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The Functional Roles of Methionine and Arginine in Intestinal and Bone Health of Poultry: Review

Department of Poultry Science, University of Georgia, Athens, GA 30602, USA
Author to whom correspondence should be addressed.
Animals 2023, 13(18), 2949;
Submission received: 18 August 2023 / Revised: 14 September 2023 / Accepted: 16 September 2023 / Published: 18 September 2023
(This article belongs to the Special Issue Precision Feeding and Nutrition in Poultry Production)



Simple Summary

Intestinal health and bone health are two major contributors to the well-being of poultry. Maintaining a balanced and healthy status of the intestines and bones can lead to optimal growth performance and productivity. Recent studies have illuminated the functional roles of certain amino acids, highlighting their unique contributions to various physiological processes and the synthesis of metabolically important molecules. Methionine and arginine are two notable examples of such amino acids. In this review, we explore how methionine and arginine may influence intestinal and bone health and the potential mechanisms behind these effects.


This review explores the roles of methionine and arginine in promoting the well-being of poultry, with a specific focus on their impacts on intestinal and bone health. The metabolic pathways of methionine and arginine are elucidated, highlighting their distinct routes within the avian system. Beyond their fundamental importance in protein synthesis, methionine and arginine also exert their functional roles through their antioxidant capacities, immunomodulating effects, and involvement in the synthesis of metabolically important molecules such as S-adenosylmethionine, nitric oxide, and polyamines. These multifaceted actions enable methionine and arginine to influence various aspects of intestinal health such as maintaining the integrity of the intestinal barrier, regulating immune responses, and even influencing the composition of the gut microbiota. Additionally, they could play a pivotal role in promoting bone development and regulating bone remodeling, ultimately fostering optimal bone health. In conclusion, this review provides a comprehensive understanding of the potential roles of methionine and arginine in intestinal and bone health in poultry, thereby contributing to advancing the nutrition, overall health, and productivity of poultry in a sustainable manner.

1. Introduction

The global poultry industry holds immense significance in meeting the continuously increasing demand for high-quality protein-rich food, driven by the continuous rise in the global population [1]. To achieve optimal growth and productivity of the birds, ensuring their health and well-being is essential. Among the critical factors that impact the performance of poultry, this review paper will specifically focus on two critical aspects: intestinal health and bone health.
The intestines are responsible for the digestion and absorption of essential nutrients from the feed consumed by poultry [2]. Furthermore, the intestinal tract is immensely important in the immune system of the animals. It serves as the physical barrier and also hosts abundant organized lymphoid tissue and immune effector cells, which collectively provide protection against pathogens and toxins [3,4,5]. Nevertheless, the intestines possess the most extensive exposed surface in the body [6]. The constant exposure to a wide range of potentially harmful substances makes them susceptible to many diseases, such as coccidiosis and necrotic enteritis, which have a significant impact on the poultry industry [7,8]. Maintaining a healthy intestinal tract has been a focus of research for decades, and this area is now gaining more attention due to the growing awareness of animal welfare, food safety, and the increasing public scrutiny towards the use of antibiotic growth promoters [9].
Likewise, bone health is also a significant contributor to the overall well-being of the birds [10,11]. The skeletal system serves as the foundation for the structure of the birds, providing support and enabling efficient movement [12]. Healthy bones are essential for preventing fractures, deformities, and other musculoskeletal issues, such as lameness, which can severely impact the comfort and performance of the birds [13]. Especially broilers undergo rapid growth, which places significant demands on their skeletal systems [12]. Ensuring proper bone development and strength is crucial to meet the birds’ physiological needs, prevent welfare issues, and optimize productivity.
In recent years, research has shed light on the functional roles of specific amino acids, with methionine (Met) and arginine (Arg) being two notable examples [14,15]. Met is an essential amino acid, and it is usually considered as the first limiting amino acid in corn and soybean meal-based diets for poultry [16]. Met plays a crucial role in protein synthesis as it serves not only as a fundamental building block of proteins but also as the initiating amino acid that is typically incorporated as the first residue to the polypeptide chain during translation [17]. Beyond its role in protein synthesis, it also contributes to the maintenance of oxidative balance due to its antioxidant capacity [18]. Met and its metabolite S-adenosylmethionine (SAM) act as methyl donors, a function that is essential for normal cellular metabolism [16]. Recent studies have further revealed its involvement in regulating immune responses [19,20]. Arg is also considered an essential amino acid for poultry. In addition to its significance in protein synthesis, it plays a vital role in various physiological processes. The immunomodulating effects of Arg have been widely reported because it is the precursor of nitric oxide (NO), which possesses potent immune regulatory effects and pathogen suppression capacity [15,21]. Arg has also been shown to affect lymphoid organ development and lymphocyte functions [22,23]. Furthermore, Arg contributes to the wound healing process by serving as the precursor of various polyamines and collagens [24,25]. Investigating the impacts of these two amino acids on poultry health holds the potential to devise effective strategies to enhance productivity, overcome challenges, and ensure better animal welfare. Abundant studies have been conducted to demonstrate the beneficial effects of Met and Arg supplementation on the intestinal health of poultry, whereas more research needs to be carried out to study its effects on the bone health of the birds (Table 1).
The objective of this review paper is to provide an overview of the current knowledge regarding the roles of Met and Arg in poultry intestinal health and bone health. We expect that the findings presented in this review will contribute to a deeper understanding of this subject and ultimately contribute to improvements in the health, performance, and productivity of poultry.

2. Metabolism of Methionine and Arginine

2.1. Methionine Metabolism

Methionine is an essential amino acid and usually considered the first limiting amino acid in corn and soybean meal based poultry diets [46]. It is classified as a sulfur-containing amino acid and is involved in a variety of important physiological processes, including protein synthesis, methylation reactions, and antioxidant activity [26,47].
Methionine is metabolized through a complex series of enzymatic actions mainly in the liver (Figure 1). In a concise overview, the initial step of Met metabolism involves its transformation into SAM through a process known as methylation, catalyzed by the enzyme, methionine adenosyltransferase (MAT) [23,24]. SAM is a highly reactive molecule and serves as a key methyl donor for many important cellular processes, including the synthesis of DNA, RNA, proteins, and neurotransmitters. SAM is subsequently converted to S-adenosylhomocysteine (SAH), which is then further metabolized to homocysteine (Hcy). Hcy can then be remethylated back to Met with the active form of folate, 5-methyltetrahydrofolate (5-MTHF), being the methyl donor, thereby interlinking the metabolism of Met and folate. This process is catalyzed by methionine synthase (MTR) with vitamin B12 as the cofactor. Hcy alternatively undergoes transsulfuration to form cystathionine first and then cysteine. This process relies on vitamin B6 as a cofactor. Cysteine can then be further metabolized to form the vital endogenous antioxidant, glutathione (GSH) [48,49], or serve as a precursor for taurine synthesis [50].

2.2. Arginine Metabolism

Birds do not possess the entire urea cycle due to the absence of carbamoyl phosphate synthase (CPS1) and ornithine carbamoyltransferase (OTC). Consequently, they cannot synthesize Arg from metabolically generated ammonia or ornithine within the urea cycle [15,51]. Additionally, the limited activities of argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL) in birds hinder the adequate synthesis of Arg from citrulline [52]. As a result, the availability of Arg in birds is highly dependent on their diets, making Arg essential for poultry.
In addition to its role in protein synthesis, Arg undergoes metabolism through four distinct pathways (Figure 2) [51,53]. One pathway involves a two-step enzymatic process where Arg, along with glycine, is metabolized to creatine by arginine:glycine amidinotransferase (AGAT), with SAM acting as the methyl donor. The other pathway involves the conversion of Arg to agmatine through the action of arginine decarboxylase (ADC). Agmatine is subsequently converted to the polyamine known as putrescine. Putrescine serves as a precursor for the synthesis of two other polyamines, namely, spermine and spermidine.
However, the primary metabolic significance of Arg lies in two well-regulated pathways that compete for its utilization [51,54]. In the first pathway, Arg is metabolized by nitric oxide synthase (NOS) to produce NO. NO is a vital molecule involved in various metabolic processes, including immunity regulation and pathogen suppression. In the second pathway, Arg is metabolized by arginase to produce ornithine. Ornithine, in addition to being converted to putrescine, can also be transformed into proline [55]. Both polyamines and proline play crucial roles in cell proliferation, tissue repair, and wound healing processes.

3. Methionine and Arginine in Intestinal Health

3.1. Methionine and Arginine in Intestinal Development and Repair

The intestinal epithelium, which comprises a single layer of epithelial cells and a protein-rich mucus layer, has one of the highest turnover rates in the body [56]. The renewal of epithelial cells in the intestinal epithelium involves a highly coordinated process of cellular proliferation, differentiation, migration, and apoptosis. This constant cell turnover relies on ongoing protein synthesis, which is largely mediated through the activation of mTOR pathway [57]. In addition to serving as essential building blocks of proteins, Met and Arg have been shown to activate mTORC1 [58,59]. Met activates the mTOR signaling pathway by promoting the methylation of phosphatase 2A through the action of SAM. Furthermore, previous studies showed that SAM could bind to the S-adenosylmethionine sensor upstream of mTORC1 (SAMTOR), counteracting its inhibitory effects on mTORC1 activity [59,60]. On the other hand, Arg activates the mTOR pathway through inhibiting the activity of tuberous sclerosis complex 2, a protein that normally suppresses the mTOR pathway [61]. The mTOR pathway is essential for maintaining intestinal epithelial cell proliferation during both homeostasis and regeneration, as research showed that a disruption in this signaling pathway would lead to intestinal epithelial cell defects and hinder the intestinal regeneration [62,63].
The Wnt/β-catenin signaling pathway is also well established for its role in maintaining intestinal structure and homeostasis as it regulates the self-renewal and differentiation of the intestinal stem cells [64,65,66]. Interestingly, studies have also shown that both Met and Arg can activate the Wnt/β-catenin pathway to enhance the intestinal epithelial development [32,67]. Met is required for the sequestration of glycogen synthase kinase 3, which is an essential step in activating the Wnt signaling pathway [68]. The modulating effects of Arg on the Wnt/β-catenin signaling pathway can be attributed to the synthesis of NO, which is a known activator of this pathway [69]. Intriguingly, activation of the Wnt/β-catenin signaling pathway is closely regulated by the methylation of the Arg residues in Ras GTPase-activating protein-binding protein 1 (G3BP1) with SAM as the methyl donor. This linkage underscores the collaborative regulatory roles of Met and Arg in this pathway [68,70]. The activation roles of Met and Arg in both pathways contribute to the regenerative capacity and development of the intestine.
Beyond their roles in pathway activation, Met and Arg are indispensable for polyamine synthesis. Arg serves as the precursor for polyamine synthesis, while SAM, a product of Met metabolism, functions as the methyl donor in this process [71]. Polyamines are essential for intestinal epithelial renewal and repair, ensuring its important roles in cell proliferation, development, and migration [72,73]. Studies have demonstrated that providing dividing cells in the crypts with polyamines can stimulate mucosal growth and facilitate the repair of damaged mucosa [74,75,76]. The proposed mechanism underlying the stimulation effect of polyamines in mucosal growth involves their ability to regulate expression of various genes encoding growth promoting and inhibiting factors [71,77]. Polyamines are also shown to be vital for the expression of tight junction and adhesion junction proteins which maintain the intestinal barrier function [78,79].
Overall, Met and Arg are essential for the development and repair of the intestinal epithelium. They contribute to this process by activating pathways essential for intestinal regeneration and by participating in polyamine synthesis.

3.2. Antioxidant Effects of Methionine and Arginine on Intestinal Health

3.2.1. Oxidative Stress

The integrity of the intestinal barrier can be disrupted by various factors, among which oxidative stress is a significant contributor. Reactive oxygen species (ROS) are byproducts generated during normal metabolic processes [80,81]. Under normal conditions, the production of ROS is balanced by the antioxidant system [82]. However, an excessive production of ROS or a decline in antioxidant defenses can disrupt this equilibrium, leading to the accumulation of ROS. The highly reactive ROS will react with the cellular components causing cellular damage, dysfunction, and apoptosis, which ultimately leads to impaired organ functions and the development of oxidative stress [80]. Several factors during poultry production can cause oxidative stress to the birds, such as nutritional factors like nutrient imbalances and feed toxins, environmental factors like heat stress and stocking density stress, as well as pathological factors [83,84,85].
Oxidative stress can damage the structure and function of tight junctions, resulting in compromised intestinal barrier functions and increased permeability [86]. Oxidative stress is also known to damage the intestinal epithelial cells directly, leading to further disruption of the barrier function and inflammation. The recruited macrophage and heterophils intensify the production of ROS, stimulating a positive feedback loop that exacerbates oxidative stress and inflammation [87,88]. Oxidative stress is also reported to cause morphometric changes in the intestinal tract by reducing the villi height and lowering the villus: crypt ratio, interfering with nutrient absorption [89,90].

