ 6 ], a unique aspect of immunity in the intestine. Despite the lack of investigation into the immune modulating properties of glutamate on GALT, it is likely that it has an essential role. To date, the effects of glutamate on GALT have not been examined in vivo. However, it is likely that glutamate has an essential role as an oxidative substrate to both enterocytes and immune cells.
It is also a precursor for the synthesis of GSH, which is required to protect the intestinal mucosa and optimize immune cell function. And, finally, glutamate is a precursor for arginine, the substrate for the synthesis of NO.
A high rate of NO synthesis by neutrophils is required during the innate immune response to infection. This is an important role of the immune system in the intestine. Dietary glutamate appears essential for intestinal barrier function and likely other immune functions of the IEC, primarily as a precursor for GSH and as an oxidative substrate for enterocytes. Based on the available data, we can only hypothesize that the availability of glutamate to the cells in GALT has an immunoregulatory role.
Studies conducted in systemic immune cells suggest that glutamate is essential for T-cell activation and B-cell immunoglobulin production and we postulate from indirect evidence that glutamate has a role in the induction of oral tolerance that originates in GALT and protection from enteric infections. In most adult mammals, arginine is considered a dietary non-essential amino acid as it can be synthesized from glutamine, glutamate and proline, but becomes conditionally essential during periods of stress[ 63 , 64 ].
Moreover, the absence of arginine in the diet has been shown to have adverse effects in adults, including reproductive, metabolic and neurological derangements[ 29 ]. Arginine is classified as an essential amino acid in young mammals as endogenous synthesis cannot meet demands[ 29 ]. The immune system is particularly sensitive to changes in arginine availability during early development and various disease states. Arginine is the most plentiful nitrogen carrier in animals and is a precursor for urea, polyamines, proline, creatinine, agmatine, glutamate and protein[ 64 ].
Perhaps most importantly, for the immune system, arginine is the only precursor for nitric oxide synthase all isoforms for the synthesis of nitric oxide NO. In both the intestine and immune system, NO is essential for optimal functioning, including regulating the inflammatory response, facilitating killing of microbes by neutrophils and macrophages, and facilitating lymphocyte functions[ 63 ].
The structure and function of the intestine is sensitive to the amount of arginine in the diet during critical periods of development and disease states Table 1. Studies have shown that arginine supplementation supports the growth and the development of the intestine and mucosal barrier in weanling piglets[ 65 , 69 , 70 ]. Dietary L-arginine supplementation ranging from 0. A proposed mechanism is that feeding arginine 0.
In addition to supporting normal growth and development, supplementation with arginine has also been reported to reduce intestinal damage induced by E. Sukhotnik et al. In addition, arginine 0. The immunomodulatory properties of L-arginine are well established and have been reviewed elsewhere[ 63 , 76 , 77 ]. Arginine has a fundamental role in both the innate and adaptive immune responses. One of the primary functions of arginine in leukocytes is as a substrate for inducible nitric oxide synthase iNOS to produce NO.
Macrophages and neutrophils utilize NO to kill a variety of pathogens and malignant cells[ 63 , 76 ]. NO also appears to be important for B-cell development and T-cell receptor function[ 63 ]. The effects of arginine on GALT have been studied in both healthy and disease states and the available evidence suggest a beneficial effect on immune function.
Feeding arginine has been shown to be beneficial to GALT in inflammatory and trauma animal models, as well as healthy animals Table 1. Similarly, Fan et al. Animal models of TPN in both health and disease states have demonstrated that arginine supplementation can reverse the negative effects that TPN not providing nutrients to the intestine has on GALT. This study suggests that dietary arginine may be essential to maintaining the intestinal immune system during acute infection.
Despite these improvements in immune parameters, arginine supplementation in this model of sepsis did not significantly improve survival[ 80 ]. These studies strongly support an essential role for a systemic supply of arginine to maintaining GALT, particularly when the intestine is not receiving nutrients directly from the diet.
There is considerable support that in health and stressed conditions oral ingestion of arginine 0. Arginine also supports the growth, development and maintenance of a healthy intestinal mucosa during critical periods of development weaning and under certain health conditions. The dietary essentiality of methionine and conditional essentiality of cysteine to humans and animals has been well established[ 82 , 83 ]. Currently, there is little direct evidence demonstrating that these sulfur-containing amino acids alter immune function.
