Abstract Even though the intestine represents a small proportion of body weight in broiler chickens, its requirements for energy and nutrients are high. A healthy broiler intestine has a well-coordinated immune system that must accommodate commensal microbiota while inhibiting the colonization and proliferation of harmful pathogens. Modern commercial intensive practices impose a high sanitary pressure that may exacerbate the progression of intestinal diseases such as coccidiosis and necrotic enteritis. The incidence of these diseases may increase worldwide due to mounting pressure to limit the use of subtherapeutic antibiotics as growth promoters or ionophores for coccidial suppression/prevention in the diets of broilers. For this reason, altering dietary concentrations of some amino acids, particularly trophic amino acids, may be beneficial to modulate the intestinal physiology, immunology, and microbiology of broilers. Trophic amino acids, such as threonine, arginine, and glutamine, play a very important role on the intestinal mucosa and may support increased epithelial turnover rates to improve intestinal recovery following an insult. Furthermore, these amino acids may help to minimize over-activation of the innate immune system, which is the most expensive in terms of nutrients and energy, as well as modulate the intestinal microbiota. The objective of this review is to provide insight into the potential role of trophic amino acids in these processes and report some updated studies of their use in diets for broiler chickens. INTRODUCTION The broiler industry has experienced significant improvements in production efficiency over the past decade. Broiler genotype, management practices, environmental stressors, and immunological challenges (vaccination and infection) all influence requirements for essential nutrients. In practical conditions, the requirements for some nutrients may be higher to avoid compromising of the immune system or to modulate its response and consequently maintain the performance of the flock. Even though the intestinal tissue represents only about 5% of the body weight, it consumes 15 to 30% of the O2 and proteins in a live organism (Gaskins, 2001) and 20% of the energy (McBride and Kelly, 1990) due to its rapid turnover rate and intense cellular metabolic activity. Thus, nutritional needs of the intestine must be considered when attempting to optimize nutrient delivery to broilers raised under different sanitary environments, as the intestine may have increased nutritional requirements to maintain its cellular proliferation. An intact intestinal mucosa protects the animal against the uptake of toxic substances present in the feed, as well as from invasion by pathogenic microorganisms and the antigens they secrete. To accomplish this, the mucosa must accommodate a variety of immune cell types, including macrophages, polymorphonuclear cells, dendritic cells, and T and B-lymphocytes (Nagler-Anderson, 2001). When the immune system is activated, the organism prioritizes proliferation of defense cells, expression of receptors to recognize non-self antigens, and production of cytokines and antibodies. This increased metabolic activity, due to the activation of the immune system, may be responsible for the impaired growth performance that is often observed during periods of intestinal challenge. In coordination with the intestinal mucosa, the intestinal microbiota are responsible for the first line of defense in an animal and work by regulating cellular permeability, altering the expression of genes in goblet cells for increased mucus production and stimulating secretion of antimicrobial peptides (Laparra and Sanz, 2010). As such, a well-established intestinal microbiota bring benefits to the host due to production of vitamins, immune modulation, and inhibition of pathogens, whereas microbial imbalance may contribute to the development of metabolic and immunologic diseases (Jeurissen et al., 2002) and increase competition for nutrients with the host (Yang et al., 2009). In addition to directly causing morphological damage, diseases such as coccidiosis and necrotic enteritis (NE) can decrease the abundance of desirable groups of bacteria, particularly segmented filamentous bacteria, that play a role in the modulation of the host immune system (Antonissen et al., 2016). Nutrition affects the