3.2.2. Antioxidant Effects of Methionine and Arginine

Methionine is reported to exhibit potent antioxidant capacity through two major mechanisms [91,92]. Firstly, it produces antioxidant metabolites by undergoing metabolic processes as described in Figure 1. SAM, as one of the metabolites in the pathway, is not only an important methyl donor, but also a key metabolite modifying antioxidant enzymes, such as superoxide dismutase (SOD) and catalase (CAT) [91,92]. Such modification effects were confirmed by different research groups observing increased activities of antioxidant enzymes in birds fed Met supplemented diets [93,94,95,96,97]. Cysteine, another sulfur-containing amino acid, also exhibits antioxidant ability and is further metabolized to GSH, a well-known intrinsic antioxidant. Previous studies have also demonstrated increased GSH or improved GSH: glutathione disulfide (GSSG) ratio in broilers fed Met supplemented diets [84,98,99]. Secondly, Met residues in proteins can directly scavenge ROS. As a sulfur-containing amino acid, Met residues on the surface of proteins are readily oxidized. By scavenging ROS and being oxidized into methionine sulfoxide, Met can protect other critical components from oxidation, thus maintaining their integrity and function [17,70]. Furthermore, methionine sulfoxide can be reduced by methionine sulfoxide reductases (MSR) back to Met to restore its antioxidant capacity [20,100,101]. The antioxidant capacity of methionine and its metabolites is presented in Figure 3.
Previous research has provided evidence on the beneficial effects of Met supplementation in intestinal health through its antioxidant capacity. Dietary Met supplementation in broilers improved the GSH:GSSG ratio and glutathione peroxidase activity as well as increased the villus height (VH) and ratio of villus height to crypt depth (VH:CD) with or without stocking density challenge [29]. Met supplementation also improved the tight junction protein expression, whereas it decreased the expression of proinflammatory cytokines in broilers under heat stress [30]. Another study also demonstrated that Met supplementation increased the concentration of GSH, while it reduced the malondialdehyde (MDA) content in the duodenum mucosa. The VH and VH:CD were again improved by Met supplementation [31]. Despite not being widely recognized for its antioxidant capacity, several studies have shown that Arg supplementation can improve the oxidative status and benefit intestinal health. In an in vitro study conducted in ovine intestinal epithelial cells [38], the researchers found that Arg supplementation significantly reduced the hydrogen peroxide-induced ROS production. Furthermore, Arg also increased levels of glutathione peroxidase and tight junction protein 1, whereas it decreased the level of proinflammatory cytokines. Moreover, supplementing Arg in broiler breeders improved the oxidative status of the breeder birds as well as the one-day-old offspring [37]. Another study conducted in rats challenged with sodium nitrite showed that Arg supplementation reduced the serum MDA content and increased GSH production [102]. Additionally, both Met and Arg have been shown to activate the nuclear factor erythroid 2-related factor 2–antioxidant responsive element (Nrf2-ARE) pathway, leading to the upregulation of antioxidant enzymes and the generation of antioxidant effects [103,104].
Considering the potent antioxidant capacity and effects of Met and Arg, incorporating both Met and Arg as functional dietary supplements for poultry holds significant promise in mitigating the detrimental effects of oxidative stress on intestinal health and the overall well-being of the birds.

3.3. Methionine and Arginine in the Immune System

The intestinal tract is a major compartment of the immune system. The gut-associated lymphoid tissues (GALT) are estimated to comprise more immune cells than any other tissues [105]. The definable structures of GALT include lymphoid aggregates located within the lamina propria, Meckel’s diverticulum, Peyer’s patches, cecal tonsils, and bursa of Fabricius. In contrast to mammals, birds lack traditional lymph nodes; however, they possess numerous lymphoid aggregates that represent most of the secondary lymphoid tissues. Overall, the gut harbors diverse immune cell types, including heterophils, macrophages, dendritic cells, natural killer cells, and B and T cells, with the cellular compositions differing among different lymphoid tissues [106].
Methionine plays a critical role in both the humoral and cell-mediated immune responses in animals [107]. The impact of methionine on the humoral immune function of animals is primarily reflected in its effects on immunoglobulin levels in the body [108]. As for the cell-mediated immune responses, Met exerts regulatory effects on T cell activation and development [109]. Research showed that the activation of T cells is typically associated with an upregulation of Met transporters and SAM metabolism enzymes [110]. It was proposed that Met as well as its metabolites are taken up by the T helper cells for the synthesis of new protein and methylation of RNA and DNA, which drives activation, proliferation and differentiation of T cells [109,111]. Sufficient levels of methionine can significantly enhance antibody production as well as improve T cell proliferation in broilers [108,112,113,114]. Conversely, a deficiency of methionine significantly reduces the levels of immunoglobins in the bloodstream and inhibits the proliferation and differentiation of lymphocytes in broilers [115,116].
Numerous studies have extensively explored the immunoregulatory roles of Arg. Arg plays a significant modulatory role in immune function, primarily through the synthesis of NO by inducible NOS (iNOS) in macrophages [117,118]. NO is a versatile molecule that serves as a pivotal mediator in various immunological processes, including antimicrobial defense, immune cell regulation, and cytotoxicity [119,120]. Research has also shown its protective effects against protozoan infections [121,122]. Over the years, researchers have also shown that arginine availability is crucial for maintaining normal T cell proliferation and function. Rodriguez et al. [123] demonstrated that T cell function was significantly impaired under conditions of limited arginine supply, while this effect was completely reversed when arginine was replenished. It was proposed that arginine is indispensable for the expression of the T cell antigen receptor CD3ζ, which subsequently influences T cell function [25,123]. A recent study has also reported that Arg supplementation ameliorated the negative effect in Eimeria-infected broiler birds by enhancing the T cell function and elevating NO production [21].
Given the important roles of Met and Arg in immunity, the supplementation of Met and Arg could be a promising approach to enhance the immune response of the poultry intestine that constantly faces various challenges.

3.4. Methionine and Arginine in the Intestinal Microbiome

Numerous bacterial species inhabit the gastrointestinal tract (GIT) of chickens, with Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria being the dominant ones at the phylum level [124]. Studies have revealed that maintaining a well-balanced microbiota profile is crucial for preserving intestinal health and normal functions [125]. For instance, these microbial communities break down polysaccharides to provide amino acids and short-chain fatty acids, serving as crucial energy sources for the epithelial cells [126]. Moreover, the healthy intestinal microorganism plays a protective role against pathogens by inhibiting the adherence and colonization of the pathogens as well as modulating the immune responses of the host [124,127].
The intestinal microbiota profile is known to be influenced by dietary factors [128]. Recent research has shed light on the impact of Arg supplementation on the intestinal microbiota of chickens. Multiple studies have consistently shown that Arg supplementation can lead to an increase in the relative abundance of Firmicutes and a decrease in Proteobacteria in the ileum [34,35,129]. At the genus level, Ruan et al. [35] demonstrated that Arg supplementation resulted in a higher relative abundance of Romboutsia and a lower abundance of Clostridium sensu stricto 1. Brugaletta et al. [130] found that in the ceca, Arg supplementation decreased alpha diversity and the relative abundance of Proteobacteria, while increasing the relative abundances of Bacteroidetes and Lactobacillus salivarius. There is limited evidence regarding the effects of Met supplementation on the chicken intestinal microbiota profiles. However, Kumar et al. [131] reported that Met supplementation could enhance glycolysis and energy generation by the cecal microbiota. Another study performed in germ-free pigs revealed that in the absence of intestinal microbiota, Met levels in the ileum and hindgut increased significantly, indicating that the intestinal microbiota were actively involved in Met metabolism [132].
In conclusion, the findings so far suggest that Arg supplementation has notable effects on the intestinal microbiota composition in chickens. However, further investigation is needed to explore the potential impacts of Met supplementation on the chicken intestinal microbiota.

4. Methionine and Arginine in Bone Health

4.1. Bone Formation, Growth and Remodeling

The majority of the skeleton is formed by the process called endochondral ossification involving the replacement of cartilage with bone tissue [133]. In the initial phase of this process, chondrocytes undergo proliferation, hypertrophy, and apoptosis, resulting in the formation of the cartilage extracellular matrix, primarily composed of type II and type X collagen and proteoglycans. Once the chondrocytes die, osteoblasts take over and secrete type I collagen and other non-collagenous bone matrix proteins such as osteopontin, osteonectin, and osteocalcin [134,135,136], depositing minerals to form the bone matrix and replace the cartilage. This replacement of cartilage initiates from the primary ossification center in the diaphysis. Concurrently, the same process occurs at both ends of the bone, known as the growth plate, leading to bone lengthening [137,138].
Bone remodeling is a continuous and essential process that takes place constantly. This process involves the coordinated activities of osteoblasts and osteoclasts [138]. Osteoblasts, which differentiate from mesenchymal stem cells (MSCs) under the regulation of runt-related transcription factor 2 (RUNX2), play a pivotal role in producing bone matrix proteins and driving bone formation [114]. On the other hand, osteoclasts, originating from hematopoietic stem cells upon activation by the receptor activator of NF-kB ligand (RANKL), function as bone-resorbing cells which break down the bone matrix, releasing calcium and phosphate back into the bloodstream [139]. Bone remodeling helps to repair microdamage in the bone matrix, thereby preventing the accumulation of old or damaged bone tissue and maintaining bone integrity. Additionally, bone remodeling aids in maintaining plasma calcium homeostasis [140]. The balance between osteoblast and osteoclast activities is tightly regulated by a variety of factors, including hormones, growth factors, mechanical stress, nutrients, and immune responses [138,141,142,143].
Recently, there has been a growing recognition of the significance of amino acids in skeletal metabolism [144,145]. Met and Arg, due to their vital roles in various metabolic processes including immune responses, antioxidant capacity and metabolically important compound synthesis, are important in maintaining bone development and normal functions [144].

4.2. Methionine and Arginine in Bone Metabolism

Previous studies have demonstrated that Met deficiency leads to deteriorated bone health. Ouattara et al. [42] conducted experiments on mice and rats subjected to a methionine-restricted diet. They observed a notable decline in key bone parameters, including volumetric bone mass density (BMD), bone mineral content, and bone microarchitecture parameters. Likewise, in another study conducted by Plummer et al. [43], the authors found that Met restriction in mice significantly decreased the cortical and trabecular BMD and also diminished bone volume and trabecular thickness. Remarkably, both studies reached a similar conclusion, suggesting that the reduction in bone health indicators may be linked to a decline in collagen synthesis and impaired osteoblast differentiation and functionality, which is further substantiated by the observed downregulation of RUNX2, the master regulator of osteogenesis. These observations were made in a mouse preosteoblast cell line cultured under low Met conditions and in the bone marrow of mice subjected to a Met deficient diet [42,43]. Fang et al. [146] also demonstrated that Met supplementation in fish could increase type 1 collagen synthesis. This finding further reinforces the significance of Met in collagen synthesis by osteoblasts. The mechanism behind this could be attributed to the important role Met plays in protein synthesis and mTOR signaling, as described in the previous section [144]. Vijayan [41] also demonstrated that Met supplementation to ovariectomized rats improved BMD and disrupted the development of osteoclasts.
Arginine may contribute to bone development also by influencing collagen synthesis, because it is a precursor for proline and hydroxyproline, which are essential amino acids for collagen formation [55,144]. Furthermore, Van’T Hof and Ralston [147] stated in their review paper that NO is of significant importance in bone formation and reabsorption. It has been suggested that the regulatory effects of NO are primarily governed by endothelial nitric oxide synthase (eNOS), which is the predominant isoform of NOS in the bone [148]. In eNOS(−/−) transgenic mice, researchers found significant abnormalities in bone formation [149,150]. Moreover, multiple studies have demonstrated that supplementation of NO donors can improve bone formation and strength in preclinical animal models [151] as well as reduce fracture risk in humans [152,153]. Given the importance of Arg in NO synthesis, Arg might further exert its influence in bone health. One recent study demonstrated that the absence of argininosuccinate lyase (ASL) in osteoblasts would lead to impairment of osteoblast differentiation [154]. Another study conducted in human MSCs further revealed that Arg supplementation in human MSCs enhanced osteoblastogenesis and inhibited adipogenesis through regulating the Wnt signaling pathway [45]. Previous studies have also shown that Arg supplementation in rats, broilers, and layers could improve bone mineralization and prevent bone loss [44,155,156].
Overall, through influencing collagen synthesis or NO metabolism, Met and Arg might exert their beneficial roles in bone development and formation. Because collagen is produced by mature osteoblasts, it is necessary to further investigate the roles of Met, Arg, and their metabolites on osteogenic differentiation of mesenchymal stem cells.

