key: cord-0891074-pgsykrqx
authors: Chase, Christopher C.L.
title: Enteric Immunity: Happy Gut, Healthy Animal
date: 2018-02-01
journal: Vet Clin North Am Food Anim Pract
DOI: 10.1016/j.cvfa.2017.10.006
sha: 816fa47b64256a73d8635151611f7b79618735cd
doc_id: 891074
cord_uid: pgsykrqx

In this article, key concepts important for enteric immunity are discussed. The gastrointestinal tract is the largest immune organ of the body. The mucosal barrier, the tight junctions and the “kill zone,” along with the gut mucosa and maintaining an “anti-inflammatory” state are essential for “good gut health.” The microbiome, the microorganisms in the gastrointestinal tract, which has more cells then the entire animal’s body, is essential for immune development, immune response, and maximizing ruminant productivity. Direct-fed microbials aid in both microbiome stability “homeostasis” and immune function.

In the last decade, there has been an explosion of knowledge on the immune system with substantial implications for enteric health. This increase in knowledge revolves around the realization that the gastrointestinal (GI) tract is the largest immune organ of the body. It is understood that the mucosal immune system begins development in the fetus but does not become functional until epithelial cells of the mucosa in the neonate interact with microorganisms (microbiome) and/or their products in the gut lumen. The interaction between the epithelial cells and the microbiome is necessary for proper immune development, including immune system maturation, regulation, and maintenance of homeostasis. In this article, the interaction of immune system, microbiome, and the ability to maximize immunity are discussed.

The bovine mucosal immune system prevents bacterial invasion and shapes the gut microbiota, whereas the gut microbiota influences immune system development. The fetal calf is predominately protected by the innate immune system (Fig. 1) . 1 The innate immune response of phagocytic cells (neutrophils and macrophages) does not fully develop until late gestation and declines before gestation because of fetal cortisol levels. 2 Humoral elements such as complement are present but are at levels below that of the adult. Interferon can be induced in the fetus as early as 60 days of gestation. 3 All of the cellular components of the acquired immune response are present in the fetal calf. 4 The number of peripheral blood T cells dramatically decrease, beginning 1 month before birth of the calf, as they traffic and populate lymphoid tissues of the fetal calf before birth (decrease w60% to 30% at birth). B cells are much lower in the developing fetus (1%-2%). 4, 5 The enteric mucosal lymphoid organ system begins developing at 100 days of gestation when the mesenteric lymph nodes are present (Fig. 2) . [6] [7] [8] The continuous ileal Peyer patch (IPP) (see Fig. 2 ) becomes quite active by day 85 of gestation. 9 The B lymphocytes present are almost exclusively immunoglobulin M (IgM) 1 cells, and if the IPP are removed, the animals remain deficient in B cells for at least 1 year because the IPP is the major source of the peripheral B-cell pool. 9 Because the IPP is the site of both proliferation and negative selection, IPP follicles can be inferred as the major site for generation of the preimmune B-cell repertoire in ruminants, [8] [9] [10] whereas the discreet Peyer patches (PPs), distributed throughout the jejunum, function as induction sites for the generation of IgA plasma cells (see Fig. 2 ). 10 The role of the rumen in mucosal immunity is unclear because there are few leukocytes in the developing rumen. The first few weeks after birth are essential for long-term enteric immunity as the expression of host microRNAs (miR), and the presence of commensal microorganisms determines long-term gut and host health. 11 By day 21 of age, there is a maximum induction of host miR by high levels of microorganisms of the microbiome. 11 These immune developments include induction of tolerance to dietary components, reduction of mast cells that causes increased gut permeability, and decreased pathogen responses. Changes in diet in the early period of 7 to 21 days of age greatly influence microbiome and miR and therefore the level and longevity of the enteric immune response. 11 