composition of the microbiota (Pan and Yu, 2014), and the function that the microorganisms are going to perform on the host. Additionally, nutritional strategies targeted at regeneration of injured intestinal mucosa have the potential to improve recovery through beneficial effects on the microbiota, digestive physiology, immune system, and inflammation. Increased dietary amino acid density has been studied to reduce the atrophy of the intestinal mucosa (Ruemmele et al., 1999; Murakami et al., 2012; Gottardo et al., 2016; Zulkifli et al., 2016), stimulate the local immune system (Wu, 1998), and maintain the balance of the microbiota (Faure et al., 2006; Fasina et al., 2010; Chen et al., 2016; Dong et al., 2017). In this regard, a reduction of 2.3% of dietary amino acids modified the structure, composition, and predicted function of the cecal microbiota of chickens (Bortoluzzi et al., 2017). Indeed, amino acids regulate expression of genes and the production of molecules, including polyamines and nitric oxide (Fernandes and Murakami, 2010), needed for a well-functioning gastrointestinal tract (GIT; Li et al., 2007). In particular, threonine (Thr), arginine (Arg), and glutamine (Gln) have been studied for their roles in mucin production (Fernandez et al., 1994), immune function (Tan et al., 2014a,b; Chen et al., 2016), and epithelial proliferation (Scheppach et al., 1996), respectively. Therefore, the objective of this review is to provide insight into the role of Thr, Arg, and Gln on the physiological, immunological, and microbiological parameters of the broiler intestine and their beneficial effects for coccidiosis/NE-infected birds. COCCIDIOSIS AND NECROTIC ENTERITIS: DISTURBANCE OF INTESTINAL FUNCTION Coccidiosis is the most important parasitic disease in commercial poultry production systems (Allen and Fetterer, 2002). In chickens, coccidiosis is caused by up to 7 Eimeria species, including E. acervulina, E. brunetti, E. maxima, E. mitis, E. praecox, E. necatrix, and E. tenella. After being ingested, sporulated oocysts release the sporocysts that invade epithelial cells (Allen and Fetterer, 2002) and stimulate mucus production by goblet cells as a response to eliminate the coccidia. Due in part to this increased mucogenesis, coccidiosis is considered a primary predisposing factor for the development of NE (Dahiya et al., 2006; Collier et al., 2008), since mucus provides a substrate for the proliferation of Clostridium perfringens (a commensal bacterium and causative agent of NE). Furthermore, the lesions caused by Eimeria increase leakage of plasma proteins into the intestinal lumen (Prescott et al., 2016) and decrease nutrient digestion and absorption, providing additional substrates that can lead to bacterial imbalance (Pedroso et al., 2012). Two main components are responsible for maintaining the intestinal mucosa integrity. The first is the mucosal layer, which serves as a barrier between luminal contents and enterocytes lining the intestine. Mucin-type glycoproteins that make up the mucosal layer can aggregate different bacterial species, and in some cases, prevent the attachment of pathogens to the intestinal epithelium (Star et al., 2012). The intestinal mucosal layer is a key component of the innate immune response, and the development of the immune system of the bird varies according to age and section of intestine, which appears to be faster in proximal than in distal intestinal segments (Zhang et al., 2015). These authors observed that expression of the MUC2 gene, the primary secreting muco-protein, rapidly increases from embryonic d 14 to post-hatch d 1 in the ileum and cecum of broiler chickens. On the other hand, the gene expression of immunoglobulin A (IgA), the primary antibody in mucosal secretions that prevents the entry of commensal or pathogenic bacteria into subephitelial areas (Brisbin et al., 2008), had slower development from embryonic d 14 to post-hatch d 5 followed by rapid development up to d 21 and 14 in the ileum and cecum, respectively (Zhang et al., 2015). The second barrier component of the intestine is the enterocyte layer. The intestinal epithelium of the chicken is constantly renewed as proliferating cells in the mucosal crypts differentiate, predominantly to enterocytes, and migrate to the upper part of the villus, where they are eventually lost through desquamation (Uni, 