Overview of the gut immune system

The intestinal tract is a primary interface between the host and its environment, which is specifically adapted (e.g. large surface area) for the digestion and absorption of nutrients. However, a large, selectively permeable surface increases the potential for undesirable microorganisms and substances to gain access to more sterile compartments of the body, while numerous microbes residing in the intestine do not represent a threat to the host (and may, in fact, perform beneficial functions), and so the intestinal immune system must learn to respond appropriately (i.e. overt activation vs. tolerance; although precise mechanisms remain somewhat unclear) (Russler-Germain et al., Reference Russler-Germain, Rengarajan and Hsieh2017). The intestine must, therefore, achieve an intricate balance to enable it to perform these functions, which includes an effective barrier. The importance and vulnerability of the intestine is reflected in the gut-associated lymphoid tissue (GALT) being considered the largest immune organ in the body, which is estimated to contain more than 70% of all the host's immune cells (Kagnoff, Reference Kagnoff1993).

The mucus layer is the first component of the ‘gut barrier’ and, depending on gastrointestinal tract location, consists of an outer, loosely adhered layer and an inner, denser layer adhered to the underlying epithelium. The outer mucus layer is generally associated with microbes, whereas the inner layer is more hostile due to the high concentrations of secretory IgA (produced by intestinal B/plasma cells) and antimicrobial peptides (AMPs; produced by Paneth cells). Together, the mucus layer(s) and AMPs are referred to as the glycocalyx. The glycocalyx seeks to trap invading microbes and facilitate their removal with assistance from peristalsis (Stokes, Reference Stokes2017). Beneath the glycocalyx is a single layer of epithelial cells that help separate the intestinal lumen from the underlying lamina propria. The epithelial cells are differentiated into four types; absorptive enterocytes, mucus-secreting goblet cells, Paneth cells (AMPs), and endocrine cells. The spaces between epithelial cells are sealed by tight junctions (TJ) to effectively form a continuous barrier and to help regulate paracellular permeability.

The intestine has both organized (Peyer's patches and mesenteric lymphoid nodes (chickens are devoid of encapsulated lymph nodes)) and diffuse (epithelia and the lamina propria of both the villi and crypts) lymphoid tissues. These tissues contain dendritic cells, macrophages, B/plasma cells, CD4+ and CD8+ T cells, natural killer cells and granulocytes. The Peyer's patches are considered inductive sites, with the lamina propria and epithelium as effector sites. Specialized microfold (M) cells, overlaying the Peyer's patches, facilitate the sampling and transportation of antigens across the epithelium. Mucosal dendritic cells residing in the dome of Peyer's patches receive M cell or paracellularly acquired antigen before migrating to interact with, and activate, naïve T cells present in the GALT. The antigen may also be acquired from areas of the epithelium away from Peyer's patches, by dendritic cells manipulating TJ and extending dendrites into the intestinal lumen to directly sample the contents and through their phagocytosis of epithelial cells along with any antigenic material they contain.

