Functions and Signaling Pathways of Amino Acids in Intestinal Inflammation

He, Fang; Wu, Chenlu; Li, Pan; Li, Nengzhang; Zhang, Dong; Zhu, Quoqiang; Ren, Wenkai; Peng, Yuanyi

doi:https://doi.org/10.1155/2018/9171905

BioMed Research International

On this page

Abstract Introduction Conclusion Abbreviations Conflicts of Interest Acknowledgments References Copyright Related Articles

Special Issue

Impact of Nutritional and Environmental Factors on Inflammation, Oxidative Stress, and the Microbiome

View this Special Issue

Review Article | Open Access

Volume 2018 | Article ID 9171905 | https://doi.org/10.1155/2018/9171905

Functions and Signaling Pathways of Amino Acids in Intestinal Inflammation

Fang He,^1,2Chenlu Wu,¹Pan Li,¹Nengzhang Li,¹Dong Zhang,³Quoqiang Zhu,³Wenkai Ren,²and Yuanyi Peng¹

Academic Editor: Lidong Zhai

Received30 Sept 2017

Revised30 Nov 2017

Accepted13 Dec 2017

Published26 Feb 2018

Abstract

Intestine is always exposed to external environment and intestinal microorganism; thus it is more sensitive to dysfunction and dysbiosis, leading to intestinal inflammation, such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and diarrhea. An increasing number of studies indicate that dietary amino acids play significant roles in preventing and treating intestinal inflammation. The review aims to summarize the functions and signaling mechanisms of amino acids in intestinal inflammation. Amino acids, including essential amino acids (EAAs), conditionally essential amino acids (CEAAs), and nonessential amino acids (NEAAs), improve the functions of intestinal barrier and expressions of anti-inflammatory cytokines and tight junction proteins but decrease oxidative stress and the apoptosis of enterocytes as well as the expressions of proinflammatory cytokines in the intestinal inflammation. The functions of amino acids are associated with various signaling pathways, including mechanistic target of rapamycin (mTOR), inducible nitric oxide synthase (iNOS), calcium-sensing receptor (CaSR), nuclear factor-kappa-B (NF-κB), mitogen-activated protein kinase (MAPK), nuclear erythroid-related factor 2 (Nrf2), general controlled nonrepressed kinase 2 (GCN2), and angiotensin-converting enzyme 2 (ACE2).

1. Introduction

The intestine is supreme digestive organ of humans and numerous animals including the small intestine and large intestine. Small intestine covers the ileum, jejunum, and duodenum, while large intestine includes the colon, cecum, and rectum [1]. Intestinal tract has numerous functions, including digestion and absorption of nutrients, recognition of external factors, and transduction of signaling concerned with innate and adaptive immunity [2]. Continuing to experience external stressors (e.g., dietary ingredients, intestinal microorganism, and environmental factors), easily, leads to intestinal damage and dysfunction [3]. Thus the intestine is usually in a situation of inflammation, which is related to certain illness, including diarrhea, inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS) [4]. IBD comprise Crohn’s disease (CD) and ulcerative colitis (UC) [5]. CD is normally located in whole intestine, influencing primarily intestinal wall [6]. UC is limited in the colon as well as rectum, affecting mainly the mucosal layer [7]. The production of proinflammatory cytokines, including interleukin-1 (IL-1), IL-6, IL-17, IL-22, IL-23, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), highly shapes the development of IBD [8].

The metabolic profiling of amino acid in UC differs from control group, which indicates certain amino acids would be novel biomarkers for early diagnosis and treatment of patients with UC [9]. For example, the levels of glutamine (Gln), glutamate (Glu), methionine (Met), tryptophan (Trp), and histidine (His) are significantly lower in UC patients than in the normal control group, but asparagine (Asp) and isoleucine (Ile) are quite the reverse. Recent studies also show that amino acids have significant roles in the intestinal inflammation. For example, Trp of essential amino acids (EAAs) exerts beneficial regulatory function in mucosal growth or maintenance and alleviation of intestinal inflammation by 5-hydroxytryptophan (5-HT) signaling pathway [10], in the recovery of colitis by caspase recruitment domain family member 9 (Card9) [11, 12], and in the function of intestinal homeostasis and anti-inflammation by aryl hydrocarbon receptor (AHR) ligands in the intestine [13, 14]. Gln, one of nonessential amino acids (NEAAs), regulates anti-inflammatory effects dependent on its function by intestinal tight junctions (TJ), mechanistic target of rapamycin (mTOR), mitogen-activated protein kinase (MAPKs), and nuclear factor-kappa-B (NF-κB) signaling pathways [15–18]. Arg is a conditionally essential amino acid (CEAAs) and has a critical function in treating intestinal inflammation by manipulation of immune responses, oxidative system, and intestinal metabolism [6, 19, 20]. Leu is a member of branched chain amino acids (BCAAs), and its deprivation may ameliorate colitis and intestinal inflammation via the amino acid sensor general controlled nonrepressed kinase (GCN2) [21, 22]. Aromatic amino acids (AAAs), including Trp, Phe, and Tyr, attenuate intestinal inflammation through activating calcium-sensing receptor (CaSR) in piglets [23]. The review aims to summarize the roles and molecular mechanisms of amino acids in the intestinal inflammation.