2006). As described by Fernando and McCraw (1973), this turnover rate increases considerably during an intestinal challenge, but the magnitude and duration of this response varies among intestinal regions and regionality of challenge. For example, these authors reported that in E. acervulina-infected chickens the villus height of the duodenum reached its minimum value at 6 d post infection, tending to return to normal afterwards, but still below that of non-challenged birds. On the other hand, the impact of the infection on villus height in the jejunum was less pronounced (Fernando and McCraw, 1973), possibly because E. acervulina infects the duodenum, and/or due to compensatory cellular proliferation in the jejunum stimulated by the disruption in the duodenum. Therefore, E. acervulina not only dramatically increased turnover rate in the duodenum (target tissue), but also had effects throughout the small intestine. Even though Fernando and McCraw (1973) did not report the performance of the birds, this suggests that in the recovery phase previously infected birds tend to have better performance, as observed by Bortoluzzi et al. (2015). Intestinal inflammation in coccidiosis-infected broilers results in villus necrosis, characterized by decreased villus: crypt ratio, crypt dilatation and goblet cell depletion, as well as increased expression of inflammatory genes (iNOS, IL-1β, IL-8, and MyD88; Tan et al., 2014a). Furthermore, the co-infection of Eimeria with C. perfringens induces a higher level of inflammation when compared with birds infected with Eimeria or C. perfringens alone (Collier et al., 2008), supporting the hypothesis that the host inflammatory response to eliminate coccidia provides a growth advantage for C. perfringens. Several studies have tried to explain the main changes that occur in the intestinal immune cells following NE infection (Collier et al., 2008; Park et al., 2008; Kim et al., 2014), even though the immunopathology of NE in chickens is still not fully elucidated (Oh and Lillehoj, 2016). The activation of the immune system with moderate levels of inflammation is essential for the survival of the bird following an infection, which can require subsequent tissue repair (Tan et al., 2014a), and eventually recovery of the bird. In a recent study by Kim et al. (2014) on the immune response to NE, 1,049 genes were differentially expressed in intraepithelial lymphocytes of infected chickens, in which 601 were up- and 448 were down-regulated. The totality of these genes (1,049) was grouped into 5 primary biological functions, which were all related with the immune response. This kind of study generates a huge amount of data that must be carefully interpreted; however, once we can predict the sequence of genes, and timing of expression, different nutritional strategies may be developed with the objective to optimize the immune response to facilitate pathogen clearance, minimize tissue damage, and maximize growth rate. Shifts in the gut microbiota also are associated with NE (Stanley et al., 2012; Stanley et al., 2014; Antonissen et al., 2016). Even though C. perfringens is known to be the causative agent of NE, the changes in the overall structure of the microbiota, caused by the over proliferation of C. perfringens, also can contribute to the establishment and progression of the disease (Stanley et al., 2012). Using 16S rRNA sequencing, Stanley et al. (2012) showed that in C. perfringens-infected chickens, the structure of the cecal microbiota drastically changed, affecting mainly members of the orders Clostridiales and Lactobacillales. Additionally, some short chain fatty acid (SCFA)-producing bacteria were decreased due to NE challenge, showing that not only C. perfringens proliferation but also the overall dysbiosis that it causes may be related to the pathogenesis of the disease. Nutrient availability as well as cross-feeding mechanisms among different bacterial groups in the gut also may be affected by shifts in the microbiota induced by C. perfringens (Stanley et al., 2014). Thus, it is reasonable to argue that different dietary nutrients in NE-infected flocks may indirectly optimize immunity through growth and proliferation of commensal bacteria that play important roles in modulating the host immune system, or vice versa. AMINO ACIDS AND INTESTINAL HEALTH In addition to its aforementioned