Antimicrobial host defense (and homeostasis) rely on signaling pathways induced by germ-line-encoded pattern recognition receptors (PRRs) of the innate immune system (Kogut et al. Reference Kogut2017). These PRRs are present on epithelial cells, lamina propria dendritic cells and macrophages, and these receptors detect microbe-associated molecular patterns (MAMPs) on or in major groups of microbes (Janeway and Medzhitov, Reference Janeway and Medzhitov2002) or damage-associated molecular patterns (DAMPs), including uric acid, ATP, DNA fragments and mitochondrial contents (Garg et al., Reference Garg, Nowis, Golab, Vandenabeele, Krysko and Agostinis2010; Krysko et al., Reference Krysko, Agostinis, Krysko, Garg, Bachert, Lambrecht and Vandenabeele2011), which are host-based indicators of cell damage. MAMPs are critical for pathogen replication and survival and are unique to large groups of microorganisms but not to host cells; thus providing the host with an efficient, non-self means of detecting invading pathogens. Recognition of MAMPs induces various extracellular activation cascades and intracellular signaling pathways, leading to the inflammatory response, recruitment of phagocytic cells for clearance of the pathogens, and mobilization of professional antigen-presenting cells. PRRs are present in two separate compartments of the host: cell membranes and cell cytoplasm. PRRs on cell membranes have assorted functional activities, including promotion of phagocytosis, presentation of MAMPs to other PRRs, and the initiation of major intracellular signaling pathways. Recognition of MAMPs by PRRs, either alone or in heterodimerization with other PRRs (e.g. toll-like receptors (TLRs); nucleotide-binding oligomerization domain proteins (NLR); retinoic-acid-inducible gene-I (RLRs); C-type lectins) induces intracellular signals responsible for the activation of genes that encode pro-inflammatory cytokines, anti-apoptotic factors, and AMPs (Carpenter and O'Neill, Reference Carpenter and O'Neill2007; Lee and Kim, Reference Lee and Kim2007; Takeuchi and Akira, Reference Takeuchi and Akira2010). At least 11 different TLRs have been identified in the chicken (Keestra et al., Reference Keestra, de Zoete, Bouwman, Vaezirad and van Putten2013), two of which appear to be absent in mammals: chTLR15, which recognizes bacterial and fungal proteases (Keestra et al., Reference Keestra, de Zoete, Bouwman, Vaezirad and van Putten2013) and chTLR21, which is a functional ortholog of mammalian TLR9 that recognizes CpG oligodeoxynucleotides in bacterial DNA (He et al., Reference He, MacKinnon, Genovese and Kogut2011). In mammals, the RLR family contains RIG-I, MDA5, and LGP2 as members, but chickens lack RIG-I (Magor et al., Reference Magor, Miranzo Navarro, Barber, Petkau, Fleming-Canepa, Blyth and Blaine2013). The lack of the RIG-I family undoubtedly accounts for the susceptibility of chickens to ssRNA viruses such as influenza A and Newcastle disease virus, but the MDA5 family can, at least partially, compensate for the lack of RIG-I (Karpala et al., Reference Karpala, Stewart, McKay, Lowenthal and Bean2011). Regarding NLRs, in mammals, these have been classified into four subfamilies, including members such as NOD1, NOD2, NACHT, NALPs, and IPAF (Kawai and Akira, Reference Kawai and Akira2009), while only three NLRs have been found in the chicken genome (NOD1, NLRP3, NLRC5), with two being functionally described (e.g. Lian et al., Reference Lian, Ciraci, Chang, Hu and Lamont2012).

Various components contribute to the immune capability and defense of the intestine to ensure the effective acquisition of nutrients and tolerance, while attempting to exclude potential pathogens and their products.

Development of the gut immune system

Various studies have investigated the development of the gut immune system in chickens. From histological data, Bar-Shira and Friedman (Reference Bar-Shira and Friedman2006) found that before and immediately after hatch, heterophils are present in the intestine and, based on β-defensin gene expression, the gut seems to be a site where granulocytes become functionally mature. The numbers of mature granulocytes and heterophils in the lamina propria at hatch are very low but become more apparent by 2 days of age (DOA), with numbers of mature heterophils in all intestinal segments increasing as birds get older (Bar-Shira and Friedman, Reference Bar-Shira and Friedman2006). The GALT contains functionally immature T and B lymphocytes at hatch, with functional maturation occurring in two stages during the first 2 weeks of life (Bar-Shira et al., Reference Bar-Shira, Sklan and Friedman2003). Substantial recruitment of CD3+ T cells occurs by 4 days post-hatch (DPH) and continues thereafter, but with diminished magnitude. Similarly, the further population of the GALT by B cells begins as early as 4 DPH and continues to increase during the first 2 weeks of life. Lammers et al. (Reference Lammers, Wieland, Kruijt, Jansma, Straetemans, Schots, den Hartog and Parmentier2010) used immunohistochemistry and qRT–PCR to demonstrate that endogenous intestinal IgA is virtually undetectable before 14 DOA, but increases rapidly from 21 DOA (reaching a maximum by 70 DOA) in layer chicks. Responses to oral and rectal immunogens are generally not detected before 5 DPH (Bar-Shira et al., Reference Bar-Shira, Sklan and Friedman2003) and mature with age. Taken together, these studies indicate that cellular immune responses mature earlier, are necessary for antibody responses, and that the immaturity of T cells is primarily responsible for a lack of antibody responses in young birds (Bar-Shira et al., Reference Bar-Shira, Sklan and Friedman2003).