Colostrum is composed of antibodies, cytokines, and cells. Antibody is the most important component of colostrum and provides an immediate source of antibody for the intestinal tract. Bovine colostrum contains w55 mg/mL of total IgG (48 mg/ mL IgG1, 3 mg/mL IgG2, and 4 mg/mL IgA). 13 Preparturient vaccination of the cow for enteric diseases, such as colibacillosis, Clostridium perfringens, cryptosporidiosis, 14 and rotaviruses, 15 results in production of pathogen-specific antibodies that provide protection for the neonate against severe disease. A second component of colostrum is cytokines. 16, 17 These immunologic hormones help in the development of the fetal immune response. These cytokines are produced by the immune cells that traffic to the mammary gland. Interleukin 1-beta (IL-1b), IL-6, tumor necrosis factor alpha (TNF-a), and interferon-gamma are present in bovine colostrum and associated with a proinflammatory response and may help in the recruitment and development of neonatal lymphocytes into the gut to aid in normal immune development. Colostrum rapidly improves the ability of neutrophils to phagocytize bacteria, which is accomplished by absorption of proinflammatory cytokines. 18 Colostrum also contains high levels of the anti-inflammatory cytokines IL-10 19 and transforming growth factor beta (TGF-b) 20 that suppress local secretion of proinflammatory cytokines in the intestine to maintain tight junctions and also allow gut microbial colonization. The third component of colostrum is cells. Colostrum contains viable leukocytes in percentages similar to peripheral blood with more macrophages (40%-50%) and less lymphocytes (22%-25%) and neutrophils (25%-37%). 21, 22 The vast majority of lymphocytes are T lymphocytes with less than 5% being B lymphocytes. Some of these maternal cells enter the circulation and reach peak levels 24 hours after birth. 23 Animals that receive colostrum containing maternal leukocytes develop gut antigenpresenting cells (APC; macrophages and dendritic cells [DC]) faster, 22 which is important because APCs are the keystone cell for the development of an acquired immune response to pathogens or vaccines. Additional pathogen-specific maternal T lymphocytes from vaccinated cows have been isolated from the neonatal calf with maximum proliferation at 1 day following birth. 24 The exact role of these cells in the long-term development of pathogen-specific mucosal-acquired immunity is not clear, because they are no longer detectable at 7 days of age.

The enteric mucosal immune system provides the first immune defense barrier for more than 90% of potential pathogens (Figs. 3 and 4) . The gut mucosal immune system alone contains more than a trillion (10 12 ) lymphocytes and has a greater concentration of antibodies than other tissue in the body. It protects against harmful pathogens but also tolerize (induces tolerance) the immune system to dietary antigens and normal microbial flora. The components of the gut mucosal immune system are integrated together (see Figs. 3 and 4) . 25 The health of the enterocytes, which are the epithelial cells that line the GI tract, is important not only for the growth and development of cattle, through secretion and absorption in the gut, but also to provide a first immune response to microorganisms (see Fig. 4 ). The goblet cells secrete mucous and mucins (the enterocytes also secrete mucins) that provide the initial mucous barrier (see Fig. 4 ). [26] [27] [28] [29] The mucosal barrier contains defensins (also known as antimicrobial peptides [AMP] and host defense proteins [HDP]) produced by the enterocytes (see Fig. 4 ). Secretory immunoglobulin A (sIgA) is produced when dimeric IgA is secreted by the plasma cells in the lamina propria (LP) and is transported to the mucosal surface of the epithelial cell. The inner mucous layer along with the AMP Chase and sIgA forms a "kill zone" that few pathogens or commensals have evolved strategies to penetrate (see Fig. 4 ). 26 The "kill zone" along with the tight junctions that knit the enterocytes together forms a "barrier" against pathogens.