barrier role, the primary function of the GIT is efficient digestion and absorption of nutrients. To support these functions, nutritionists must understand the intestinal immune system and its relationship with the microbial community as a distinct organ with specific nutrient needs. In practice, nutrient profiles used in feed formulations for broiler chickens are typically based on economically important production outcomes, such as weight gain, feed intake, feed conversion ratio, and carcass yield (Kidd, 2004). The nutrient and energy needs for immunity or disease resistance, however, may be understudied. Enteric challenges such as coccidiosis or NE may alter the development of the immune response, and certain nutrients such as amino acids may become limiting factors to produce key proteins required for appropriate immune function. In the last few years, an increasing number of publications have shown the effects of higher concentrations of amino acids on the development and immunity of the GIT in broiler chickens under normal and challenged conditions (Tan et al., 2014a,b; Chen et al., 2016; Gottardo et al., 2016; Rochell et al., 2016a). Increasing dietary levels of highly digestible amino acids may help compensate for malabsorption during periods of intestinal challenge. Coccidiosis has been shown to be detrimental to amino acid digestibility (Adedokun et al., 2016; Rochell et al., 2016b). Rochell et al. (2016b) observed that increasing the inoculation dose of E. acervulina linearly decreased the apparent (i.e., not corrected for endogenous amino acid losses) ileal digestibility of all measured amino acids, except for tryptophan and glycine. While correction of digestibility values for endogenous losses improves their accuracy (Lemme et al., 2004), the impact of intestinal diseases such as coccidiosis on endogenous amino acid flow is not yet clear. Adedokun et al. (2016), using birds challenged with a coccidial vaccine at 14 or 35 d of age, reported that the impact of the challenge on ileal endogenous amino acid (IEAA) losses, evaluated one wk later, was higher in 35- vs. 14-day-old challenged birds (Table 1). Feed intake, body weight gain, and apparent and standardized ileal digestibility, however, were more affected in 14 vs. 35 d challenged birds (Table 1). Therefore, the authors argued that because younger birds are more susceptible to Eimeria infection, there is an increased destruction of the mucosa, brush border membrane, and the mucus layer that covers the epithelial cells, resulting in a reduction in the quantity of IEAA flow in the GIT. Table 1. Effect of age and coccidial vaccine challenge on performance, and apparent ileal amino acids (AIAA) digestibility of 21- and 42-d-old broiler chickens fed a regular broiler chicken diet; and, ileal endogenous amino acid losses (IEAA; mg/kg DMI) of 21- and 42-d-old broiler chickens fed a nitrogen-free diet. Adapted from Adedokun et al. (2016). Age, d Treatment1 Probability2 NCH 14 to 21 CHA 14 to 21 NCH 35 to 42 CHA 35 to 42 d CVC Age CVC*age Feed intake, g 507b 347c 970a 985a <.0001 0.001 <0.001 Gain, g 333b 218c 499a 516a <.0001 0.035 0.006 Feed efficiency 0.633a 0.627a 0.512b 0.523b <.0001 0.563 0.270 Age, d Treatment1 Probability2 NCH 14 to 21 CHA 14 to 21 NCH 35 to 42 CHA 35 to 42 d CVC Age CVC*age Feed intake, g 507b 347c 970a 985a <.0001 0.001 <0.001 Gain, g 333b 218c 499a 516a <.0001 0.035 0.006 Feed efficiency 0.633a 0.627a 0.512b 0.523b <.0001 0.563 0.270 AIAA digestibility Probability2 IEAA loss Probability2 Treat NCH CHA NCH CHA CVC Age CVC* NCH CHA NCH CHA CVC Age CVC* Age, d 21d 21d 42 d 42 d age 21d 21d 42 d 42 d age Arg 84.0a 71.5b 86.5a 85.3a 0.0002 <.0001 0.001 634a,b 463b 434b 834a 0.22 0.36 0.004 His 77.9a 58.8b 83.0a 79.3a <.0001 <.0001 0.004 258 183 200 321 0.58 0.34 0.025 Ile 75.5a 57.1b 80.6a 76.9a <.0001 <.0001 0.006 610 464 420 716 0.36 0.70 0.011 Leu 78.5a 63.1b 83.0a 76.9a 0.0001 <.0001 0.004 921 701 672 1130 0.35 0.48 0.011 Lys 83.1a 73.0b 85.3a 82.8a 0.0006 0.0011 0.027 556 349 318 599 0.68 0.95 0.01 Met 90.6a 81.1b 91.4a 88.4a <.0001 0.0018 0.009 200a,b 149a,b 134b 259a 0.22 0.46 0.005 Thr 68.8a 49.5b 75.4a 70.0a 0.0001 <.0001 0.019 1013 832 729 1052 0.61 0.81 0.076 Trp 67.4a 56.9c 77.1a 72.6a,b 0.0013 <.0001 0.170 138c 154b 151b 230a 0.005 0.008 0.05 Val 74.0a 53.8b 78.6a 75.1a <.0001 <.0001 0.003 809 637 589 949 0.40 0.68 