4.3. Oxidative Stress, Intestinal Health and Bone Health

Oxidative stress is not only detrimental to intestinal health but also poses a great threat to bone health. Several reviews have extensively examined the influence of oxidative stress on bone health [157,158]. In essence, it triggers the apoptosis of osteoblasts and osteocytes, while promoting osteoclast formation through upregulating RANKL [159]. Consequently, this disruption generates an imbalance within the bone remodeling process, impeding mineralization and osteogenesis, and increasing bone resorption, ultimately leading to increased bone loss [11,157,160]. A recent study investigating the impact of hydrogen peroxide-induced oxidative stress on chicken compact bone-derived MSCs revealed that oxidative stress significantly increased apoptosis and decreased osteogenic differentiation of the cells, and this was accompanied by a universal decrease in osteogenesis-related gene expression and a decline in vitro mineralization [161]. Likewise, another study found that oxidative stress suppressed the expression of osteogenesis-related genes in chicken embryos, consequently impairing proper bone development [162]. Both studies confirmed the negative effects of oxidative stress on chicken bone development. Emerging observations have also indicated that oxidative stress is involved in various bone-related conditions including osteoporosis, bone tumor progression, and inflammatory joint diseases [163,164,165]. In vivo and in vitro studies have shown that antioxidant supplementations can mitigate oxidative stress and contribute to activation of osteoblast differentiation, mineralization, and reduction in osteoclast activity [166,167,168]. Considering the antioxidant capacities of Met and Arg discussed above, their supplementations might alleviate oxidative stress and benefit bone health.
Although appearing distinct, the intestinal health and bone health are intricately interconnected and the immune system emerges as a significant factor that bridges the gap between them [11]. On one hand, the bone marrow serves as the hemopoietic organ, offering a specialized environment for the development of hematopoietic stem cells, which are the shared origin of various immune cell types [169]. On the other hand, the intestine is considered the largest immune organ that is constantly encountering challenges [170]. As seen in multiple previous studies [171,172,173], the disturbance of the immune system caused by enteric diseases such as coccidiosis and enteric enteritis leads to the occurrence and development of bone disorders [11,169]. This process is once more propelled by the imbalance between osteoblast and osteoclast activities triggered by the upregulation of RANKL, which is induced by cytokines released from activated immune cells [174,175]. Acknowledging the protective role of Met and Arg in intestinal barrier functions and their immunomodulatory effects, it is plausible to speculate that these amino acids might contribute to the prevention of bone disorders by maintaining intestinal health.

4.4. Methionine and Arginine Effects on Bone Health in Different Growth Periods

Bone development in chickens differs during the early and late growth periods. During the early growth period (first 2–3 weeks of age), especially for the meat-type broilers, the cortex of the bones exhibits high porosity because the rate at which osteoblasts fill the osteon canals cannot match the rapid bone growth [176,177]. Consequently, birds are particularly vulnerable to developing skeletal abnormalities, emphasizing the significance of maintaining optimal bone health during this period [178]. As the birds age, the bones progressively mineralize as the osteoblasts mineralize and seal the inner canals [167]. Previous research showed that in broiler birds, the thickness and mineral density of tibia bones steadily increased with age, peaking at 4 to 5 weeks of age and remaining constant thereafter [179]. However, as the birds age, the increasingly higher body weight can place stress on the skeletal structure [180]. Furthermore, during the late growth period, the birds are more susceptible to oxidative stress due to the decline in their antioxidant defense system [181]. Additionally, they are more vulnerable to stress factors such as stocking density and high temperature [182]. These factors pose risks to bone health through different mechanisms compared with the challenges faced by the birds during the early growth period.
Given the distinct challenges to bone health during the early and late growth periods, it is reasonable to expect that the effects of dietary Met and Arg on bone development could vary. During the early growth phase, ensuring an adequate supply of Met and Arg may contribute to the production of more collagen and bone matrix proteins, supporting bone development. In contrast, during the late growth period, these functional amino acids might exert their effects on bone health through their antioxidant capacity and immunomodulating properties. However, it is worth noting that there is a limited body of research on this specific topic. Further studies are needed to better understand how Met and Arg supplementation can influence bone development during different growth stages and the mechanisms through which they exert their effects.

5. Potential Risks of Excessive Methionine and Arginine

Despite the considerable potential benefits associated with Met and Arg supplementation in poultry, excessive intake of these amino acids could give rise to unfavorable outcomes. One particular concern is the potential development of hyperhomocysteinemia due to excessive Met intake [183,184,185]. A high level of Hcy has been correlated with increased cardiovascular disease, inflammation, and compromised bone health [186,187,188]. Therefore, it is important to maintain normal blood Hcy levels when supplementing extra Met. One effective approach is to ensure adequate intake of B vitamins (B6, B12, and folate) to facilitate its conversion to methionine or cysteine [189] as they act as the cofactors for enzymes involved in its metabolism. However, folate and its derivatives are also known to be essential for the reproduction of certain pathogens such as Eimeria spp. [190,191]. Given the close relationship between Met and folate metabolism, excessive Met might favor the development of Eimeria spp. as one previous study showed that extra Met supplementation led to increased oocyst shedding in broilers [192]. Another noteworthy point is the antagonism between Arg and lysine when feeding excessive Arg to the birds, which may reduce food consumption, weight gain and Arg utilization in animal metabolism [193].
It is crucial to acknowledge that the functional roles of Met and Arg in various physiological processes, as discussed in earlier sections, could lead to an increased demand for these amino acids in stressful environments or during conditions of disease challenge. As previously suggested, the optimal Arg: Lys ratio increased in broilers under heat stress conditions [194]. Therefore, it is of utmost importance to supplement optimal amounts of Met and Arg in poultry diets, especially under challenging conditions, to produce the peak performance and productivity of the birds.

6. Conclusions

In conclusion, this review comprehensively examines the functional roles of Met and Arg in promoting intestinal and bone health in poultry. These amino acids are integral not only to protein synthesis but also to diverse physiological functions. Within the intestinal context, Met and Arg contribute to development, repair, antioxidant defense, immune response, and microbiome modulation, collectively fostering optimal gut health. In terms of bone health, they are important in bone formation, growth, and remodeling, underscoring their significance in maintaining skeletal integrity (Figure 4). While their benefits are evident, caution is advised regarding excessive intake which could lead to adverse effects. Ultimately, a thorough understanding of the functions of Met and Arg offers insights into enhancing poultry nutrition and well-being.