Once microorganisms breech the barriers, the innate immune system is the first responder to pathogen invasion. The system consists of white blood cells (macrophages, monocytes, DC, basophils, neutrophils, eosinophils, mast cells, and natural killer [NK] cells) (Fig. 5) , complement, and the secreted immune system mediators, including chemokines and cytokines. These innate immune mediators include interferon, the proinflammatory mediators TNF-a, IL-1b, IL-6, macrophage inflammatory protein 1-alpha, and the anti-inflammatory mediator IL-10. 30 The innate response occurs in 2 waves. The first wave that occurs in the first few hours following damage or infection features the activation of macrophages, the major producer of proinflammatory cytokines that recruit other white blood cells and activate neutrophils, nonspecific killers of bacteria to increase killing of pathogens. If the proinflammatory response in the gut mucosa is excessive, "leaky gut" will occur (Fig. 6A) . 31, 32 The proinflammatory cytokines, particularly TNF-a, stimulate the myosin II regulatory light chain kinase (MLCK), which causes the tight junctions to break down so the epithelium becomes leaky (see Fig. 6A ). Mucosa epithelium needs to be hyporesponsive under the influence of the anti-inflammatory cytokines 31 so healthy mucosa enterocytes will maintain tight junctions. A local increase of the anti-inflammatory cytokine IL-10 results in inhibition of the local proinflammatory response and increases eosinophils in the tissue. Cattle that are resistant to GI parasites like Cooperia and Ostertagia have an increase of both proinflammatory and anti-inflammatory mediators in the mucosa with a large influx of eosinophils into the tissue and lumen. 33 With only a proinflammatory response, there is little resolution of disease and enhanced collateral damage and immunopathology. 34 Immunopathology is seen in protozoal diseases like cryptosporidia, where localized neutrophilia is enhanced in young animals [34] [35] [36] and also has been hypothesized as the major contributor to the lesions of C perfringens alpha toxin. 37 The proinflammatory anti-inflammatory mucosal response increases with Enteric Immunity: Happy Gut, Healthy Animal age and results in less disease. Neutrophils (see Fig. 5 ) also known as polymorphonuclear cells die after a short time at sites of inflammation. The hydrolytic enzymes are released and contribute to the inflammatory response and tissue destruction, which contributes to collateral damage and enhanced disease. Neutrophil granule proteins induce adhesion and emigration of inflammatory monocytes to the site of inflammation. Neutrophils also create extracellular defenses by the formation of neutrophil extracellular traps (NETs) (Fig. 6B) . [38] [39] [40] The NET formation is induced by agents like bacterial aggregates and biofilms, fungal hyphae, and protozoan parasites (cryptosporidia, Neospora, and coccidiosis) that cannot be phagocytized. 35, 36, 41, 42 Neutrophils use the potent oxidative metabolism system to kill bacteria. The NET reaction is one of the most potent bactericidal mechanisms of neutrophils and is Enterocytes sense the microbiota and their metabolites to induce the production of AMPs. Goblet cells produce mucin and mucous that is organized into a dense, more highly cross-linked inner proteoglycan gel that forms an adherent inner mucous layer, and a less densely cross-linked outer mucous layer. The outer layer is highly colonized by constituents of the microbiota. The inner mucous layer is largely impervious to bacterial colonization or penetration due to its high concentration of bactericidal AMPs, as well as commensals sIgA, which is moved from their basolateral surface, where it is bound by the polymeric Immunoglobulin receptor (pIgR), to the inner mucous layer. Responding to the microbiotal components, innate lymphoid cells (ILC), lymphoid tissue inducer cells (LTi), and NK produce cytokines, which stimulate AMP production and maintain the epithelial barrier. potentially fungicidal, parasiticidal, and virucidal. The eosinophil is capable of the same phagocytic and metabolic functions as the neutrophils but focuses the host's defense against the tissue phase of parasitic infections (see Fig. 5 ). Eosinophils are more capable of exocytosis than phagocytosis; that is, rather than ingesting and killing small particles, they efficiently attach to and kill migrating parasites that are too large to be ingested. Eosinophils are also important in helping to control certain types of allergic responses. Basophils and mast cells (see Fig. 5 ) have been associated primarily with allergic reactions because of their binding of IgE. These cells have an important regulatory role. They release inflammatory mediators necessary for the activation of the acquired immune response. 43, 44 Interferon, the last component of the innate response, sets up an immediate wall against virus infections. The second wave that occurs a day or 2 later is the NK cells (see Fig. 5 ) that enhance defensin production, 25,26 kill parasites, 35, 36 and virally infect cells 45 but also produce cytokines to help the adaptive immune response. 45 The adaptive phase occurs in the organized gut-associated lymphoid tissues (GALT) described above. 8 GALT is the initial induction site for mucosal immunity for antigens that are sampled from mucosal surfaces. The number and maturity of DCs and T cells in the GALT in the jejunum and ileum are very similar in the newborn and the weaned calf, indicating that the mucosal adaptive response is functional at birth. 46 The DCs are important because they are APCs that help in discriminating between dietary antigens, commensal microflora, and pathogens, and in providing a proper adaptive immune response with T cells.

These mucosal aggregates or follicles of B cells, T cells, and DCs are covered by epithelium that contains specialized epithelial cells called dome or M cells that are found Enteric Immunity: Happy Gut, Healthy Animal in the GALT. These dome cells pinocytose antigen and transport it across the epithelial layer (Fig. 7) . 47 The antigen may then be processed by APCs and presented to T and B lymphocytes; indeed, intestinal APCs play a central role in the induction and maintenance of mucosal immunity. 47 These follicles are organized like lymph nodes with T-cell areas and B-cell germinal centers. 7, 46 The lymphocytes that emigrate from these organized areas into the surrounding LP are referred to as diffuse lymphocytes. 48 The hallmark of the mucosal immune system is that local stimulation will result in memory T and B cells in the nearby mucosal tissue but also in other mucosal tissues.