0.023 Ala 76.4a 57.6b 81.3a 76.9a <.0001 <.0001 0.004 675 506 487 816 0.41 0.53 0.016 Glu 82.3a 68.4b 85.8a 83.4a <.0001 <.0001 0.003 1603 1150 1101 1903 0.43 0.55 0.01 Gly 71.3a 53.8b 76.0a 72.0a 0.0002 <.0001 0.010 746 597 595 955 0.32 0.33 0.02 AIAA digestibility Probability2 IEAA loss Probability2 Treat NCH CHA NCH CHA CVC Age CVC* NCH CHA NCH CHA CVC Age CVC* Age, d 21d 21d 42 d 42 d age 21d 21d 42 d 42 d age Arg 84.0a 71.5b 86.5a 85.3a 0.0002 <.0001 0.001 634a,b 463b 434b 834a 0.22 0.36 0.004 His 77.9a 58.8b 83.0a 79.3a <.0001 <.0001 0.004 258 183 200 321 0.58 0.34 0.025 Ile 75.5a 57.1b 80.6a 76.9a <.0001 <.0001 0.006 610 464 420 716 0.36 0.70 0.011 Leu 78.5a 63.1b 83.0a 76.9a 0.0001 <.0001 0.004 921 701 672 1130 0.35 0.48 0.011 Lys 83.1a 73.0b 85.3a 82.8a 0.0006 0.0011 0.027 556 349 318 599 0.68 0.95 0.01 Met 90.6a 81.1b 91.4a 88.4a <.0001 0.0018 0.009 200a,b 149a,b 134b 259a 0.22 0.46 0.005 Thr 68.8a 49.5b 75.4a 70.0a 0.0001 <.0001 0.019 1013 832 729 1052 0.61 0.81 0.076 Trp 67.4a 56.9c 77.1a 72.6a,b 0.0013 <.0001 0.170 138c 154b 151b 230a 0.005 0.008 0.05 Val 74.0a 53.8b 78.6a 75.1a <.0001 <.0001 0.003 809 637 589 949 0.40 0.68 0.023 Ala 76.4a 57.6b 81.3a 76.9a <.0001 <.0001 0.004 675 506 487 816 0.41 0.53 0.016 Glu 82.3a 68.4b 85.8a 83.4a <.0001 <.0001 0.003 1603 1150 1101 1903 0.43 0.55 0.01 Gly 71.3a 53.8b 76.0a 72.0a 0.0002 <.0001 0.010 746 597 595 955 0.32 0.33 0.02 a–cMeans within a row with no common superscripts are significantly different (P < 0.05). 1Each bird was gavaged with 12× the recommended dose of coccidial vaccine on d 15 and 36 and sampled on d 21 and 42, respectively. NCH = not challenged; CHA = challenged. 2CVC = coccidial vaccine challenge. View Large Furthermore, to account for increased endogenous amino acid flow and reduced digestibility during a challenge, in a subsequent trial, Adedokun et al. (2016) supplemented higher levels of lysine, methionine, threonine, isoleucine, tryptophan, and valine, and observed that the feed efficiency of challenged broilers was positively affected by the higher dietary concentration of these amino acids. Dry matter, nitrogen and energy digestibility, and metabolizable energy values were lower in coccidiosis challenged birds, but were not restored by amino acid supplementation alone. The better feed efficiency observed in birds supplemented with amino acids shows that when the absorptive capacity of the intestine is impaired, supplemental amino acids with higher digestibility are beneficial to partially restore the growth performance of the animals. The observation of Adedokun et al. (2016) of improved feed efficiency without effects on the digestibility measures in either unchallenged or challenged broiler chickens fed higher concentrations of amino acids may reflect better development of the intestinal mucosa (Gottardo et al., 2016). Broiler chickens fed higher amino acid (Arg, Thr, and Gln) concentrations and challenged with coccidiosis and Escherichia coli had significantly more cells containing proliferating cell nuclear antigen (PCNA; indicative of mitotic division) per villus in the jejunum one wk after challenge, indicating that these amino acids were supporting intestinal recovery. Lower numbers of PCNA positive cells at 2 and 3 wk post infection indicated that the beneficial effects of Arg, Thr, and Gln were confined to the early period of the recovery phase (Gottardo et al., 2016). As the timing of altered amino acid needs during intestinal infections becomes better defined, specialized diets could potentially be matched with the pattern of disease progression in the field to provide intestinal support to broilers when they are most susceptible. According to Wu (2009), dietary amino acids promote intestinal repair through induction of enzymes needed for the mitotic process, such as ornithine-decarboxylase required for the synthesis of polyamines, as well as through altering the expression of genes involved in anti-inflammatory and reparative processes. For instance, studies in mammals have shown that dietary supplementation of Arg and Gln increased the expression of antioxidant genes and reduced mRNA of pro-inflammatory genes in the small intestine and adipose tissue (Fu et al., 2005; Wang et al., 2008; Jobgen et al., 2009). Accordingly, amino acid manipulation of diets appears to be an important nutritional strategy when targeting the