However, indirectly their efficacy is supported by evidence that their metabolites taurine, GSH and homocysteine have immunomodulatory properties in vitro [ 82 ]. GSH also see glutamate section functions as a free radical scavenger and may support proper immune cell function through a role in T-cell proliferation, and inflammatory cytokine regulation[ 6 , 82 , 83 ]. GSH also has a crucial role in protecting the intestinal epithelium from electrophile and fatty acid hydroperoxide damage[ 29 ].
There is evidence that taurine and homocysteine have immunodulatory properties. Taurine is an end product of cysteine metabolism and diets devoid of taurine in cats resulted in reduced lymphocyte numbers, and mononuclear cells with impaired respiratory burst capacity[ 82 ].
In an in vitro model, homocysteine promoted monocyte activation and increased their adhesion to endothelial cells[ 84 ]. At present there are no feeding studies to provide direct support for the effect of homocysteine or taurine on immune function in GALT. There is some evidence that dietary methionine and cysteine are important to ensure the health of the intestine and immune function during development and in inflammatory states Table 1.
For example, Bauchart-Thevret et al. Cysteine also appears to be therapeutic in stressed inflammatory states, through improving intestinal inflammation and permeability. An infusion of L-cysteine 0. In addition, less inflammatory cell infiltration, crypt damage and lower intestinal permeability were observed in the pigs supplemented with L-cysteine Table 1 [ 86 ]. While these studies demonstrate the importance of sulfur containing amino acids to gut health in healthy and stressed animals, there is no direct evidence of the effects on lymphocyte or macrophage cell function in GALT.
Threonine is a dietary essential amino acid that has been shown to have a particularly high retention rate in the intestine, which suggests an important function in the gut[ 55 , 87 ]. Threonine has a major role in mucin synthesis, a glycoprotein that is required to protect the intestinal epithelium Table 1 [ 88 ]. Mucin production is reduced in diets low or deficient in threonine in healthy rats and piglets[ 88 — 91 ].
Feeding a diet low in threonine 0. Consistent with this, threonine-deficient piglets were found to have higher paracellular permeability which would increase the risk of infectious organisms or their products coming in contact with the body[ 92 ]. To date, there are no studies examining the effect of feeding threonine on the function of immune cells in GALT. However, Hamard et al. Chickens fed 0. Feeding trials, primarily conducted in pigs and rodents, have established convincing evidence that not only the total protein intake but the availability of specific dietary amino acids, in particular glutamine, glutamate, and arginine, and perhaps methionine, cysteine and threonine, are essential to optimizing the immune functions of the intestine and specific immune cells located in GALT.
These amino acids modulate their effects by maintaining the integrity, growth and immune functions of the epithelial cells in the intestine, as well as improve T-cell numbers and function, the secretion of IgA, and regulate inflammatory cytokine secretion.
The studies conducted using feeding regimes TPN that bypass the oral route suggest that amino acids delivered in the blood from other parts of the body are important for maintaining GALT.
To date the majority of the studies have focussed on modulating single amino acids in a diet that contains many different proteins combinations of amino acids and determined function by measuring selective often single parameters functions. Evidence for some of these immunoactive amino acids comes primarily from in vitro studies or cells isolated from the systemic immune system blood.
Intraepithelial lymphocytes: These are lymphocytes that are positioned in the basolateral spaces between lumenal epithelial cells, beneath the tight junctions they are "inside" the epithelium, but not inside epithelial cells as the name may incorrectly suggest. Another important component of the GI immune system is the M or microfold cell.
M cells are a specific cell type in the intestinal epithelium over lymphoid follicles that endocytose a variety of protein and peptide antigens. Instead of digesting these proteins, M cells transport them into the underlying tissue, where they are taken up by local dendritic cells and macrophages.
Dendritic cells and macrophages that receive antigens from M cells present them to T cells in the GALT, leading ultimately to appearance of immunoglobulin A-secreting plasma cells in the mucosa. Dendritic cells below the epithelium can also sample lumenal antigens by pushing pseudopods between epithelial cells. The secretory IgA is transported through the epithelial cells into the lumen, where, for example, it interferes with adhesion and invasion of bacteria.
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