In the mucosal lymphoid tissues, mature T cells and B cells that have been stimulated by antigen and induced to switch to produce IgA will leave the submucosal lymphoid tissue and reenter the bloodstream. 49 These lymphocytes will exit the bloodstream through high endothelial venules (HEV) as described above and locate in the LP (see Fig. 7) . B cells will differentiate into plasma cells that will secrete dimeric IgA. Many of these cells will return to the same mucosal surface from which they originated, 49 but others will be found at different mucosal surfaces throughout the body. The homing of lymphocytes to other mucosa-associated lymphoid tissue sites throughout the body is referred to as the "common mucosal immune system" (Fig. 8) . Therefore, oral immunization can result in the migration of IgA precursor cells to the bronchi in the respiratory tract and subsequent secretion of IgA onto the bronchial mucosa.

The microbiome is essential for immune development in the neonatal calf; then the microbiome-gut-immune-brain axis maintains the health of the calf. [50] [51] [52] [53] As the calf develops, there is a "succession" of microbes that finally culminates in what is called a "climax" community that occurs as the gut transitions to an anaerobic environment. 50, 54 Microbiome succession is influenced by nutrition, stress, and environment. This microbial community of commensals and their metabolites controls the health of the gut mucosa and the underlying immune cells in the LP (Fig. 9) . 51,55 These Enteric Immunity: Happy Gut, Healthy Animal commensal metabolites stimulate enterocytes to produce TGF-b, which is essential for the development of T-regulatory (Treg) lymphocytes that produce antiinflammatory IL-10 (see Fig. 9 ). The microbial components in the microbiome also stimulate the enterocytes to produce serum amyloid A that stimulates DCs to activate another important mucosa regulatory T cell, T H 17 cells (see Fig. 9 ). These microbial metabolites also directly stimulate an NK-like cell, type 3 innate lymphoid cells to produce IL-22 to induce the enterocytes to produce more defensins (eg, REGIIIg and REGIIIb) (see Fig. 9 ). The composition of the microbiome varies by gut location with the numbers and diversity of populations being high in the rumen and increasing dramatically from the abomasum to the colon with the ileum being a key organ for microbial-immune development. These microbial communities (the microbiome) have evolved to help protect the animal by improving barrier and immune function; understanding the complexity of the gut microbial ecosystem is essential. 51, 56 The stress of weaning, co-mingling, and abrupt diet changes results in major microbial population shifts in the luminal microbial ecosystem, the microbiome. Stress lowers the defenses against pathogen entry, leading to increased risk of disease. Stress also leads to dysbiosis, the loss of good bacteria with an overgrowth of harmful organisms (Fig. 10) . 57, 58 However, dysbiosis is not just the loss of microbiome, it results in depletion of the "kill zone"(see Fig. 4 ); the mucous layer becomes thinner, and the amount of sIgA and defensins declines precipitously to allow the barrier to become weakened, allowing pathogens to interact with the mucosa and cause disease. In addition, commensal organisms that help stimulate the mucosa to be antiinflammatory are no longer available so tight junctions become weakened; "leaky gut" occurs, and pro-inflammatory responses occur that further weaken the gut epithelium (see Fig. 6A ). One major factor leading to the dysbiosis and diarrhea that we can learn from pigs is low feed and water intake. 59 Dysbiosis is also associated with susceptibility to Johne disease. 60 Homeostasis, "maintaining" a stable microbiome, is essential for good health and production. Oral antibiotics affect the microbiome homeostasis and therefore effect gut immunity and the incidence of disease. For example, the use of the antimicrobial bacitracin methylene disalicylate 61 altered the fecal microbial composition of calves by increasing the number of opportunistic pathogens such as Escherichia, Enterococcus, and Shigella, and decreasing beneficial bacteria. In another study, the microbiome population of Lactobacillus decreased with all antibiotic treatments, but the greatest reduction in Lactobacillus was observed with oxytetracycline, a broadspectrum antibiotic. 61 To make things worse, the reduction of lactic acid-producing bacteria (Lactobacillus) during weaning raises intestinal pH, increasing disease susceptibility because low gut pH is bactericidal to Escherichia coli. 59 It takes weeks to months to return the microbiome populations back to normal following antibiotic treatment. Passive immune therapy has been used for more than 50 years in calf enteric disease. Polyclonal antisera has been administered orally and/or subcutaneously to prevent/ treat bacterial diarrheal diseases colibacillosis and C perfringens type A and C with variable results. 62 One of the first successful uses of passive treatment was the oral administration of K-99 monoclonal antibody for the prevention/treatment of colibacillosis in calves. 63 Antirotavirus chicken egg yolk immunoglobulins fed in milk replacer decreased rotavirus diarrhea and enhanced rotavirus antibody-secreting cells. 64 Major success has been obtained by vaccinating cows before calving to enhance passive colostral antibodies for the protection of the calf against colibacillosis, C perfringens type C enterotoxemia, rotavirus, and coronavirus diarrhea. 62, 65, 66 Both parenteral and mucosal vaccinations have been used to prevent enteric disease. Immune protection has been done indirectly by vaccinating the cow to obtain high levels of colostral antibodies for passive transfer to the calf against the neonatal diseases discussed above. 62, 65, 66 In the neonate, acquired immunity with parenteral vaccination of the neonatal calf has been used for C perfringens type C in herds wherein the disease occurs in calves older than 14 days of age. 62 Although oral and intranasal vaccines for rotavirus and coronavirus have the potential for active mucosal immunity in the neonatal calf (less than a week of age), 67 early onset of these diseases (<14 days of age) along with the induction time for the immune response (7-10 days) makes efficacy poor in young calves (<14 days of age). Interestingly, oral coronavirus infections result in infection of both the enteric and the respiratory system 68 so coronavirus vaccines administered intranasal stimulated the common mucosal system and provided respiratory protection (see Fig. 8 ). 69 Several Salmonella vaccines: inactivated (whole cell; Rough mutants lacking oligosaccharide side chains (Re) mutant common core), MLV (genetically altered), and subunit (siderophores) vaccines have been licensed for parenteral administered but efficacy has been less then optimal. 70, 71 A major problem with Salmonella vaccines has been adverse reactions. The off-label oral administration of MLV Salmonella vaccines also has variable efficacy. 70, 72 There is a single Mycobacterium avium subsp paratuberculosis (MAP; paratuberculosis; Johne disease) vaccine available. The vaccine is efficacious and used in sheep. 73 The parenterally administered whole inactivated bacterin with Freund's adjuvant also produces cross-reactivity to both paratuberculosis and bovine tuberculosis tests. 74, 75 These false positives interfere with national bovine tuberculosis eradication testing programs, which limits the use of the vaccine to approval by regulatory officials. Cross-reactivity is also a major deterrent for animal health companies to design new MAP vaccines for cattle.