In pigs, only small numbers of leukocytes are found in the lamina propria at birth, which then becomes populated in a staged process in conventionally reared animals (Stokes, Reference Stokes2017). Dendritic cells (MHC II+) soon appear in the lamina propria during the first week of life, while T cells appear less rapidly and in a phased way (Vega-Lopez et al., Reference Vega-Lopez, Bailey, Telemo and Stokes1995). These initial T cells express the CD2 and CD3 surface markers but not CD4 or CD8. After 2 weeks, the intestinal mucosa is colonized by CD4+ T cells, but CD8+ cells do not appear in any meaningful numbers until after 3 weeks of age. Between 2 and 4 weeks of age, IgM-expressing B cells begin to appear, followed by IgA + plasma cells by 6 weeks of age (Stokes, Reference Stokes2017). Thus, it is not until around 6 weeks of age that a mature intestinal architecture is achieved, characterized by large numbers of dendritic cells and CD4+ T cells of resting, advanced memory phenotype (Inman et al., Reference Inman, Haverson, Konstantinov, Jones, Harris, Smidt, Miller, Bailey and Stokes2010). Before 6 weeks of age, the young pig can progressively mount active immune responses to live viruses and dietary components, but the quality and quantity of these responses are very different to that of immunologically ‘mature’ animals (Stokes et al., Reference Stokes, Bailey, Haverson, Harris, Jones, Inman, Pie, Oswald, Williamson, Akkermans, Sowa, Rothkotter and Miller2004).

Important factors that can influence the development of the gut immune system

Various factors influence the development of the gut immune system. Amongst these, exposure to microorganisms or antigen is considered the most important. Intestinal microbes and antigens drive maintenance of gut barrier function and development of the mucosal immune system, with studies in germ-free animals demonstrating an influence on the organization of lymphoid tissue (e.g. Peyer's patches), secretion of AMPs and accumulation of various immune cells at mucosal sites (Honda and Littman, Reference Honda and Littman2012). Indeed, germ-free animals have both poorly developed mucosal and systemic immune systems, and do not generate normal oral tolerance to dietary proteins (Hooper et al., Reference Hooper, Littman and Macpherson2012). Normal immunological functioning and responses can, however, be achieved if these animals are subsequently colonized by a conventional or a defined microbiota. Similarly, antimicrobials have the potential to influence the development of the immune system. Lee et al. (Reference Lee, Lillehoj, Lee, Jang, Park, Bautista, Ritter, Hong, Siragusa and Lillehoj2012) reported that feeding antimicrobials (decoquinate and monensin) to broiler chicks between 1 and 43 DOA altered the percentages of MHCII+ and CD4+ intestinal intraepithelial lymphocytes and their expression of various cytokines and chemokines compared with untreated controls. While direct effects of antimicrobials on gut immune-related cells, even at sub-therapeutic concentrations, is possible (Niewold, Reference Niewold2007), it is more likely that these effects are mediated through changes to the intestinal microbiome (Broom, Reference Broom2017).

Differences in rearing environment have also been shown to influence both the pattern of immune cell accumulation in the intestinal mucosa and immune system development of young animals (Inman et al., Reference Inman, Haverson, Konstantinov, Jones, Harris, Smidt, Miller, Bailey and Stokes2010). Similarly, maternally derived antibodies or other factors, such as, hormones, antioxidants, etc. (Sandell et al., Reference Sandell, Tobler and Hasselquist2009), can influence the development of the immune system and affect vaccine efficacy. Passively acquired antibodies can interfere with antigen processing and presentation, B and T-cell functions, and the magnitude and dynamics of an immune response (Hodgins et al., Reference Hodgins, Kang, deArriba, Parreño, Ward, Yuan, To and Saif1999). Therefore, while helping to provide essential protection against disease in young animals, the quantity and quality of maternally derived antibodies (or other factors) can influence gut immune development and responses to vaccination. Stressors, including feed and water deprivation after hatch/birth, may also alter the development of GALT functionality. Bar-Shira et al. (Reference Bar-Shira, Sklan and Friedman2005) reported that withholding feed and water from chicks for 72 h PH decreased intestinal and systemic antibody responses following rectal antigen immunization, delayed colonization by B and T lymphocytes, altered cytokine expression by T cells and lowered bursa weight. These effects were most prominent in the hindgut during the first 2 weeks of life, but full recovery did occur after this time. The authors proposed that feed deprivation had delayed development of the hindgut microbial community, which, in turn, had delayed development of the GALT in this region of the intestine. Likewise, McLamb et al. (Reference McLamb, Gibson, Overman, Stahl and Moeser2013) demonstrated that stressed (weaned) piglets had impaired mucosal immune responses to enterotoxigenic Escherichia coli, which increased intestinal injury and clinical disease. Host genetics are another factor with the potential to profoundly influence the development of the GALT. Two genetically divergent broiler chicken lines showed differences in the expression of immune-related and cell-cycle-related genes after hatch and through 16 DOA, respectively, in gut tissue and in the composition of the intestinal microbiota (Schokker et al., Reference Schokker, Veninga, Vastenhouw, Bossers, de Bree, Kaal-Lansbergen, Rebel and Smits2015).