Author Contributions

Conceptualization and writing, G.L.; conceptualization, review and editing, W.K.K. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Henchion, M.; Hayes, M.; Mullen, A.M.; Fenelon, M.; Tiwari, B. Future Protein Supply and Demand: Strategies and Factors Influencing a Sustainable Equilibrium. Foods 2017, 6, 53. [Google Scholar] [CrossRef]
  2. Ravindran, V.; Abdollahi, M.R. Nutrition and Digestive Physiology of the Broiler Chick: State of the Art and Outlook. Animals 2021, 11, 2795. [Google Scholar] [CrossRef]
  3. Takiishi, T.; Fenero, C.I.M.; Câmara, N.O.S. Intestinal barrier and gut microbiota: Shaping our immune responses throughout life. Tissue Barriers 2017, 5, e1373208. [Google Scholar] [CrossRef]
  4. Adedokun, S.A.; Olojede, O.C. Optimizing Gastrointestinal Integrity in Poultry: The Role of Nutrients and Feed Additives. Front. Vet. Sci. 2018, 5, 348. [Google Scholar] [CrossRef]
  5. Ruth, M.R.; Field, C.J. The immune modifying effects of amino acids on gut-associated lymphoid tissue. J. Anim. Sci. Biotechnol. 2013, 4, 27. [Google Scholar] [CrossRef]
  6. Yegani, M.; Korver, D.R. Factors affecting intestinal health in poultry. Poult. Sci. 2008, 87, 2052–2063. [Google Scholar] [CrossRef]
  7. Alizadeh, M.; Shojadoost, B.; Boodhoo, N.; Astill, J.; Taha-Abdelaziz, K.; Hodgins, D.C.; Kulkarni, R.R.; Sharif, S. Necrotic enteritis in chickens: A review of pathogenesis, immune responses and prevention, focusing on probiotics and vaccination. Anim. Health Res. Rev. 2021, 22, 147–162. [Google Scholar] [CrossRef]
  8. Blake, D.P.; Knox, J.; Dehaeck, B.; Huntington, B.; Rathinam, T.; Ravipati, V.; Ayoade, S.; Gilbert, W.; Adebambo, A.O.; Jatau, I.D.; et al. Re-calculating the cost of coccidiosis in chickens. Vet. Res. 2020, 51, 115. [Google Scholar] [CrossRef]
  9. Cervantes, H.M. Antibiotic-free poultry production: Is it sustainable? J. Appl. Poult. Res. 2015, 24, 91–97. [Google Scholar] [CrossRef]
  10. Kolakshyapati, M.; Flavel, R.J.; Sibanda, T.Z.; Schneider, D.; Welch, M.C.; Ruhnke, I. Various bone parameters are positively correlated with hen body weight while range access has no beneficial effect on tibia health of free-range layers. Poult. Sci. 2019, 98, 6241–6250. [Google Scholar] [CrossRef]
  11. Sharma, M.K.; Regmi, P.; Applegate, T.; Chai, L.; Kim, W.K. Osteoimmunology: A Link between Gastrointestinal Diseases and Skeletal Health in Chickens. Animals 2023, 13, 1816. [Google Scholar] [CrossRef]
  12. Bradshaw, R.; Kirkden, R.; Broom, D. A review of the aetiology and pathology of leg weakness in broilers in relation to welfare. Avian Poult. Biol. Rev. 2002, 13, 45–104. [Google Scholar] [CrossRef]
  13. Kierończyk, B.; Rawski, M.; Józefiak, D.; Świątkiewicz, S. Infectious and non-infectious factors associated with leg disorders in poultry—A review. Ann. Anim. Sci. 2017, 17, 645–669. [Google Scholar]
  14. Wu, G. Amino acids: Metabolism, functions, and nutrition. Amino Acids 2009, 37, 1–17. [Google Scholar] [CrossRef]
  15. Castro, F.L.d.S.; Kim, W.K. Secondary Functions of Arginine and Sulfur Amino Acids in Poultry Health: Review. Animals 2020, 10, 2106. [Google Scholar] [CrossRef]
  16. Bunchasak, C. Role of dietary methionine in poultry production. J. Poult. Sci. 2009, 46, 169–179. [Google Scholar] [CrossRef]
  17. Sasaki, J.; Nakashima, N. Methionine-independent initiation of translation in the capsid protein of an insect RNA virus. Proc. Natl. Acad. Sci. USA 2000, 97, 1512–1515. [Google Scholar] [CrossRef]
  18. Brosnan, J.T.; Brosnan, M.E.; Bertolo, R.F.P.; Brunton, J.A. Methionine: A metabolically unique amino acid. Livest. Sci. 2007, 112, 2–7. [Google Scholar] [CrossRef]
  19. Martínez, Y.; Li, X.; Liu, G.; Bin, P.; Yan, W.; Más, D.; Valdivié, M.; Hu, C.-A.A.; Ren, W.; Yin, Y. The role of methionine on metabolism, oxidative stress, and diseases. Amino Acids 2017, 49, 2091–2098. [Google Scholar] [CrossRef]
  20. Levine, R.L.; Moskovitz, J.; Stadtman, E.R. Oxidation of methionine in proteins: Roles in antioxidant defense and cellular regulation. IUBMB Life 2000, 50, 301–307. [Google Scholar] [CrossRef]
  21. Liu, G.; Ajao, A.M.; Shanmugasundaram, R.; Taylor, J.; Ball, E.; Applegate, T.J.; Selvaraj, R.; Kyriazakis, I.; Olukosi, O.A.; Kim, W.K. The effects of arginine and branched-chain amino acid supplementation to reduced-protein diet on intestinal health, cecal short-chain fatty acid profiles, and immune response in broiler chickens challenged with Eimeria spp. Poult. Sci. 2023, 102, 102773. [Google Scholar] [CrossRef]
  22. Abdukalykova, S.; Zhao, X.; Ruiz-Feria, C. Arginine and vitamin E modulate the subpopulations of T lymphocytes in broiler chickens. Poult. Sci. 2008, 87, 50–55. [Google Scholar] [CrossRef]
  23. Lee, J.; Austic, R.; Naqi, S.; Golemboski, K.; Dietert, R. Dietary arginine intake alters avian leukocyte population distribution during infectious bronchitis challenge. Poult. Sci. 2002, 81, 793–798. [Google Scholar] [CrossRef]
  24. Khajali, F.; Wideman, R. Dietary arginine: Metabolic, environmental, immunological and physiological interrelationships. World’s Poult. Sci. J. 2010, 66, 751–766. [Google Scholar] [CrossRef]
  25. Popovic, P.J.; Zeh, H.J.; Ochoa, J.B. Arginine and Immunity123. J. Nutr. 2007, 137, 1681S–1686S. [Google Scholar] [CrossRef]
  26. Teng, P.-Y.; Liu, G.; Choi, J.; Yadav, S.; Wei, F.; Kim, W.K. Effects of levels of methionine supplementations in forms of L- or DL-methionine on the performance, intestinal development, immune response, and antioxidant system in broilers challenged with Eimeria spp. Poult. Sci. 2023, 102, 102586. [Google Scholar] [CrossRef]
  27. Lai, A.; Yuan, Z.; Wang, Z.; Chen, B.; Zhi, L.; Huang, Z.; Zhang, Y. Dietary Methionine Increased the Growth Performances and Immune Function of Partridge Shank Broilers after Challenged with Coccidia. Animals 2023, 13, 613. [Google Scholar] [CrossRef]
  28. Khatlab, A.d.S.; Del Vesco, A.P.; de Oliveira Neto, A.R.; Fernandes, R.P.M.; Gasparino, E. Dietary supplementation with free methionine or methionine dipeptide mitigates intestinal oxidative stress induced by Eimeria spp. challenge in broiler chickens. J. Anim. Sci. Biotechnol. 2019, 10, 58. [Google Scholar] [CrossRef]
  29. Miao, Z.Q.; Dong, Y.Y.; Qin, X.; Yuan, J.M.; Han, M.M.; Zhang, K.K.; Shi, S.R.; Song, X.Y.; Zhang, J.Z.; Li, J.H. Dietary supplementation of methionine mitigates oxidative stress in broilers under high stocking density. Poult. Sci. 2021, 100, 101231. [Google Scholar] [CrossRef]
  30. Del Vesco, A.P.; Khatlab, A.d.S.; Santana, T.P.; Pozza, P.C.; Menck Soares, M.A.; Brito, C.O.; Barbosa, L.T.; Gasparino, E. Heat stress effect on the intestinal epithelial function of broilers fed methionine supplementation. Livest. Sci. 2020, 240, 104152. [Google Scholar] [CrossRef]
  31. Shen, Y.B.; Ferket, P.; Park, I.; Malheiros, R.D.; Kim, S.W. Effects of feed grade L-methionine on intestinal redox status, intestinal development, and growth performance of young chickens compared with conventional DL-methionine. J. Anim. Sci. 2015, 93, 2977–2986. [Google Scholar] [CrossRef] [PubMed]
  32. Zhong, C.; Tong, D.Q.; Zhang, Y.R.; Wang, X.Q.; Yan, H.C.; Tan, H.Z.; Gao, C.Q. (DL)-methionine and (DL)-methionyl-(DL)-methionine increase intestinal development and activate Wnt/β-catenin signaling activity in domestic pigeons (Columba livia). Poult. Sci. 2022, 101, 101644. [Google Scholar] [CrossRef] [PubMed]
  33. Wu, B.; Li, L.; Ruan, T.; Peng, X. Effect of methionine deficiency on duodenal and jejunal IgA(+) B cell count and immunoglobulin level of broilers. Iran. J. Vet. Res. 2018, 19, 165–171. [Google Scholar]
  34. Zhang, B.; Lv, Z.; Li, Z.; Wang, W.; Li, G.; Guo, Y. Dietary l-arginine Supplementation Alleviates the Intestinal Injury and Modulates the Gut Microbiota in Broiler Chickens Challenged by Clostridium perfringens. Front. Microbiol. 2018, 9, 1716. [Google Scholar] [CrossRef]
  35. Ruan, D.; Fouad, A.M.; Fan, Q.L.; Huo, X.H.; Kuang, Z.X.; Wang, H.; Guo, C.Y.; Deng, Y.F.; Zhang, C.; Zhang, J.H.; et al. Dietary L-arginine supplementation enhances growth performance, intestinal antioxidative capacity, immunity and modulates gut microbiota in yellow-feathered chickens. Poult. Sci. 2020, 99, 6935–6945. [Google Scholar] [CrossRef]
  36. Castro, F.L.S.; Teng, P.-Y.; Yadav, S.; Gould, R.L.; Craig, S.; Pazdro, R.; Kim, W.K. The effects of L-Arginine supplementation on growth performance and intestinal health of broiler chickens challenged with Eimeria spp. Poult. Sci. 2020, 99, 5844–5857. [Google Scholar] [CrossRef] [PubMed]
  37. Duan, X.; Li, F.; Mou, S.; Feng, J.; Liu, P.; Xu, L. Effects of dietary L-arginine on laying performance and anti-oxidant capacity of broiler breeder hens, eggs, and offspring during the late laying period. Poult. Sci. 2015, 94, 2938–2943. [Google Scholar] [CrossRef]
  38. Zhang, H.; Zhang, Y.; Liu, X.; Elsabagh, M.; Yu, Y.; Peng, A.; Dai, S.; Wang, H. L-Arginine inhibits hydrogen peroxide-induced oxidative damage and inflammatory response by regulating antioxidant capacity in ovine intestinal epithelial cells. Ital. J. Anim. Sci. 2021, 20, 1620–1632. [Google Scholar] [CrossRef]
  39. Tan, J.; Applegate, T.J.; Liu, S.; Guo, Y.; Eicher, S.D. Supplemental dietary l-arginine attenuates intestinal mucosal disruption during a coccidial vaccine challenge in broiler chickens. Br. J. Nutr. 2014, 112, 1098–1109. [Google Scholar] [CrossRef]
  40. Laika, M.; Jahanian, R. Increase in dietary arginine level could ameliorate detrimental impacts of coccidial infection in broiler chickens. Livest. Sci. 2017, 195, 38–44. [Google Scholar] [CrossRef]
  41. Vijayan, V.; Khandelwal, M.; Manglani, K.; Gupta, S.; Surolia, A. Methionine down-regulates TLR4/MyD88/NF-κB signalling in osteoclast precursors to reduce bone loss during osteoporosis. Br. J. Pharmacol. 2014, 171, 107–121. [Google Scholar] [CrossRef]
  42. Ouattara, A.; Cooke, D.; Gopalakrishnan, R.; Huang, T.H.; Ables, G.P. Methionine restriction alters bone morphology and affects osteoblast differentiation. Bone Rep. 2016, 5, 33–42. [Google Scholar] [CrossRef]
  43. Plummer, J.; Park, M.; Perodin, F.; Horowitz, M.C.; Hens, J.R. Methionine-Restricted Diet Increases miRNAs That Can Target RUNX2 Expression and Alters Bone Structure in Young Mice. J. Cell. Biochem. 2017, 118, 31–42. [Google Scholar] [CrossRef]
  44. Castro, F.L.S.; Su, S.; Choi, H.; Koo, E.; Kim, W.K. L-Arginine supplementation enhances growth performance, lean muscle, and bone density but not fat in broiler chickens. Poult. Sci. 2019, 98, 1716–1722. [Google Scholar] [CrossRef]
  45. Huh, J.-E.; Choi, J.-Y.; Shin, Y.-O.; Park, D.-S.; Kang, J.W.; Nam, D.; Choi, D.-Y.; Lee, J.-D. Arginine Enhances Osteoblastogenesis and Inhibits Adipogenesis through the Regulation of Wnt and NFATc Signaling in Human Mesenchymal Stem Cells. Int. J. Mol. Sci. 2014, 15, 13010–13029. [Google Scholar] [CrossRef]
  46. Ravindran, V.; Bryden, W.L. Amino acid availability in poultry—In vitro and in vivo measurements. Aust. J. Agric. Res. 1999, 50, 889–908. [Google Scholar] [CrossRef]