Mucosal delivered vaccines have the advantage of not being affected by maternal antibody interference, being able to induce a response in neonates less than 7 days of age, and priming the common mucosal immune system (for example, oral coronavirus vaccination would provide specific coronavirus immunity to the respiratory mucosa). 67 The use of novel adjuvants with parenteral vaccines 76 that induce mucosal responses in addition to novel mucosal delivered adjuvants will also enhance enteric immunity. 77 The area with the most opportunity that is also the least characterized is the use of direct-fed microbials to enhance enteric immunity and animal health while reducing antimicrobial usage. 78 Direct-fed microbials includes nutraceuticals, prebiotics, probiotics, and other dietary supplements. The effect of these direct-fed microbials on gut mucosal immunity and health has generated much interest. 50, 51, 54, 56, 61 Prebiotics (oligosaccharides, beta-glucan, and fiber), fiber metabolites (butyric acid and other short chain fatty acids), organic acids (ie, formic acid, citric acid), and botanicals (ie, vanilla, oregano, pepper oil) enhance the tight junctions in mucosal barrier and have an antiinflammatory effect on mucosa (see Fig. 9 ). [79] [80] [81] [82] Probiotics (ie, yeast, Lactobacillus, Bifidobacteria, and their metabolites) maintain microbiome homeostasis, increase secretory IgA, and decrease local inflammatory and APC responses to improve mucosal immunity (see Fig. 9 ). [83] [84] [85] [86] [87] [88] This anti-inflammatory activity could have an impact on protozoal (eg, coccidia and cryptosporidia) and bacterial diseases (eg, Salmonella and Johne disease) where a proinflammatory response is part of the pathogenesis mechanism. Additional research needs to be done to further understand mechanisms and develop formulations that contain combinations of direct-fed microbials for different applications and age groups.