For many of the factors outlined above, the effects could be through a direct, or indirect, impact on the gut microbiome, which, in turn, influences the development and functionality of the gut immune system. Similarly, oral exogenous factors, such as feed components, reportedly influence the development of the GALT, but, often, it is not possible to delineate the probable mode of action (e.g. microbiome modulation).

Issues and consequences of gut immune system developmental phases

The previous sections have outlined the dynamics and importance of the gut immune system and its development. It is apparent that the GALT, particularly acquired responses, are not functionally mature until at least 2 weeks of age in chickens and 6 weeks of age in pigs. Therefore, there is a clear window where these species are reliant on passive immunity and innate immune responses, which are better developed than adaptive responses at or immediately after hatch or birth. Both species are inherently immunocompromised as, following absorption of the yolk sac, chicks do not receive further on-going maternal immune protection, whereas pigs do receive such protection via colostrum and then milk, but pigs are born devoid of passive immunity due to the epitheliochorial placenta preventing the passage of large macromolecules, such as immunoglobulins, in utero (Sterzl et al., Reference Sterzl, Rejnek and Trávnícek1966). In many mammals, colostrum and milk provide significant concentrations of IgA to the neonate's intestine to help compensate for poor endogenous IgA production. IgA provision to chicks from the egg/yolk sac is less clear and intestinal IgA ‘deficiency’ may occur around 2+ weeks due to depleted maternal IgA before endogenous production is properly established, with the potential to impair the gut ‘barrier’ and thus prevention of microbial penetration of the mucosa (Lammers et al., Reference Lammers, Wieland, Kruijt, Jansma, Straetemans, Schots, den Hartog and Parmentier2010).

It is during this immunocompromised period (i.e. early weeks of life) that poultry and pigs are typically vaccinated against potential pathogens that they are likely to encounter. Ideally, vaccination seeks to prime the acquired immune system and thus provide memory to the antigen and respond rapidly if and when it is next encountered. Thus, the relatively slower functional development of acquired immunity and the time to generate an initial response to antigen (approximately 7 days) undoubtedly compromises vaccine efficacy at this time and contributes to the vulnerability of these young animals. Moreover, suboptimal vaccine responses in young animals can also make it difficult to protect against, and reduce carriage of, foodborne human pathogens, such as Salmonella. Many vaccines for use in young animals require the use of adjuvants to aid in the induction of a meaningful immune response. Most vaccine antigens are directed toward the lymphocytes of the acquired immune system, which are poorly developed early in life. Adjuvants, however, induce the innate immune response to produce the required co-stimulatory molecules to activate acquired responses that result in protection, although the use of the best adjuvants is limited due to detrimental side effects.

The initial colonizing microbiota and rearing factors drive the development of the GALT, but modern animal production practices have become more ‘artificial’, and thus it is probable that these animals do not acquire the most appropriate gut microbiota, in terms of composition, functionality or diversity, to optimally drive this development. Likewise, it is common for young animals to experience various stressors early in life, which can affect GALT development. For example, newly hatched chicks may be deprived of feed and water for many hours before arrival or during transit to farms. Although Bar-Shira et al. (Reference Bar-Shira, Sklan and Friedman2005) reported that GALT development and immune responses recovered fully by 2 weeks of age following interruption due to 72 h of feed and water deprivation, this report also indicated that such practices may contribute significantly to immune function and vulnerability in the period shortly after hatch. Similarly, commercial weaning of pigs, which generally occurs at 3–4 weeks of age, removes enteric protection provided by maternal antibodies and other antimicrobial factors in milk, at a time when the young pig is still immunologically naïve. This, again, may place great importance on the better-developed host innate defenses (Stokes, Reference Stokes2017).