  47. Zhang, S.; Gilbert, E.R.; Saremi, B.; Wong, E.A. Supplemental methionine sources have a neutral impact on oxidative status in broiler chickens. J. Anim. Physiol. Anim. Nutr. 2018, 102, 1274–1283. [Google Scholar] [CrossRef]
  48. Wu, G.; Fang, Y.-Z.; Yang, S.; Lupton, J.R.; Turner, N.D. Glutathione Metabolism and Its Implications for Health. J. Nutr. 2004, 134, 489–492. [Google Scholar] [CrossRef]
  49. Wang, S.-T.; Chen, H.-W.; Sheen, L.-Y.; Lii, C.-K. Methionine and Cysteine Affect Glutathione Level, Glutathione-Related Enzyme Activities and the Expression of Glutathione S-Transferase Isozymes in Rat Hepatocytes. J. Nutr. 1997, 127, 2135–2141. [Google Scholar] [CrossRef]
  50. Stipanuk, M.H.; Ueki, I. Dealing with methionine/homocysteine sulfur: Cysteine metabolism to taurine and inorganic sulfur. J. Inherit. Metab. Dis. 2011, 34, 17–32. [Google Scholar] [CrossRef]
  51. Wu, G.; Morris, S.M., Jr. Arginine metabolism: Nitric oxide and beyond. Biochem. J. 1998, 336, 1–17. [Google Scholar] [CrossRef]
  52. Tamir, H.; Ratner, S. Enzymes of arginine metabolism in chicks. Arch. Biochem. Biophys. 1963, 102, 249–258. [Google Scholar] [CrossRef]
  53. Rath, M.; Müller, I.; Kropf, P.; Closs, E.I.; Munder, M. Metabolism via Arginase or Nitric Oxide Synthase: Two Competing Arginine Pathways in Macrophages. Front. Immunol. 2014, 5, 532. [Google Scholar] [CrossRef]
  54. Stechmiller, J.K.; Childress, B.; Cowan, L. Arginine Supplementation and Wound Healing. Nutr. Clin. Pract. 2005, 20, 52–61. [Google Scholar] [CrossRef]
  55. Albaugh, V.L.; Mukherjee, K.; Barbul, A. Proline Precursors and Collagen Synthesis: Biochemical Challenges of Nutrient Supplementation and Wound Healing. J. Nutr. 2017, 147, 2011–2017. [Google Scholar] [CrossRef]
  56. Arike, L.; Seiman, A.; van der Post, S.; Rodriguez Piñeiro, A.M.; Ermund, A.; Schütte, A.; Bäckhed, F.; Johansson, M.E.V.; Hansson, G.C. Protein Turnover in Epithelial Cells and Mucus along the Gastrointestinal Tract Is Coordinated by the Spatial Location and Microbiota. Cell Rep. 2020, 30, 1077–1087.e73. [Google Scholar] [CrossRef] [PubMed]
  57. Saxton, R.A.; Sabatini, D.M. mTOR Signaling in Growth, Metabolism, and Disease. Cell 2017, 168, 960–976. [Google Scholar] [CrossRef]
  58. Kong, X.; Tan, B.; Yin, Y.; Gao, H.; Li, X.; Jaeger, L.A.; Bazer, F.W.; Wu, G. l-Arginine stimulates the mTOR signaling pathway and protein synthesis in porcine trophectoderm cells. J. Nutr. Biochem. 2012, 23, 1178–1183. [Google Scholar] [CrossRef]
  59. Kitada, M.; Xu, J.; Ogura, Y.; Monno, I.; Koya, D. Mechanism of Activation of Mechanistic Target of Rapamycin Complex 1 by Methionine. Front. Cell Dev. Biol. 2020, 8, 715. [Google Scholar] [CrossRef]
  60. Takahara, T.; Amemiya, Y.; Sugiyama, R.; Maki, M.; Shibata, H. Amino acid-dependent control of mTORC1 signaling: A variety of regulatory modes. J. Biomed. Sci. 2020, 27, 87. [Google Scholar] [CrossRef]
  61. Carroll, B.; Maetzel, D.; Maddocks, O.D.; Otten, G.; Ratcliff, M.; Smith, G.R.; Dunlop, E.A.; Passos, J.F.; Davies, O.R.; Jaenisch, R.; et al. Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity. eLife 2016, 5, e11058. [Google Scholar] [CrossRef]
  62. Sampson, L.L.; Davis, A.K.; Grogg, M.W.; Zheng, Y. mTOR disruption causes intestinal epithelial cell defects and intestinal atrophy postinjury in mice. FASEB J. 2016, 30, 1263–1275. [Google Scholar] [CrossRef]
  63. Guan, Y.; Zhang, L.; Li, X.; Zhang, X.; Liu, S.; Gao, N.; Li, L.; Gao, G.; Wei, G.; Chen, Z. Repression of mammalian target of rapamycin complex 1 inhibits intestinal regeneration in acute inflammatory bowel disease models. J. Immunol. 2015, 195, 339–346. [Google Scholar] [CrossRef]
  64. Clevers, H.; Nusse, R. Wnt/β-catenin signaling and disease. Cell 2012, 149, 1192–1205. [Google Scholar] [CrossRef]
  65. Ootani, A.; Li, X.; Sangiorgi, E.; Ho, Q.T.; Ueno, H.; Toda, S.; Sugihara, H.; Fujimoto, K.; Weissman, I.L.; Capecchi, M.R. Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat. Med. 2009, 15, 701–706. [Google Scholar] [CrossRef]
  66. Schuijers, J.; Junker, J.P.; Mokry, M.; Hatzis, P.; Koo, B.-K.; Sasselli, V.; Van Der Flier, L.G.; Cuppen, E.; Van Oudenaarden, A.; Clevers, H. Ascl2 acts as an R-spondin/Wnt-responsive switch to control stemness in intestinal crypts. Cell Stem Cell 2015, 16, 158–170. [Google Scholar] [CrossRef]
  67. Hou, Q.; Dong, Y.; Huang, J.; Liao, C.; Lei, J.; Wang, Y.; Lai, Y.; Bian, Y.; He, Y.; Sun, J.; et al. Exogenous L-arginine increases intestinal stem cell function through CD90+ stromal cells producing mTORC1-induced Wnt2b. Commun. Biol. 2020, 3, 611. [Google Scholar] [CrossRef]
  68. Albrecht, L.V.; Bui, M.H.; De Robertis, E.M. Canonical Wnt is inhibited by targeting one-carbon metabolism through methotrexate or methionine deprivation. Proc. Natl. Acad. Sci. USA 2019, 116, 2987–2995. [Google Scholar] [CrossRef]
  69. Du, Q.; Zhang, X.; Liu, Q.; Zhang, X.; Bartels, C.E.; Geller, D.A. Nitric oxide production upregulates Wnt/β-catenin signaling by inhibiting Dickkopf-1. Cancer Res. 2013, 73, 6526–6537. [Google Scholar] [CrossRef]
  70. Bikkavilli, R.K.; Malbon, C.C. Arginine methylation of G3BP1 in response to Wnt3a regulates β-catenin mRNA. J. Cell Sci. 2011, 124, 2310–2320. [Google Scholar] [CrossRef]
  71. Larqué, E.; Sabater-Molina, M.; Zamora, S. Biological significance of dietary polyamines. Nutrition 2007, 23, 87–95. [Google Scholar] [CrossRef]
  72. Sánchez-Jiménez, F.; Medina, M.Á.; Villalobos-Rueda, L.; Urdiales, J.L. Polyamines in mammalian pathophysiology. Cell. Mol. Life Sci. 2019, 76, 3987–4008. [Google Scholar] [CrossRef]
  73. McCORMACK, S.A.; Viar, M.J.; Johnson, L.R. Polyamines are necessary for cell migration by a small intestinal crypt cell line. Am. J. Physiol.-Gastrointest. Liver Physiol. 1993, 264, G367–G374. [Google Scholar] [CrossRef] [PubMed]
  74. Lan, A.; Blachier, F.; Benamouzig, R.; Beaumont, M.; Barrat, C.; Coelho, D.; Lancha, A., Jr.; Kong, X.; Yin, Y.; Marie, J.-C. Mucosal healing in inflammatory bowel diseases: Is there a place for nutritional supplementation? Inflamm. Bowel Dis. 2015, 21, 198–207. [Google Scholar] [CrossRef]
  75. Wang, J.-Y.; Johnson, L.R. Polyamines and ornithine decarboxylase during repair of duodenal mucosa after stress in rats. Gastroenterology 1991, 100, 333–343. [Google Scholar] [CrossRef]
  76. Wang, J.-Y.; McCormack, S.; Viar, M.; Johnson, L. Stimulation of proximal small intestinal mucosal growth by luminal polyamines. Am. J. Physiol.-Gastrointest. Liver Physiol. 1991, 261, G504–G511. [Google Scholar] [CrossRef]
  77. Wang, J.-Y. Polyamines and mRNA stability in regulation of intestinal mucosal growth. Amino Acids 2007, 33, 241–252. [Google Scholar] [CrossRef]
  78. Guo, X.; Rao, J.N.; Liu, L.; Zou, T.-T.; Turner, D.J.; Bass, B.L.; Wang, J.-Y. Regulation of adherens junctions and epithelial paracellular permeability: A novel function for polyamines. Am. J. Physiol.-Cell Physiol. 2003, 285, C1174–C1187. [Google Scholar] [CrossRef]
  79. Timmons, J.; Chang, E.T.; Wang, J.Y.; Rao, J.N. Polyamines and Gut Mucosal Homeostasis. J. Gastrointest. Dig. Syst. 2012, 2, 001. [Google Scholar] [CrossRef]
  80. Zhu, H.; Jia, Z.; Misra, H.; Li, Y.R. Oxidative stress and redox signaling mechanisms of alcoholic liver disease: Updated experimental and clinical evidence. J. Dig. Dis. 2012, 13, 133–142. [Google Scholar] [CrossRef]
  81. Zhang, J.; Wang, X.; Vikash, V.; Ye, Q.; Wu, D.; Liu, Y.; Dong, W. ROS and ROS-Mediated Cellular Signaling. Oxidative Med. Cell. Longev. 2016, 2016, 4350965. [Google Scholar] [CrossRef]
  82. Matés, J.M.; Pérez-Gómez, C.; Núñez de Castro, I. Antioxidant enzymes and human diseases. Clin. Biochem. 1999, 32, 595–603. [Google Scholar] [CrossRef]
  83. Liu, G.; Magnuson, A.D.; Sun, T.; Tolba, S.A.; Starkey, C.; Whelan, R.; Lei, X.G. Supplemental methionine exerted chemical form-dependent effects on antioxidant status, inflammation-related gene expression, and fatty acid profiles of broiler chicks raised at high ambient temperature1. J. Anim. Sci. 2019, 97, 4883–4894. [Google Scholar] [CrossRef]
  84. Magnuson, A.D.; Liu, G.; Sun, T.; Tolba, S.A.; Xi, L.; Whelan, R.; Lei, X.G. Supplemental methionine and stocking density affect antioxidant status, fatty acid profiles, and growth performance of broiler chickens. J. Anim. Sci. 2020, 98, skaa092. [Google Scholar] [CrossRef]
  85. Sharma, M.K.; Liu, G.; White, D.L.; Tompkins, Y.H.; Kim, W.K. Effects of mixed Eimeria challenge on performance, body composition, intestinal health, and expression of nutrient transporter genes of Hy-Line W-36 pullets (0–6 wks of age). Poult. Sci. 2022, 101, 102083. [Google Scholar] [CrossRef]
  86. Rao, R. Oxidative stress-induced disruption of epithelial and endothelial tight junctions. Front. Biosci. J. Virtual Libr. 2008, 13, 7210–7226. [Google Scholar] [CrossRef]
  87. Mishra, B.; Jha, R. Oxidative Stress in the Poultry Gut: Potential Challenges and Interventions. Front. Vet. Sci. 2019, 6, 60. [Google Scholar] [CrossRef]
  88. Wang, Y.; Chen, Y.; Zhang, X.; Lu, Y.; Chen, H. New insights in intestinal oxidative stress damage and the health intervention effects of nutrients: A review. J. Funct. Foods 2020, 75, 104248. [Google Scholar] [CrossRef]
  89. He, X.; Lu, Z.; Ma, B.; Zhang, L.; Li, J.; Jiang, Y.; Zhou, G.; Gao, F. Effects of chronic heat exposure on growth performance, intestinal epithelial histology, appetite-related hormones and genes expression in broilers. J. Sci. Food Agric. 2018, 98, 4471–4478. [Google Scholar] [CrossRef]
  90. Burkholder, K.; Thompson, K.; Einstein, M.; Applegate, T.; Patterson, J. Influence of stressors on normal intestinal microbiota, intestinal morphology, and susceptibility to Salmonella enteritidis colonization in broilers. Poult. Sci. 2008, 87, 1734–1741. [Google Scholar] [CrossRef]
  91. Lozano-Sepulveda, S.A.; Bautista-Osorio, E.; Merino-Mascorro, J.A.; Varela-Rey, M.; Muñoz-Espinosa, L.E.; Cordero-Perez, P.; Martinez-Chantar, M.L.; Rivas-Estilla, A.M. S-adenosyl-L-methionine modifies antioxidant-enzymes, glutathione-biosynthesis and methionine adenosyltransferases-1/2 in hepatitis C virus-expressing cells. World J. Gastroenterol. 2016, 22, 3746–3757. [Google Scholar] [CrossRef]
  92. Kachungwa Lugata, J.; Ortega, A.D.S.V.; Szabó, C. The Role of Methionine Supplementation on Oxidative Stress and Antioxidant Status of Poultry-A Review. Agriculture 2022, 12, 1701. [Google Scholar] [CrossRef]
  93. Del Vesco, A.P.; Gasparino, E.; Grieser, D.O.; Zancanela, V.; Gasparin, F.R.; Constantin, J.; Oliveira Neto, A.R. Effects of methionine supplementation on the redox state of acute heat stress-exposed quails. J. Anim. Sci. 2014, 92, 806–815. [Google Scholar] [CrossRef]
  94. Del Vesco, A.P.; Gasparino, E.; de Oliveira Grieser, D.; Zancanela, V.; Soares, M.A.M.; de Oliveira Neto, A.R. Effects of methionine supplementation on the expression of oxidative stress-related genes in acute heat stress-exposed broilers. Br. J. Nutr. 2015, 113, 549–559. [Google Scholar] [CrossRef]