The enteric mucosal immune system provides the first immune defense barrier for more than 90% of potential pathogens. The gut mucosal immune system alone contains more than a trillion (10 12 ) lymphocytes and has a greater concentration of antibodies than other tissue in the body. It protects against harmful pathogens but also induces immune system tolerance to dietary antigens and normal microbial flora. The health of the enterocytes, which are the epithelial cells that line the GI tract, is important not only for the growth and development of cattle, through secretion and Enteric Immunity: Happy Gut, Healthy Animal absorption in the gut, but also to provide a first immune response to enteric microorganisms. The enterocytes maintain a "kill zone" barrier to keep out pathogens in concert with the commensal microorganisms (microbiome) and other cells of the immune system. The microbiome functions best when it is in a stable condition, "homeostasis." Disruptions in the microbiome's homeostasis result in dysbiosis, which decreases the "kill zone," allows "leaky gut," and increases inflammation. Increased inflammation is seen as an important part of pathogenesis of infectious diseases, including coccidia, cryptosporidia, C perfringens type A, Salmonella, and Johne disease. Maintaining microbiome homeostasis, the "kill zone," and the mucosa anti-inflammatory response are the keys to maintaining good gut and animal health and reducing antimicrobial usage.

Neonatal immune development in the calf and its impact on vaccine response

Bovine neonatal immunology

Establishment of persistent infection with non-cytopathic bovine viral diarrhoea virus in cattle is associated with a failure to induce type I interferon

T-cell subsets in blood and lymphoid tissues obtained from fetal calves, maturing calves, and adult bovine

Lymphocyte subpopulations and neutrophil function in calves during the first 6 months of life

Ontogeny of the bovine immune response

Terminology: nomenclature of mucosaassociated lymphoid tissue

MALT structure and function in farm animals

Immunoglobulin diversity, B-cell and antibody repertoire development in large farm animals

Transcriptome analysis reveals regional and temporal differences in mucosal immune system development in the small intestine of neonatal calves

Potential regulatory role of micro-RNAs in the development of bovine gastrointestinal tract during early life

Model systems to analyze the role of miRNAs and commensal microflora in bovine mucosal immune system development

Immune components of bovine colostrum and milk

Protection of calves against cryptosporidiosis with immune bovine colostrum induced by a Cryptosporidium parvum recombinant protein

Modulation by colostrum-acquired maternal antibodies of systemic and mucosal antibody responses to rotavirus in calves experimentally challenged with bovine rotavirus

Detection of cytokines in bovine colostrum

Proinflammatory cytokines in bovine colostrum potentiate the mitogenic response of peripheral blood mononuclear cells from newborn calves through IL-2 and CD25 expression

Compensation of preliminary blood phagocyte immaturity in the newborn calf

Modulation of human immune responses by bovine interleukin-10

Kinetics and biological function of transforming growth factor-b isoforms in bovine and human colostrum

Uptake of colostral leukocytes in the intestinal tract of newborn calves

Effects of the ingestion of whole colostrum or cell-free colostrum on the capacity of leukocytes in newborn calves to stimulate or respond in one-way mixed leukocyte cultures

Colostrum induced phenotypic and trafficking changes in maternal mononuclear cells in a peripheral blood leukocyte model for study of leukocyte transfer to the neonatal calf

Effect of maternal cells transferred with colostrum on cellular responses to pathogen antigens in neonatal calves

Reciprocal interactions of the intestinal microbiota and immune system

Intestinal epithelial cells and their role in innate mucosal immunity

Host inflammatory response inhibits Escherichia coli O157:H7 adhesion to gut epithelium through augmentation of mucin expression

The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system

Keeping bacteria at a distance

Regulation of toll-like receptors-mediated inflammation by immunobiotics in bovine intestinal epitheliocytes: role of signaling pathways and negative regulators

Epithelial barriers in homeostasis and disease

Intestinal permeability defects: is it time to treat?