Promoting gut antimicrobial protection

It is clear that young poultry and pigs are inherently reliant on maternally-derived antibodies and their innate immune defenses, due to the slower development and responsiveness of their acquired immune capability. By ‘young’, we mean the period of weeks following hatch or birth, which, particularly in animals reared for meat, represents a significant portion of their life. Similarly, innate defenses may also be important during specific times of stress, for example, heat stress, diet changes (e.g. weaning), periods of feed withdrawal or during transit to the processing plant, all of which have been associated with negative immune consequences (Quinteiro-Filho et al., Reference Quinteiro-Filho, Rodrigues, Ribeiro, Ferraz-de-Paula, Pinheiro, Sa, Ferreira and Palermo-Neto2012). Historically, the use of antimicrobials, including their use as growth promoters, have undoubtedly helped to compensate for deficiencies in host intestinal defenses, but these options have become limited due to legislation in response to concerns about the development of antimicrobial resistance (Castanon, Reference Castanon2007; Gadde et al., Reference Gadde, Kim, Oh and Lillehoj2017). Therefore, the foundations for optimum animal health and performance should now be based on attempting to promote (1) the magnitude and quality of passive immunity, (2) innate defenses, and (3) the speed of functional development of acquired responses.

A primary focus for enteric health should be on bolstering gut barrier function, including the microbiome and maternally derived factors, as limiting microbial (or related products) penetration of the intestinal mucosa will help minimize further interaction with and activation of submucosa defense processes and the downstream metabolic consequences. The gut microbiota plays a vital role in both supporting barrier function and driving the development of the GALT. Nurmi and Rantala (Reference Nurmi and Rantala1973) provided a clear demonstration that orally gavaging newly hatched chicks with the gut contents from ‘healthy’ adult chickens profoundly increased their resistance to Salmonella infection, which led to the ‘competitive exclusion’ concept and contributed to the development of probiotic products based on defined microbial strain(s). Although manipulable throughout life, the initial colonizing gut microbiota strongly influences its subsequent composition, succession phases and intestinal immune function, indicating that the application of appropriate microbial products early in life (e.g. immediately PH or birth) is likely to be most effective to assist barrier function and GALT development. Indeed, the focus has also turned to even earlier intervention through the in ovo application of probiotics to impact intestinal microbial colonization (e.g. Majidi-Mosleh et al., Reference Majidi-Mosleh, Sadeghi, Mousavi, Chamani and Zarei2017), expression of immune-related genes and early growth performance (Pender et al., Reference Pender, Kim, Potter, Ritzi, Young and Dalloul2017). Similarly, prebiotics, through the provision of substrates for beneficial microbes, can help shape a favorably functioning microbiome (Pourabedin and Zhao, Reference Pourabedin and Zhao2015) and the combination of pro and prebiotics (synbiotics) may be more effective than either alone. For example, Madej and Bednarczyk (Reference Madej and Bednarczyk2016) reported that a synbiotic, delivered in ovo, more effectively stimulated GALT development (determined by B and T-cell populations) PH than prebiotic alone. Other agents with the potential to positively influence the early gut microbiome, barrier and GALT development (e.g. bacteriophages, egg-yolk antibodies, enzymes, phytochemicals, fatty acids, etc.) may also be valuable additives for farmed animals and have been reviewed elsewhere (Gadde et al., Reference Gadde, Kim, Oh and Lillehoj2017). Alternatively, direct, exogenous supplementation (or endogenous promotion) of other key components of the gut barrier (e.g. AMPs, sIgA, TJs, etc.) could represent effective and metabolically favorable approaches to optimize intestinal function. Both recombinant porcine β-defensin 2 (Peng et al., Reference Peng, Wang, Xie, Song, Wang, Yin, Zhou and Li2016) and egg-yolk antibody (Owusu-Asiedu et al., Reference Owusu-Asiedu, Nyachoti and Marquardt2003) dietary supplementation have been shown to alter the gut structure or microbiota composition, reduce intestinal disorders and increase growth performance of weaned piglets. Increasing the maternal production and transfer of immune components (e.g. IgA) to their offspring is another potential method of enhancing antimicrobial protection. For example, dietary supplementation of sows with short-chain fructooligosaccharide increased colostral IgA and influenced the development of intestinal immune function in their piglets (Le Bourgot et al., Reference Le Bourgot, Ferret-Bernard, Le Normand, Savary, Menendez-Aparicio, Blat, Appert-Bossard, Respondek and Le Huerou-Luron2014).