  95. Kalvandi, O.; Sadeghi, A.; Karimi, A. Methionine supplementation improves reproductive performance, antioxidant status, immunity and maternal antibody transmission in breeder Japanese quail under heat stress conditions. Arch. Anim. Breed. 2019, 62, 275–286. [Google Scholar] [CrossRef]
  96. Reda, F.M.; Swelum, A.A.; Hussein, E.O.; Elnesr, S.S.; Alhimaidi, A.R.; Alagawany, M. Effects of varying dietary DL-methionine levels on productive and reproductive performance, egg quality, and blood biochemical parameters of quail breeders. Animals 2020, 10, 1839. [Google Scholar] [CrossRef]
  97. Chen, Y.; Chen, X.; Zhang, H.; Zhou, Y. Effects of dietary concentrations of methionine on growth performance and oxidative status of broiler chickens with different hatching weight. Br. Poult. Sci. 2013, 54, 531–537. [Google Scholar] [CrossRef]
  98. Ruan, T.; Li, L.; Lyu, Y.; Luo, Q.; Wu, B. Effect of methionine deficiency on oxidative stress and apoptosis in the small intestine of broilers. Acta Vet. Hung. 2018, 66, 52–65. [Google Scholar] [CrossRef]
  99. Chang, Y.; Tang, H.; Zhang, Z.; Yang, T.; Wu, B.; Zhao, H.; Liu, G.; Chen, X.; Tian, G.; Cai, J. Zinc methionine improves the growth performance of meat ducks by enhancing the antioxidant capacity and intestinal barrier function. Front. Vet. Sci. 2022, 9, 774160. [Google Scholar] [CrossRef]
  100. Shin, S.H.; Yoon, H.; Chun, Y.S.; Shin, H.W.; Lee, M.N.; Oh, G.T.; Park, J.W. Arrest defective 1 regulates the oxidative stress response in human cells and mice by acetylating methionine sulfoxide reductase A. Cell Death Dis. 2014, 5, e1490. [Google Scholar] [CrossRef]
  101. Moskovitz, J. Methionine sulfoxide reductases: Ubiquitous enzymes involved in antioxidant defense, protein regulation, and prevention of aging-associated diseases. Biochim. Biophys. Acta 2005, 1703, 213–219. [Google Scholar] [CrossRef] [PubMed]
  102. El-Sheikh, N.M.; Khalil, F.A. l-Arginine and l-glutamine as immunonutrients and modulating agents for oxidative stress and toxicity induced by sodium nitrite in rats. Food Chem. Toxicol. 2011, 49, 758–762. [Google Scholar] [CrossRef]
  103. Liang, M.; Wang, Z.; Li, H.; Cai, L.; Pan, J.; He, H.; Wu, Q.; Tang, Y.; Ma, J.; Yang, L. l-Arginine induces antioxidant response to prevent oxidative stress via stimulation of glutathione synthesis and activation of Nrf2 pathway. Food Chem. Toxicol. 2018, 115, 315–328. [Google Scholar] [CrossRef] [PubMed]
  104. Wang, Z.; Liang, M.; Li, H.; Cai, L.; He, H.; Wu, Q.; Yang, L. l-Methionine activates Nrf2-ARE pathway to induce endogenous antioxidant activity for depressing ROS-derived oxidative stress in growing rats. J. Sci. Food Agric. 2019, 99, 4849–4862. [Google Scholar] [CrossRef] [PubMed]
  105. Kasahara, Y. Intraepithelial lymphocytes in birds. Adv. Host Def. Mech. 1994, 37, 163–174. [Google Scholar]
  106. Smith, A.L.; Powers, C.; Beal, R.K. Chapter 13—The Avian Enteric Immune System in Health and Disease. In Avian Immunology, 2nd ed.; Schat, K.A., Kaspers, B., Kaiser, P., Eds.; Academic Press: Boston, MA, USA, 2014; pp. 227–250. [Google Scholar] [CrossRef]
  107. Ruan, T.; Li, L.; Peng, X.; Wu, B. Effects of methionine on the immune function in animals. Health 2017, 9, 857–869. [Google Scholar] [CrossRef]
  108. Takahashi, K.; Konashi, S.; Akiba, Y.; Horiguchi, M. Effects of marginal excess or deficiency of dietary methionine on antibody production in growing broilers. Anim. Sci. Technol. 1993, 64, 13–19. [Google Scholar]
  109. Zhao, T.; Lum, J.J. Methionine cycle-dependent regulation of T cells in cancer immunity. Front. Oncol. 2022, 12, 969563. [Google Scholar] [CrossRef]
  110. Sinclair, L.V.; Howden, A.J.M.; Brenes, A.; Spinelli, L.; Hukelmann, J.L.; Macintyre, A.N.; Liu, X.; Thomson, S.; Taylor, P.M.; Rathmell, J.C.; et al. Antigen receptor control of methionine metabolism in T cells. eLife 2019, 8, e44210. [Google Scholar] [CrossRef] [PubMed]
  111. Klein Geltink, R.I.; Pearce, E.L. The importance of methionine metabolism. eLife 2019, 8, e47221. [Google Scholar] [CrossRef]
  112. Swain, B.K.; Johri, T.S. Effect of supplemental methionine, choline and their combinations on the performance and immune response of broilers. Br. Poult. Sci. 2000, 41, 83–88. [Google Scholar] [CrossRef]
  113. Mirzaaghatabar, F.; Saki, A.A.; Zamani, P.; Aliarabi, H.; Hemati Matin, H.R. Effect of different levels of diet methionine and metabolisable energy on broiler performance and immune system. Food Agric. Immunol. 2011, 22, 93–103. [Google Scholar] [CrossRef]
  114. Bouyeh, M. Effect of Excess Lysine and Methionine on Immune system and Performance of Broilers. Ann. Biol. Res. 2012, 3, 3218–3224. [Google Scholar]
  115. Wu, B.; Cui, H.; Peng, X.; Fang, J.; Cui, W.; Liu, X. Pathology of bursae of Fabricius in methionine-deficient broiler chickens. Nutrients 2013, 5, 877–886. [Google Scholar] [CrossRef] [PubMed]
  116. Wu, B.-y.; Cui, H.-m.; Peng, X.; Fang, J.; Cui, W.; Liu, X.-d. Effect of Methionine Deficiency on the Thymus and the Subsets and Proliferation of Peripheral Blood T-Cell, and Serum IL-2 Contents in Broilers. J. Integr. Agric. 2012, 11, 1009–1019. [Google Scholar] [CrossRef]
  117. Li, P.; Yin, Y.-L.; Li, D.; Woo Kim, S.; Wu, G. Amino acids and immune function. Br. J. Nutr. 2007, 98, 237–252. [Google Scholar] [CrossRef]
  118. Durante, W.; Johnson, F.K.; Johnson, R.A. Arginase: A critical regulator of nitric oxide synthesis and vascular function. Clin. Exp. Pharmacol. Physiol. 2007, 34, 906–911. [Google Scholar] [CrossRef]
  119. Bogdan, C. Nitric oxide and the immune response. Nat. Immunol. 2001, 2, 907–916. [Google Scholar] [CrossRef] [PubMed]
  120. Bogdan, C. Nitric oxide synthase in innate and adaptive immunity: An update. Trends Immunol. 2015, 36, 161–178. [Google Scholar] [CrossRef]
  121. James, S.L. Role of nitric oxide in parasitic infections. Microbiol. Rev. 1995, 59, 533–547. [Google Scholar] [CrossRef]
  122. Gradoni, L.; Ascenzi, P. Nitric oxide and anti-protozoan chemotherapy. Parassitologia 2004, 46, 101–103. [Google Scholar]
  123. Rodriguez, P.C.; Zea, A.H.; Culotta, K.S.; Zabaleta, J.; Ochoa, J.B.; Ochoa, A.C. Regulation of t cell receptor cd3ζ chain expression byl-arginine. J. Biol. Chem. 2002, 277, 21123–21129. [Google Scholar] [CrossRef]
  124. Oakley, B.B.; Lillehoj, H.S.; Kogut, M.H.; Kim, W.K.; Maurer, J.J.; Pedroso, A.; Lee, M.D.; Collett, S.R.; Johnson, T.J.; Cox, N.A. The chicken gastrointestinal microbiome. FEMS Microbiol. Lett. 2014, 360, 100–112. [Google Scholar] [CrossRef]
  125. Diaz Carrasco, J.M.; Casanova, N.A.; Fernández Miyakawa, M.E. Microbiota, gut health and chicken productivity: What is the connection? Microorganisms 2019, 7, 374. [Google Scholar] [CrossRef]
  126. Dunkley, K.; Dunkley, C.; Njongmeta, N.; Callaway, T.; Hume, M.; Kubena, L.; Nisbet, D.; Ricke, S. Comparison of in vitro fermentation and molecular microbial profiles of high-fiber feed substrates incubated with chicken cecal inocula. Poult. Sci. 2007, 86, 801–810. [Google Scholar] [CrossRef] [PubMed]
  127. Hou, K.; Wu, Z.-X.; Chen, X.-Y.; Wang, J.-Q.; Zhang, D.; Xiao, C.; Zhu, D.; Koya, J.B.; Wei, L.; Li, J.; et al. Microbiota in health and diseases. Signal Transduct. Target. Ther. 2022, 7, 135. [Google Scholar] [CrossRef]
  128. Pan, D.; Yu, Z. Intestinal microbiome of poultry and its interaction with host and diet. Gut Microbes 2014, 5, 108–119. [Google Scholar] [CrossRef]
  129. Zhang, B.; Li, G.; Shahid, M.S.; Gan, L.; Fan, H.; Lv, Z.; Yan, S.; Guo, Y. Dietary l-arginine supplementation ameliorates inflammatory response and alters gut microbiota composition in broiler chickens infected with Salmonella enterica serovar Typhimurium. Poult. Sci. 2020, 99, 1862–1874. [Google Scholar] [CrossRef]
  130. Brugaletta, G.; Zampiga, M.; Laghi, L.; Indio, V.; Oliveri, C.; De Cesare, A.; Sirri, F. Feeding broiler chickens with arginine above recommended levels: Effects on growth performance, metabolism, and intestinal microbiota. J. Anim. Sci. Biotechnol. 2023, 14, 33. [Google Scholar] [CrossRef]
  131. Kumar, S.; Adhikari, P.; Oakley, B.; Kim, W.K. Changes in cecum microbial community in response to total sulfur amino acid (TSAA: DL-methionine) in antibiotic-free and supplemented poultry birds. Poult. Sci. 2019, 98, 5809–5819. [Google Scholar] [CrossRef] [PubMed]
  132. Wu, X.; Han, Z.; Liu, B.; Yu, D.; Sun, J.; Ge, L.; Tang, W.; Liu, S. Gut microbiota contributes to the methionine metabolism in host. Front. Microbiol. 2022, 13, 1065668. [Google Scholar] [CrossRef]
  133. Whitehead, C.C. Overview of bone biology in the egg-laying hen. Poult. Sci. 2004, 83, 193–199. [Google Scholar] [CrossRef]
  134. Fujisawa, R.; Tamura, M. Acidic bone matrix proteins and their roles in calcification. Front. Biosci.-Landmark 2012, 17, 1891–1903. [Google Scholar] [CrossRef]
  135. Zhu, Y.S.; Gu, Y.; Jiang, C.; Chen, L. Osteonectin regulates the extracellular matrix mineralization of osteoblasts through P38 signaling pathway. J. Cell. Physiol. 2020, 235, 2220–2231. [Google Scholar] [CrossRef] [PubMed]
  136. Blair, H.C.; Larrouture, Q.C.; Li, Y.; Lin, H.; Beer-Stoltz, D.; Liu, L.; Tuan, R.S.; Robinson, L.J.; Schlesinger, P.H.; Nelson, D.J. Osteoblast Differentiation and Bone Matrix Formation In Vivo and In Vitro. Tissue Eng. Part B Rev. 2017, 23, 268–280. [Google Scholar] [CrossRef]
  137. Mackie, E.J.; Ahmed, Y.A.; Tatarczuch, L.; Chen, K.S.; Mirams, M. Endochondral ossification: How cartilage is converted into bone in the developing skeleton. Int. J. Biochem. Cell Biol. 2008, 40, 46–62. [Google Scholar] [CrossRef]
  138. Allen, M.R.; Burr, D.B. Chapter 4—Bone Modeling and Remodeling. In Basic and Applied Bone Biology; Burr, D.B., Allen, M.R., Eds.; Academic Press: San Diego, CA, USA, 2014; pp. 75–90. [Google Scholar] [CrossRef]
  139. Delaisse, J.M. The reversal phase of the bone-remodeling cycle: Cellular prerequisites for coupling resorption and formation. Bonekey Rep. 2014, 3, 561. [Google Scholar] [CrossRef]
  140. Hadjidakis, D.J.; Androulakis, I.I. Bone remodeling. Ann. N. Y. Acad. Sci. 2006, 1092, 385–396. [Google Scholar] [CrossRef]
  141. Mammoli, F.; Castiglioni, S.; Parenti, S.; Cappadone, C.; Farruggia, G.; Iotti, S.; Davalli, P.; Maier, J.A.M.; Grande, A.; Frassineti, C. Magnesium Is a Key Regulator of the Balance between Osteoclast and Osteoblast Differentiation in the Presence of Vitamin D3. Int. J. Mol. Sci. 2019, 20, 385. [Google Scholar] [CrossRef]
  142. Morris, H.A.; O’Loughlin, P.D.; Anderson, P.H. Experimental evidence for the effects of calcium and vitamin D on bone: A review. Nutrients 2010, 2, 1026–1035. [Google Scholar] [CrossRef]
  143. Park, J.K.; Lee, E.M.; Kim, A.Y.; Lee, E.J.; Min, C.W.; Kang, K.K.; Lee, M.M.; Jeong, K.S. Vitamin C deficiency accelerates bone loss inducing an increase in PPAR-γ expression in SMP30 knockout mice. Int. J. Exp. Pathol. 2012, 93, 332–340. [Google Scholar] [CrossRef] [PubMed]
  144. Devignes, C.-S.; Carmeliet, G.; Stegen, S. Amino acid metabolism in skeletal cells. Bone Rep. 2022, 17, 101620. [Google Scholar] [CrossRef]