capacity and responsiveness of the GIT to cope with a pathogen; therefore, we will further discuss the roles of Thr, Arg, and Gln on the GIT of the host under both normal and disease-challenged scenarios. Threonine Poultry species do not synthesize Thr de novo, which makes it a nutritionally essential amino acid for broiler chickens. In diets based on corn and soybean meal, Thr is considered to be the third most limiting amino acid after methionine and lysine (Corzo et al., 2007). Thr participates in the synthesis of protein, and its catabolism generates many products important for metabolism, such as glycine, acetyl-CoA, and pyruvate (Kidd and Kerr, 1996). Compared with other amino acids, broiler chickens have a high Thr requirement for maintenance due to its rapid turnover rate and high abundance in intestinal secretions (Fernandez et al., 1994). Thr is the major component of intestinal mucin in animals, representing approximately 30% of its total amino acid content (Faure et al., 2002). Due to its importance in maintaining barrier function, mucin is not digested by the normal mechanisms within the GIT. Consequently, Thr secreted as mucin is eventually lost in the excreta or fermented by cecal microorganisms, making it almost unrecoverable for the animal. Therefore, factors that induce mucin secretion may increase dietary Thr requirements, such as bacterial load, which can influence endogenous amino acid flow through mucin production (Adedokun et al., 2012) and decrease its availability for growth; for instance, based on body weight gain, the requirement of Thr from 21 to 42 d was 0.77% in broilers raised on used litter vs. 0.74% in broilers raised on new litter (Corzo et al., 2007). Faure et al. (2007) reported that systemic infection, induced by E. coli injection, increased the utilization of Thr for protein synthesis in the small intestinal wall, mucosa, and mucin in rats; additionally, the utilization of Thr for the synthesis of mucin was 70% higher in infected than in control rats; this study shows the increment in Thr utilization not only during intestinal, but during systemic infections as well. Studies have indicated that the components of the immune system are responsive to manipulations in dietary Thr (Wang et al., 2006; Zhang et al., 2014, 2016, 2017; Chen et al., 2016). In addition to mucin production, Thr is a major component of immunoglobulins (Ig), particularly IgA, which is secreted by the intestinal mucosa and accounts for more than 2/3 of all Ig in the body (Slack et al., 2012). IgA is essential for maintaining intestinal homeostasis by preventing the attachment and entry of bacteria in intraepithelial cells, or eliminating bacteria from the basolateral space to the lumen (Macpherson et al., 2001; Brisbin et al., 2008). Zhang et al. (2014) evaluated the dietary Thr requirement for ducks from 15 to 35 d of age and observed that serum natural IgY (with IgM, the predominant Ig in the serum of chickens and ducks) increased linearly when dietary Thr increased, even though Thr had no effect on villus height, crypt depth, goblet cells, or MUC2 gene expression. In chickens, using an ex vivo explant, Zhang et al. (2017) showed that Thr deprivation to the medium up-regulated the expression of IL-8, MUC2, and IgA, which was reversed by Thr addition, implying that Thr is essential for the well functioning of the local immune system. Also in chickens, Thr supplementation changes the microbial balance in the intestine and modulates the immune system by increasing IgA secretion and down-regulating the expression of the inflammatory genes INF-γ and IL-1 β (Chen el al., 2016). Similarly, the effect of decreasing the expression of IL-1β also was observed in coccidiosis-infected broilers fed higher dietary Thr (1.8 vs. 5.3 g/kg; Wils-Plotz et al., 2013). Using a subclinical NE infection model, Star et al. (2012) showed that a dietary Thr: Lys ratio of 0.67 promoted better body weight gain than a ratio of 0.63 in infected chickens, without improvements in the incidence or severity of lesion scores. As stated by Faure et al. (2007), in pathological situations, the defense and repair will increase the demand for amino acids, especially Thr, and if the extra requirement for Thr is not met by the diet, muscle protein will be mobilized. Thr supplementation to a low crude protein diet restored the bacteria diversity