Modulation of the GALT response could also be a target for improving the intestinal microbial defense. PRRs are regarded as the ‘gatekeepers’ of the innate immune system. Exogenous PRR/TLR ligands could stimulate innate immune pathways and lead to up-regulation of related responses. In addition, TLRs are considered key to recognizing commensal microbes and thus have a primary role in the maintenance of intestinal homeostasis. Single or combined TLR ligands have been shown to effectively increase innate immune responses in chickens, which has led to investigation into their use as adjuvants (Gupta et al., Reference Gupta, Deb, Dey and Chellappa2014). Moreover, TLR ligands have also been reported to promote adaptive immunity, increasing B and T-cell responsiveness (Khoruts et al., Reference Khoruts, Mondino, Pape, Reiner and Jenkins1998; St Paul et al., Reference St Paul, Brisbin, Abdul-Careem and Sharif2013), although the precise mechanism for this is not entirely understood. PRR binding initiates signaling pathways, which leads to the production of various mediators, including cytokines. Indeed, exogenous cytokines have been evaluated for immunomodulation and enhancement of protection against infectious diseases in poultry (Kogut, Reference Kogut2000; Umar et al., Reference Umar, Arif, Shah, Munir, Yaqoob, Ahmed, Khan, Younus and Shahzad2015). Better understanding of signaling pathways, effector functions and interactions with metabolism (immunometabolism) will help to establish the most appropriate targets for improved disease prevention and efficient growth. Part of this progress is likely to include the translation of advancements in mucosal immunology into effective mucosal immunomodulators and vaccines to aid intestinal development and function (i.e. microbial defense and nutrient acquisition). A further area for development is the genetic or phenotypic selection of animals with appropriate innate immune and performance markers. Focus in one of the author's labs has concentrated on up-regulating the innate immune response in chickens, particularly during early life. Selecting chickens based on increased expression of pro-inflammatory mediators (IL-1β, IL-6, CXCLi2, and CCLi2) by peripheral blood heterophils has improved resistance to Salmonella enterica serovar Enteritidis (Swaggerty et al., Reference Swaggerty, Pevzner and Kogut2014), Eimeria tenella (Swaggerty et al., Reference Swaggerty, Pevzner and Kogut2015) and Clostridium perfringens-induced necrotic enteritis (Swaggerty et al., Reference Swaggerty, McReynolds, Byrd, Pevzner, Duke, Genovese, He and Kogut2016). The benefits of increased innate inflammatory responses for enhanced resistance to a range of important poultry and pig pathogens have recently been reviewed (Broom and Kogut, Reference Broom and Kogut2017). Likewise, modulating the (avian) immune system, primarily through nutrition, has recently been considered (Kogut, Reference Kogut2017).

Innate immune pathways can also be triggered by metabolites (e.g. free fatty acids, carbohydrates, and lipids) that act as DAMPs and are sensed by PRRs (Assmann and Finlay, Reference Assmann and Finlay2016; Lackey and Olefsky, Reference Lackey and Olefsky2016). Continuous activation of these PRRs through excessive nutrient intake and a concurrent increase in metabolic pathways in the mitochondria of activated immune cells (McGettrick and O'Neill, Reference McGettrick and O'Neill2013; Tannahill et al., Reference Tannahill, Curtis, Adamik, Palsson-McDermott, McGettrick, Goel, Frezza, Bernard, Kelly, Foley, Zheng, Gardet, Tong, Jany, Corr, Haneklaus, Caffrey, Pierce, Walmsley, Beasley, Cummins, Nizet, Whyte, Taylor, Lin, Masters, Gottlieb, Kelly, Clish, Auron, Xavier and O'Neill2013), which causes overproduction of various metabolites via the Krebs cycle (succinate, citrate, NAD+) and glycolysis (lactate) (McGettrick and O'Neill, Reference McGettrick and O'Neill2013; Tannahill et al., Reference Tannahill, Curtis, Adamik, Palsson-McDermott, McGettrick, Goel, Frezza, Bernard, Kelly, Foley, Zheng, Gardet, Tong, Jany, Corr, Haneklaus, Caffrey, Pierce, Walmsley, Beasley, Cummins, Nizet, Whyte, Taylor, Lin, Masters, Gottlieb, Kelly, Clish, Auron, Xavier and O'Neill2013), results in the production of multiple inflammatory mediators and a chronic, low-grade inflammatory response (meta-inflammation). Thus, modern animal production, with increased feed intakes and growth rates, likely predisposes animals to meta- or chronic inflammation, which may undermine gut homeostasis and effective antimicrobial protection (Kogut, Reference Kogut2017). Thus, future studies focusing on immune strategies for efficient animal production should help to identify appropriate innate pathways or processes that promote robust defense, while minimizing undesirable stimulation and responses.