  145. Lv, Z.; Shi, W.; Zhang, Q. Role of Essential Amino Acids in Age-Induced Bone Loss. Int. J. Mol. Sci. 2022, 23, 11281. [Google Scholar] [CrossRef]
  146. Fang, C.C.; Feng, L.; Jiang, W.D.; Wu, P.; Liu, Y.; Kuang, S.Y.; Tang, L.; Liu, X.A.; Zhou, X.Q. Effects of dietary methionine on growth performance, muscle nutritive deposition, muscle fibre growth and type I collagen synthesis of on-growing grass carp (Ctenopharyngodon idella). Br. J. Nutr. 2021, 126, 321–336. [Google Scholar] [CrossRef] [PubMed]
  147. Van’T Hof, R.J.; Ralston, S.H. Nitric oxide and bone. Immunology 2001, 103, 255–261. [Google Scholar] [CrossRef]
  148. Grassi, F.; Fan, X.; Rahnert, J.; Weitzmann, M.N.; Pacifici, R.; Nanes, M.S.; Rubin, J. Bone Re/Modeling Is More Dynamic in the Endothelial Nitric Oxide Synthase(−/−) Mouse. Endocrinology 2006, 147, 4392–4399. [Google Scholar] [CrossRef]
  149. Aguirre, J.; Buttery, L.; O’Shaughnessy, M.; Afzal, F.; de Marticorena, I.F.; Hukkanen, M.; Huang, P.; MacIntyre, I.; Polak, J. Endothelial nitric oxide synthase gene-deficient mice demonstrate marked retardation in postnatal bone formation, reduced bone volume, and defects in osteoblast maturation and activity. Am. J. Pathol. 2001, 158, 247–257. [Google Scholar] [CrossRef]
  150. Armour, K.E.; Armour, K.J.; Gallagher, M.E.; Gödecke, A.; Helfrich, M.H.; Reid, D.M.; Ralston, S.H. Defective bone formation and anabolic response to exogenous estrogen in mice with targeted disruption of endothelial nitric oxide synthase. Endocrinology 2001, 142, 760–766. [Google Scholar] [CrossRef] [PubMed]
  151. Hukkanen, M.; Platts, L.; Lawes, T.; Girgis, S.; Konttinen, Y.T.; Goodship, A.; MacIntyre, I.; Polak, J.M. Effect of nitric oxide donor nitroglycerin on bone mineral density in a rat model of estrogen deficiency-induced osteopenia. Bone 2003, 32, 142–149. [Google Scholar] [CrossRef]
  152. Pouwels, S.; Lalmohamed, A.; van Staa, T.; Cooper, C.; Souverein, P.; Leufkens, H.G.; Rejnmark, L.; de Boer, A.; Vestergaard, P.; de Vries, F. Use of organic nitrates and the risk of hip fracture: A population-based case-control study. J. Clin. Endocrinol. Metab. 2010, 95, 1924–1931. [Google Scholar] [CrossRef] [PubMed]
  153. Wimalawansa, S.J. Nitroglycerin therapy is as efficacious as standard estrogen replacement therapy (Premarin) in prevention of oophorectomy-induced bone loss: A human pilot clinical study. J. Bone Miner. Res. 2000, 15, 2240–2244. [Google Scholar] [CrossRef]
  154. Jin, Z.; Kho, J.; Dawson, B.; Jiang, M.-M.; Chen, Y.; Ali, S.; Burrage, L.C.; Grover, M.; Palmer, D.J.; Turner, D.L.; et al. Nitric oxide modulates bone anabolism through regulation of osteoblast glycolysis and differentiation. J. Clin. Investig. 2021, 131, e138935. [Google Scholar] [CrossRef]
  155. Dao, H.T.; Moss, A.F.; Bradbury, E.J.; Swick, R.A. Effects of L-arginine, guanidinoacetic acid and L-citrulline supplementation in reduced-protein diets on bone morphology and mineralization of laying hens. Anim. Nutr. 2023, 14, 225–234. [Google Scholar] [CrossRef]
  156. Pennisi, P.; D’Alcamo, M.A.; Leonetti, C.; Clementi, A.; Cutuli, V.M.; Riccobene, S.; Parisi, N.; Fiore, C.E. Supplementation of L-arginine prevents glucocorticoid-induced reduction of bone growth and bone turnover abnormalities in a growing rat model. J. Bone Miner. Metab. 2005, 23, 134–139. [Google Scholar] [CrossRef]
  157. Wauquier, F.; Leotoing, L.; Coxam, V.; Guicheux, J.; Wittrant, Y. Oxidative stress in bone remodelling and disease. Trends Mol. Med. 2009, 15, 468–477. [Google Scholar] [CrossRef]
  158. Domazetovic, V.; Marcucci, G.; Iantomasi, T.; Brandi, M.L.; Vincenzini, M.T. Oxidative stress in bone remodeling: Role of antioxidants. Clin. Cases Miner. Bone Metab. 2017, 14, 209–216. [Google Scholar] [CrossRef]
  159. Romagnoli, C.; Marcucci, G.; Favilli, F.; Zonefrati, R.; Mavilia, C.; Galli, G.; Tanini, A.; Iantomasi, T.; Brandi, M.L.; Vincenzini, M.T. Role of GSH/GSSG redox couple in osteogenic activity and osteoclastogenic markers of human osteoblast-like Sa OS-2 cells. FEBS J. 2013, 280, 867–879. [Google Scholar]
  160. Tompkins, Y.H.; Choi, J.; Teng, P.-Y.; Yamada, M.; Sugiyama, T.; Kim, W.K. Reduced bone formation and increased bone resorption drive bone loss in Eimeria infected broilers. Sci. Rep. 2023, 13, 616. [Google Scholar] [CrossRef]
  161. Tompkins, Y.H.; Liu, G.; Kim, W.K. Impact of exogenous hydrogen peroxide on osteogenic differentiation of broiler chicken compact bones derived mesenchymal stem cells. Front. Physiol. 2023, 14, 1124355. [Google Scholar] [CrossRef]
  162. Tompkins, Y.; Liu, G.; Marshall, B.; Sharma, M.K.; Kim, W.K. Effect of Hydrogen Oxide-Induced Oxidative Stress on Bone Formation in the Early Embryonic Development Stage of Chicken. Biomolecules 2023, 13, 154. [Google Scholar] [CrossRef]
  163. Altindag, O.; Erel, O.; Soran, N.; Celik, H.; Selek, S. Total oxidative/anti-oxidative status and relation to bone mineral density in osteoporosis. Rheumatol. Int. 2008, 28, 317–321. [Google Scholar] [CrossRef]
  164. Yossepowitch, O.; Pinchuk, I.; Gur, U.; Neumann, A.; Lichtenberg, D.; Baniel, J. Advanced but not localized prostate cancer is associated with increased oxidative stress. J. Urol. 2007, 178, 1238–1244. [Google Scholar] [CrossRef]
  165. Kabuyama, Y.; Kitamura, T.; Yamaki, J.; Homma, M.K.; Kikuchi, S.-i.; Homma, Y. Involvement of thioredoxin reductase 1 in the regulation of redox balance and viability of rheumatoid synovial cells. Biochem. Biophys. Res. Commun. 2008, 367, 491–496. [Google Scholar] [CrossRef]
  166. Lean, J.M.; Davies, J.T.; Fuller, K.; Jagger, C.J.; Kirstein, B.; Partington, G.A.; Urry, Z.L.; Chambers, T.J. A crucial role for thiol antioxidants in estrogen-deficiency bone loss. J. Clin. Investig. 2003, 112, 915–923. [Google Scholar] [CrossRef]
  167. Polat, B.; Halici, Z.; Cadirci, E.; Albayrak, A.; Karakus, E.; Bayir, Y.; Bilen, H.; Sahin, A.; Yuksel, T.N. The effect of alpha-lipoic acid in ovariectomy and inflammation-mediated osteoporosis on the skeletal status of rat bone. Eur. J. Pharmacol. 2013, 718, 469–474. [Google Scholar] [CrossRef] [PubMed]
  168. Jun, J.H.; Lee, S.H.; Kwak, H.B.; Lee, Z.H.; Seo, S.B.; Woo, K.M.; Ryoo, H.M.; Kim, G.S.; Baek, J.H. N-acetylcysteine stimulates osteoblastic differentiation of mouse calvarial cells. J. Cell. Biochem. 2008, 103, 1246–1255. [Google Scholar] [CrossRef]
  169. Zhou, A.; Wu, B.; Yu, H.; Tang, Y.; Liu, J.; Jia, Y.; Yang, X.; Xiang, L. Current Understanding of Osteoimmunology in Certain Osteoimmune Diseases. Front. Cell Dev. Biol. 2021, 9, 698068. [Google Scholar] [CrossRef]
  170. Hou, Q.; Huang, J.; Ayansola, H.; Masatoshi, H.; Zhang, B. Intestinal Stem Cells and Immune Cell Relationships: Potential Therapeutic Targets for Inflammatory Bowel Diseases. Front. Immunol. 2021, 11, 623691. [Google Scholar] [CrossRef]
  171. Shi, H.; Wang, J.; Teng, P.-Y.; Tompkins, Y.H.; Jordan, B.; Kim, W.K. Effects of phytase and coccidial vaccine on growth performance, nutrient digestibility, bone mineralization, and intestinal gene expression of broilers. Poult. Sci. 2022, 101, 102124. [Google Scholar] [CrossRef]
  172. Tompkins, Y.; Teng, P.; Pazdro, R.; Kim, W. Long bone mineral loss, bone microstructural changes and oxidative stress after Eimeria challenge in broilers. Front. Physiol. 2022, 13, 945740. [Google Scholar] [CrossRef]
  173. Oikeh, I.; Sakkas, P.; Blake, D.P.; Kyriazakis, I. Interactions between dietary calcium and phosphorus level, and vitamin D source on bone mineralization, performance, and intestinal morphology of coccidia-infected broilers1. Poult. Sci. 2019, 98, 5679–5690. [Google Scholar] [CrossRef]
  174. Lorenzo, J.; Horowitz, M.; Choi, Y. Osteoimmunology: Interactions of the bone and immune system. Endocr. Rev. 2008, 29, 403–440. [Google Scholar] [CrossRef] [PubMed]
  175. Dar, H.Y.; Azam, Z.; Anupam, R.; Mondal, R.K.; Srivastava, R.K. Osteoimmunology: The Nexus between bone and immune system. Front. Biosci.-Landmark 2018, 23, 464–492. [Google Scholar]
  176. Williams, B.; Waddington, D.; Murray, D.; Farquharson, C. Bone strength during growth: Influence of growth rate on cortical porosity and mineralization. Calcif. Tissue Int. 2004, 74, 236–245. [Google Scholar] [CrossRef]
  177. Williams, B.; Solomon, S.; Waddington, D.; Thorp, B.; Farquharson, C. Skeletal development in the meat-type chicken. Br. Poult. Sci. 2000, 41, 141–149. [Google Scholar] [CrossRef]
  178. Sanchez-Rodriguez, E.; Benavides-Reyes, C.; Torres, C.; Dominguez-Gasca, N.; Garcia-Ruiz, A.I.; Gonzalez-Lopez, S.; Rodriguez-Navarro, A.B. Changes with age (from 0 to 37 D) in tibiae bone mineralization, chemical composition and structural organization in broiler chickens. Poult. Sci. 2019, 98, 5215–5225. [Google Scholar] [CrossRef]
  179. Talaty, P.; Katanbaf, M.; Hester, P. Life cycle changes in bone mineralization and bone size traits of commercial broilers. Poult. Sci. 2009, 88, 1070–1077. [Google Scholar] [CrossRef]
  180. Sun, Z.W.; Fan, Q.H.; Wang, X.X.; Guo, Y.M.; Wang, H.J.; Dong, X. High stocking density alters bone-related calcium and phosphorus metabolism by changing intestinal absorption in broiler chickens. Poult. Sci. 2018, 97, 219–226. [Google Scholar] [CrossRef]
  181. Surai, P.F.; Kochish, I.I.; Fisinin, V.I.; Kidd, M.T. Antioxidant Defence Systems and Oxidative Stress in Poultry Biology: An Update. Antioxidants 2019, 8, 235. [Google Scholar] [CrossRef]
  182. Goo, D.; Kim, J.H.; Park, G.H.; Delos Reyes, J.B.; Kil, D.Y. Effect of Heat Stress and Stocking Density on Growth Performance, Breast Meat Quality, and Intestinal Barrier Function in Broiler Chickens. Animals 2019, 9, 107. [Google Scholar] [CrossRef]
  183. Miller, A.L. The methionine-homocysteine cycle and its effects on cognitive diseases. Altern. Med. Rev. 2003, 8, 7–19. [Google Scholar]
  184. Yang, Z.; Yang, Y.; Yang, J.; Wan, X.; Yang, H.; Wang, Z. Hyperhomocysteinemia Induced by Methionine Excess Is Effectively Suppressed by Betaine in Geese. Animals 2020, 10, 1642. [Google Scholar] [CrossRef]
  185. Xie, M.; Hou, S.S.; Huang, W.; Fan, H.P. Effect of Excess Methionine and Methionine Hydroxy Analogue on Growth Performance and Plasma Homocysteine of Growing Pekin Ducks. Poult. Sci. 2007, 86, 1995–1999. [Google Scholar] [CrossRef]
  186. Baszczuk, A.; Kopczyński, Z. Hyperhomocysteinemia in patients with cardiovascular disease. Adv. Hyg. Exp. Med. 2014, 68, 579–589. [Google Scholar] [CrossRef]
  187. Behera, J.; Bala, J.; Nuru, M.; Tyagi, S.C.; Tyagi, N. Homocysteine as a Pathological Biomarker for Bone Disease. J. Cell. Physiol. 2017, 232, 2704–2709. [Google Scholar] [CrossRef]
  188. Kumar, A.; Palfrey, H.A.; Pathak, R.; Kadowitz, P.J.; Gettys, T.W.; Murthy, S.N. The metabolism and significance of homocysteine in nutrition and health. Nutr. Metab. 2017, 14, 78. [Google Scholar] [CrossRef]
  189. Tinelli, C.; Di Pino, A.; Ficulle, E.; Marcelli, S.; Feligioni, M. Hyperhomocysteinemia as a Risk Factor and Potential Nutraceutical Target for Certain Pathologies. Front. Nutr. 2019, 6, 49. [Google Scholar] [CrossRef]