and increased the frequency of beneficial populations of bacteria in the cecum of laying hens (Dong et al., 2017). Increased simultaneous supplementation of L-Thr, L-Ser, L-Pro, and L-Cys, up to 20.7, 8.4, 20, and 15 mg/kg, respectively, increased the counts of beneficial bacteria Bacteroides, Enterococci, and Lactobacilli in the feces of rats treated with dextran sodium sulfate, a well-recognized model to induce ulcerative colitis in humans (Faure et al., 2006). Chen et al. (2016) reported that 10.69 mg/kg of dietary Thr (26% higher than the recommended by NRC, 1994) decreased Salmonella and Escherichia coli colonies, and increased Lactobacillus in broiler chickens. The reduction of Salmonella and E. coli observed with this higher Thr concentration may be due to its indirect effect on the host, as observed by higher mRNA expression of MUC2, lower expression of the pro-inflammatory cytokine IL-1β, and reduced inflammation (Chen et al., 2016). This implies that Thr has immunomodulatory effects on the host, and either directly or indirectly influences beneficial microbiota, rather than altering nutrient supply in the lumen. Arginine Chickens have a unique and essential dietary requirement for Arg. Compared with mammals, poultry lack key enzymes involved in de novo Arg synthesis. The genetic material of birds does not encode for the enzyme carbamoyl phosphate synthetase, which catalyzes the first step of ammonia detoxification involved in the production of citrulline from ornithine (Tamir and Ratner, 1963). Citrulline can ultimately be converted to Arg through urea cycle enzymes, and as such, citrulline, but not ornithine, can spare dietary Arg in chickens (Klose and Almquist, 1940). Additionally, chickens lack the enzymes necessary for citrulline production in the small intestine (Wu et al., 1995), precluding the supply of intestinal citrulline for Arg production in the liver or kidney as occurs in mammals. Furthermore, chickens have a very high activity of kidney arginase compared with mammals (Tamir and Ratner, 1963), so dietary supply must account for this degradation as well. In addition to its function as a protein constituent, Arg is a precursor for the synthesis of creatine, polyamines, and nitric oxide (NO) and stimulates secretion of insulin-like growth factors (IGF; Fernandes and Murakami, 2010). Arg is converted into citrulline and NO by the action of a group of enzymes called NO synthetases (Forstermann et al., 1991), which is the only path for production of NO (Fernandes and Murakami, 2010). NO has several biological functions, but it primarily acts as a cytotoxic mediator of immune-activated cells and regulator of the immune system (Hibbs et al., 1988). Depletion of Arg may be observed in coccidial-infected chickens, due to the high expression of inducible NO synthase (iNOS) in an attempt to limit the replication of Eimeria in the intestinal epithelia (Tan et al., 2014a). Indeed, a 40% reduction in dietary Arg reduced plasma NO concentrations in unchallenged birds, but did not limit increased NO production elicited by a coccidial infection, reflecting the high metabolic prioritization of Arg for NO synthesis during coccidiosis (Rochell et al., 2017). Polyamines are important for the development of the intestine in newborns (Loser et al., 1999), which may explain the positive effects of Arg supplementation on performance and small intestine morphology of one-week-old broiler chickens (Murakami et al., 2012). Polyamines can stimulate proliferation, migration, and apoptosis of intestinal cells (Ruemmele et al., 1999). Therefore, Arg, a key precursor of polyamines, may be considered as a trophic substance by supporting the mitotic process in the crypt-villus region to increase the number of cells and the size of the villus (Uni et al., 1998). It is not yet fully understood whether Arg directly affects goblet cell or enterocyte replication; however, mucosal density increased linearly with increasing dietary Arg concentration (Tan et al., 2014a), which may be an indirect effect of the polyamines. The effects of Arg on the immune system of broiler chickens also have been investigated during periods of inactive (Murakami et al., 2012) and active immune stimulation (Tan et al., 2014a,b). Tan et al. (2014a) showed that coccidiosis induced jejunal inflammation characterized by villus damage, crypt dilation, and