Local inflammation as a possible mechanism of resistance to gastrointestinal nematodes in Angus heifers

Intestinal lesions in specific-pathogen-free lambs associated with a cryptosporidium from calves with diarrhea

Innate immune responses against Cryptosporidium parvum infection

Cryptosporidiosis-an overview

Rethinking the role of alpha toxin in Clostridium perfringens-associated enteric diseases: a review on bovine necrohaemorrhagic enteritis

Influence of microbes on neutrophil life and death

Neutrophil extracellular trap formation in the Streptococcus suis-infected cerebrospinal fluid compartment

Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens

Production of extracellular traps against Aspergillus fumigatus in vitro and in infected lung tissue is dependent on invading neutrophils and influenced by hydrophobin RodA

Neutrophil extracellular trap formation as innate immune reactions against the apicomplexan parasite Eimeria bovis

Mast cell-orchestrated immunity to pathogens

Mast cells in allergy and infection: versatile effector and regulatory cells in innate and adaptive immunity

Natural killer cells in host defense against veterinary pathogens

Age-related changes in the distribution and frequency of myeloid and T cell populations in the small intestine of calves

Acquired and natural memory T cells join forces at the mucosal front line

The postnatal development of the mucosal immune system and mucosal tolerance in domestic animals

Mucosal delivery of vaccines in domestic animals

The gut microbiome and its potential role in the development and function of newborn calf gastrointestinal tract

Commensal microbiome effects on mucosal immune system development in the ruminant gastrointestinal tract

Gut/brain axis and the microbiota

Gut microbiota, the immune system, and diet influence the neonatal gut-brain axis

Understanding host-microbial interactions in rumen: searching the best opportunity for microbiota manipulation

Gut microbiota in autoimmunity: potential for clinical applications

Gut microbiome and omics: a new definition to ruminant production and health

Disruption of the gut microbiome as a risk factor for microbial infections

Characterization of the fecal bacterial microbiota of healthy and diarrheic dairy calves

The role of gut microbiota in the health and disease of pigs

The features of fecal and ileal mucosa-associated microbiota in dairy calves during early infection with mycobacterium avium subspecies paratuberculosis

Understanding the gut microbiome of dairy calves: opportunities to improve early-life gut health

Cattle enterotoxaemia and Clostridium perfringens: description, diagnosis and prophylaxis

Protection of calves against fatal enteric colibacillosis by orally administered Escherichia coli K99-specific monoclonal antibody

Egg yolk IgY: protection against rotavirus induced diarrhea and modulatory effect on the systemic and mucosal antibody responses in newborn calves

Milk supplemented with immune colostrum: protection against rotavirus diarrhea and modulatory effect on the systemic and mucosal antibody responses in calves experimentally challenged with bovine rotavirus

Evaluation of a protocol to reduce the incidence of neonatal calf diarrhoea on dairy herds

Mucosal vaccination of the newborn: an unrealized opportunity

Pathology and detection of bovine coronavirus in tissues from calves after challenge with virulent bovine coronavirus

Effect of intranasal vaccination against bovine enteric coronavirus on the occurrence of respiratory tract disease in a commercial backgrounding feedlot

Large Animal Internal Medicine

Salmonella serogroup C: current status of vaccines and why they are needed

Enteric Immunity: Happy Gut, Healthy Animal

Efficacy of oral administration of a modified-live Salmonella Dublin vaccine in calves

Paratuberculosis control: a review with a focus on vaccination

Large animal internal medicine

Johne's disease) in cattle and other susceptible species

Novel ISCOMs from Quillaja brasiliensis saponins induce mucosal and systemic antibody production, T-cell responses and improved antigen uptake

Choice and design of adjuvants for parenteral and mucosal vaccines

Editorial: gut health: the new paradigm in food animal production

Organic acids as rumen modifiers

Effects of vanillin, quillaja saponin, and essential oils on in vitro fermentation and protein-degrading microorganisms of the rumen

Medicinal plants-prophylactic and therapeutic options for gastrointestinal and respiratory diseases in calves and piglets? A systematic review

b-Glucan plus ascorbic acid in neonatal calves modulates immune functions with and without Salmonella enterica serovar Dublin

Selection of new lactic acid bacteria strains bearing probiotic features from mucosal microbiota of healthy calves: looking for immunobiotics through in vitro and in vivo approaches for immunoprophylaxis applications

Effect of oral administration of probiotics on growth performance, apparent nutrient digestibility and stress-related indicators in Holstein calves

Effect of supplementation with an electrolyte containing a Bacillus-based direct-fed microbial on immune development in dairy calves

Characterization of bifidobacteria suitable for probiotic use in calves

Comparison of probiotic lactobacilli and bifidobacteria effects, immune responses and rotavirus vaccines and infection in different host species

Effect of probiotics/prebiotics on cattle health and productivity