  190. Zaĭonts, V.; Krylov, M.; Loskot, V.; Kirillov, A. Biosynthesis of folic acid in Eimeria tenella (Coccidia). Parazitologiia 1978, 12, 3–8. [Google Scholar]
  191. Noack, S.; Chapman, H.D.; Selzer, P.M. Anticoccidial drugs of the livestock industry. Parasitol. Res. 2019, 118, 2009–2026. [Google Scholar] [CrossRef]
  192. Teng, P.-Y.; Choi, J.; Yadav, S.; Tompkins, Y.H.; Kim, W.K. Effects of low-crude protein diets supplemented with arginine, glutamine, threonine, and methionine on regulating nutrient absorption, intestinal health, and growth performance of Eimeria-infected chickens. Poult. Sci. 2021, 100, 101427. [Google Scholar] [CrossRef]
  193. Fernandes, J.I.M.; Murakami, A.E. Arginine metabolism in uricotelic species. Acta Sci. Anim. Sci. 2010, 32, 357–366. [Google Scholar] [CrossRef]
  194. Balnave, D.; Barke, J. Re-evaluation of the classical dietary arginine:lysine interaction for modern poultry diets: A review. World’s Poult. Sci. J. 2002, 58, 275–289. [Google Scholar] [CrossRef]
Figure 1. Methionine metabolism to glutathione [48,49]. THF, tetrahydrofolate; 5, 10-MTHF, 5, 10-Methylenetetrahydrofolate; 5-MTHF, 5-Methylenetetrahydrofolate; MAT, methionine adenosyltransferase; AHCYL, adenosylhomocysteinase like; MTR, methionine synthase; CBS, cystathionine-β-synthase; CTH, cystathionine gamma-lyase; GSS, glutathione synthase.
Figure 1. Methionine metabolism to glutathione [48,49]. THF, tetrahydrofolate; 5, 10-MTHF, 5, 10-Methylenetetrahydrofolate; 5-MTHF, 5-Methylenetetrahydrofolate; MAT, methionine adenosyltransferase; AHCYL, adenosylhomocysteinase like; MTR, methionine synthase; CBS, cystathionine-β-synthase; CTH, cystathionine gamma-lyase; GSS, glutathione synthase.
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Figure 2. Arginine metabolism. Dotted lines represent pathways that are less active in birds than in mammals. ASL, argininosuccinate lyase; ASS, argininosuccinate synthetase; NOS, nitric oxide synthase; ADC, arginine decarboxylase; AGAT, arginine:glycine amidinotransferase.
Figure 2. Arginine metabolism. Dotted lines represent pathways that are less active in birds than in mammals. ASL, argininosuccinate lyase; ASS, argininosuccinate synthetase; NOS, nitric oxide synthase; ADC, arginine decarboxylase; AGAT, arginine:glycine amidinotransferase.
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Figure 3. Antioxidant capacity of methionine. MSR, methionine sulfoxide reductase; SOD, superoxide dismutase; CAT, catalase; GPX, glutathione peroxidase; GR, glutathione reductase; ROS, reactive oxygen species; SAM, S-adenosylmethionine; GSH, glutathione; GSSG, glutathione disulfide. The orange and boxed represents the first and second mechanism for methionine to exert its antioxidant capacity. The blue arrows indicate upregulation of the enzymes.
Figure 3. Antioxidant capacity of methionine. MSR, methionine sulfoxide reductase; SOD, superoxide dismutase; CAT, catalase; GPX, glutathione peroxidase; GR, glutathione reductase; ROS, reactive oxygen species; SAM, S-adenosylmethionine; GSH, glutathione; GSSG, glutathione disulfide. The orange and boxed represents the first and second mechanism for methionine to exert its antioxidant capacity. The blue arrows indicate upregulation of the enzymes.
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Figure 4. Schematic model illustrating potential mechanisms of methionine and arginine in enhancing intestinal and bone health in poultry. The red arrow in the figure indicates improvement.
Figure 4. Schematic model illustrating potential mechanisms of methionine and arginine in enhancing intestinal and bone health in poultry. The red arrow in the figure indicates improvement.
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Table 1. Summary of effects of dietary supplementation of methionine and arginine in intestinal and bone health in poultry from previous studies.
Table 1. Summary of effects of dietary supplementation of methionine and arginine in intestinal and bone health in poultry from previous studies.
Methionine/Arginine Levels and Experiment SettingsType of Birds/ModelsEffects of Supplementation 1Reference
Intestinal health:
Methionine: DL-Met or L-Met at 60%, 80%, 100% of breeder recommendations.
Settings: Mixed Eimeria spp. challenge
Male Cobb 500 broilers Increased growth performance; reduced intestinal permeability; improved activities of antioxidant enzymes; and affected tight junction protein expression.[26]
Methionine: 0.33%, 0.39%, 0.45%, 0.51%, or 0.57% of diet.
Settings: Mixed Eimeria spp. challenge
Partridge Shank BroilersImproved growth performance; increased relative weight of bursa of Fabricius; increased GPX activity, increased serum TAC; increased sIgA concentration; decreased lesion score.[27]
Methionine: 0.24 or 0.45% of diet, supplemented with free Met or Met dipeptide.
Setting: Mixed Eimeria spp. challenge.
Male Cobb 500 broilersIncreased TAC and decreased SOD activity in the jejunum; increased expression of B0AT1 and TLR5 in the jejunum. [28]
Methionine: 0.35%, 0.4%, 0.45%, or 0.5% of diet.
Setting: High stocking density
Male Arbor Acres broilersImproved the GSH: GSSG ratio and GPX activity; increased the VH and VH:CD ratio.[29]
Methionine: No Met supplementation or Met supplemented at recommended level.
Setting: Heat stress.
Male Cobb 500 broilersImproved growth performance; decreased the expressions of proinflammatory cytokines in jejunum and ileum; improved the tight junction protein expressions in the ileum. [30]
Methionine: DL-Met or L-Met at 60%, 70%, 80%, 90% of breeder recommendations.Mixed sex Ross 308 broilersIncreased the concentration of GSH and reduced MDA contents in duodenum mucosa; increased the VH and VH:CD ratio.[31]
Methionine: 0.3% higher than the control diet supplemented with DL-Met or DL-methionyl-DL-Met. White king breeding pigeonsIncreased relative intestinal weight; increased VH and VH:CD ratio; increased expressions of cell proliferation markers, tight junction proteins, and PEPT1 in the jejunum; upregulated the Wnt/β-catenin signaling pathway.[32]
Methionine: No Met supplementation or Met supplemented at recommended level.Cobb broilersMet deficiency decreased IgA+ B cell count; reduced contents of sIgA, IgA, IgG and IgM in duodenum and jejunum.[33]
Arginine: 50% above recommendation in reduced protein diet.
Setting: Mixed Eimeria spp. challenge.
Male Cobb 500 broilersImproved growth performance; decreased intestinal permeability; increased macrophage NO production; increased bile IgA content; improved T cell functions. [21]
Arginine: 0.3% higher than the recommendation.
Setting: Clostridium perfringens challenge.
Male Arbor Acres broilersIncreased jejunal VH; balanced the ileal microbiota; increased relative abundance of KEGG pathways related to membrane transport, replication and repair, translation and nucleotide metabolism.[34]
Arginine: 8.5, 9.7, 10.9, 12.1, and 13.3 g/kg of diet.Female Qingyuan partridge chickensIncreased growth performance; increased activities of antioxidant enzymes; increased TAC in jejunum and ileum; decreased expression of proinflammatory cytokines in the ileum; increased sIgA production; improved ileal microbiota profile.[35]
Arginine: 1.04, 1.14, 1.24, 1.34, 1.44% of diet.
Setting: Mixed Eimeria spp. challenge.
Male Cobb 500 broilersImproved growth performance; reduced intestinal permeability; increased expression of tight junction proteins.[36]
Arginine: 0.96%, 1.16%, 1.36%, 1.56%, and 1.76% digestible arginine.Female Arbor Acres broiler breedersIncreased TAC; increased activity of GPX, and decreased MDA in the breeder and the offspring.[37]
Arginine: 350 μM in DMEM culture medium.
Setting: Oxidative stress induced by hydrogen peroxide.
Ovine intestinal epithelial cellsReduced hydrogen peroxide-induced ROS production; increased protein levels of GPX, tight junction protein 1, and nitric oxide synthase, whereas decreased the TNFα level.[38]
Arginine: 11.1, 13.3 and 20.2 g/kg of diet.
Setting: Mixed Eimeria spp. challenge.
Male Ross 708 broilersIncreased VH and decreased CD; increased goblet cell density; decreased expression of proinflammatory cytokine; increased mucosal maltase activity; 13.3 g/kg of Arg supplementation showed highest expression of anti-apoptosis gene and mTOR. [39]
Arginine: 100, 105, and 110% of the recommendation.
Setting: Mixed Eimeria spp. challenge.
Male Ross 308 broilersImproved growth performance; increased VH and VH:CD ratio; decreased oocyst count.[40]
Bone health:
Methionine: 250 mg/kg body weight in drinking water.Ovariectomized ratsIncreased bone density; decreased development of osteoclasts by inhibiting the TLR-4/MyD88/NF-κB pathway.[41]
Study 1: 0.12% and 0.84% of mice diet.
Study 2: α-MEM culture media with restricted sulfur amino acids.
Study 1: Male and female mice.
Study 2: Mouse preosteoblast cell line.
Study 1: Met deficiency decreased bone mineral density, bone mineral content, and microarchitecture parameters; increased collagen degradation.
Study 2: Met restriction delayed osteoblast differentiation and decreased expressions of genes regulating bone formation.
Methionine: 0.12% and 0.86% of diet.Young male C57BL/6J miceDecreased cortical bone density; decreased trabecular bone density, bone surface, trabecula and bone volume, and trabecular thickness; increased fragility; reduced expression of RUNX2 in bone marrow.[43]
Arginine: 70, 80, 90, 100, and 110% of the recommendation.Male Ross 308 broilers.Improved growth performance, lean deposition, and bone mineral density.[44]
Arginine: 0, 0.1, 1, and 10 µM in DMEM culture medium.Human mesenchymal stem cells.Increased osteogenic differentiation; increased expression of RUNX2, Dlx5, osterix, and wnt5a; decreased expression of adaptogenic transcription factors.[45]
1 Abbreviations: Met, methionine; Arg, arginine; GPX, glutathione peroxidase; TAC, total antioxidant capacity; SOD, superoxide dismutase; GSH, glutathione; GSSG, glutathione disulfide; sIgA, secretory immunoglobin A; IgG, immunoglobin G; IgM, immunoglobin M; ROS, reactive oxygen species; MDA, malondialdehyde; NO, nitric oxide; TLR, toll like receptor; VH, villus height; CD, crypt depth; B0AT1, neutral amino acid transporter B(0)AT1; PEPT1, peptide transporter 1; mTOR, mammalian target of rapamycin; TNFα, tumor necrosis factor alpha; MyD88, Myeloid differentiation primary response 88; NF-κB, nuclear factor kappa light chain enhancer of activated B cells.
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Liu, G.; Kim, W.K. The Functional Roles of Methionine and Arginine in Intestinal and Bone Health of Poultry: Review. Animals 2023, 13, 2949.

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Liu G, Kim WK. The Functional Roles of Methionine and Arginine in Intestinal and Bone Health of Poultry: Review. Animals. 2023; 13(18):2949.

Chicago/Turabian Style

Liu, Guanchen, and Woo Kyun Kim. 2023. "The Functional Roles of Methionine and Arginine in Intestinal and Bone Health of Poultry: Review" Animals 13, no. 18: 2949.

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