goblet cell depletion. In the same study, coccidiosis down-regulated the expression of MUC-2 and IgA, but up-regulated β-Defensin-8 and inflammatory genes (iNOS, IL-1β, IL-8, TLR4) mRNA expression. Meanwhile, Arg linearly diminished the expression of TLR4, suggesting that the anti-inflammatory effect of Arg is via suppression of the TLR4 pathway, which was verified when the inflammation was stimulated by lipopolysaccharide (Tan et al., 2014b). Glutamine Supplemental Gln has been studied in animal diets due to its effects on both intestinal structure and function (Wu et al., 1995; Wang et al., 2008; Santos et al., 2010; Santos et al., 2014; Soares et al., 2014). Gln serves as an important source of energy for enterocytes, particularly during periods of increased proliferation. As such, Gln may reduce the intestinal atrophy and support mucosal repair following an insult. Gln is also a component of glutathione, a key molecule in the defense against free radicals (Hunter and Grimble, 1994; Tahakashi et al., 1997; Kidd, 2004, 2006). Evidence suggests that the intestine competes with other organs for Gln, as the intestinal mucosa has a high capacity to remove Gln from both arterial blood and dietary supply (Coster et al., 2004). Gln may be considered an essential amino acid under inflammatory conditions, disease challenge, or surgery (Newsholme, 2001). Yi et al. (2001) observed that 1% of Gln had beneficial effects on small intestinal morphology at 3 and 14 d of age in broiler chickens. Dietary supplementation of Gln showed beneficial effects on broiler chickens subjected to delayed placement (Zulkifli et al., 2016). Even though these authors did not use a disease challenge to cause disruption of the intestinal epithelium, the delayed placement impaired the weight gain in the starter phase, and dietary Gln improved feed conversion ratio and weight gain in the overall period (1 to 42 d). This observed benefit on growth performance was likely due to higher villus height observed in Gln supplemented birds, which is also in agreement with improved morphology resulting from Gln supplementation reported by Pelicia et al. (2015). Using mice under heat stress conditions, Soares et al. (2014) showed that the supplementation with dietary Gln improved intestinal barrier function, thereby preventing the increase in the intestinal permeability and limiting the bacterial translocation induced by the heat stress. Comparable results were found in mice by Santos et al. (2010), wherein Gln reduced intestinal permeability and bacterial translocation to physiological levels and preserved mucosal integrity. In a later study to further elucidate the mechanism of action of Gln, Santos et al. (2014) reported that Gln plus NO synthase inhibitor increased bacterial translocation in all organs investigated (mesenteric lymph nodes, liver, spleen, and lungs), but Gln alone reduced the translocation to the same level as the control group. In addition, Gln increased levels of IL-10 in the serum and sIgA in the intestinal mucosa. These findings indicate that Gln not only plays a role on the intestinal barrier, but also may affect the intestinal bacteria community through its effect on NO synthesis. Gln supplementation of 1% to the diet did not decrease Salmonella Typhimurium shedding in broiler chickens, even though it improved BW gain (Fasina et al., 2010), increased villus height in the duodenum and jejunum, and enhanced performance and antibody (IgA) production (Bartell and Batal, 2007). Coccidiosis vaccinated chickens, supplemented with 0.5, 0.75, and 1% of Gln, had higher body weight at 21 and 28 d (Mussini et al., 2012), and improved feed conversion ratio, deeper crypts in the jejunum, and longer villi in the ileum when supplemented with 1% of Gln (Luquetti et al., 2016). Early weaned piglets had higher expression of genes that promote oxidative stress and immune activation; however, 1% of dietary Gln supplementation restored the function of the small intestine by increasing the expression of genes that prevent oxidative activity and stimulation of cell growth (Wang et al., 2008). Even though these results show beneficial effects of Gln on the intestinal morphology and physiology, additional work is needed to evaluate its effects on the intestinal immune system and microbial structure. 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