2. Amino Acids and Intestinal Inflammation

According to nutrition demand, amino acids are traditionally divided into 8 kinds of EAAs, 10 kinds of NEAAs, and 2 kinds of CEAAs. EAAs are only acquired from the nutrient by amino acid transporters, such as Trp, Leu, and Phe. NEAAs can be synthesized via certain elements in vivo (e.g., Glu, Gly, and Ser) [24]. There are two types of special amino acids, as they are neither the EAAs, nor the NEAAs, including Arg and His, which are EAAs for infants but not for adults; thus they are named as CEAAs. The protective functions of amino acids in the intestine may be closely connected with the apoptosis and proliferation of intestinal epithelial cells (IECs), expression of tight junction proteins (TJPs), alleviation of intestinal inflammation and oxidative stress by inhibiting NF-κB signaling pathway, and activating nuclear erythroid-related factor 2 (Nrf2) signaling pathway [25, 26]. NF-κB and Nrf2 are two critical signaling pathways that are related to inflammation and oxidation. NF-κB upregulates expressions of various proinflammatory cytokines (e.g., IL-1β, IL-6, IL-8, and TNF-α) [27]. Nrf2 suppresses the production of proinflammatory cytokines and increases the expressions of antioxidative genes [28, 29]. The oxidative stress and inflammatory mediators are the main etiological factors in IBD; hence, amino acids are expected to alleviate it as the antioxidants and anti-inflammatory agents [30, 31]. For example, gamma aminobutyric acids (GABA) signaling negatively regulates the production of proinflammatory factors via inhibiting the activation of NF-κB pathway; thus it shows various advantageous functions in the progression of IBD [32]. Another characteristic of IBD is to destroy the integrity of intestinal epithelial barrier (IEB) [33], which regulates the absorption of nutrition and restricts the entry of pathogens, composed of topmost TJs, bottom adherent junctions (AJs), and desmosomes [34]. The function of the IEB is determined by TJs, a protein complex, including occludin, claudin family, and junctional adhesion molecules (JAMs) [35, 36], and amino acids have critical roles in the expression of TJPs [37, 38]. For example, Trp enhances the expression of occluden-1, occluden-2, occludin, claudin-3, and claudin-4 in the intestine of pig [39, 40]. Arg and Glu supplementation improve permeability and TJs protein expression [41, 42]. Besides, the protective effect of amino acids is also associated with endoplasmic reticulum (ER) stress and autophagy [43]. Abundant ER stress leads to apoptosis [44] and is a critical factor for intestinal barrier integrity and intestinal homeostasis [45]. Autophagy regulated by mTOR signaling is crucial for inhibiting intestinal inflammation and maintaining intestinal homeostasis [46]. The mTOR signaling has momentous functions in cell proliferation, differentiation, growth, and metabolism [47, 48]; thus it may be a target for the therapy of intestinal inflammation. Furthermore, MAPK signaling is another important signaling pathway for amino acids and intestinal inflammation. The MAPK signaling of mammals is mainly composed of MAPKS extracellular signal-regulated kinase (ERK), the c-Jun N-terminal kinase (JNK), and p38 MAPK pathways, which play important roles in cell growth, proliferation, differentiation, migration, inflammation, and survival, and is associated with pathogenesis of several human diseases, including IBD [49–52]. Some amino acids have critical roles in the activation of MAPK pathway [53, 54]. For example, Asn improves intestinal integrity by downregulating intestinal proinflammatory cytokine through MAPKp38 and decreases enterocyte apoptosis via MAPKp38 and ERK1/2 [55]. Arg alleviates LPS induced immune damage in fish intestine and the enterocytes by downregulating MAPKp38 [56]. Gln combined with Arg decreases the production of TNF-α and other proinflammatory cytokines probably through its regulation in MAPKp38 [57].

2.1. EAAs and Intestinal Inflammation

EAAs have significant effects in intestinal inflammation. It is reported that Phe possesses beneficial effects in the treatment of IBD by inhibiting TNF-α productions and enhancing immune responses [63]. Phe with chromium has a protective effect against IBD induced by indomethacin in rats, which might be attributed to antioxidant and anti-inflammatory characteristics of Phe [30]. Phe regulates intestinal hormone release as well as glucose tolerance and inhibits food intake of rodents by CaSR, which may be a potential therapy for obesity and diabetes [64]. Met is able to modulate metabolism, innate immunity, and digestion of mammals and generate glutathione to neutralize oxidative stress [112]. Met inhibits the increase of paracellular permeability mediated by TNF-α, which may be related to antioxidant metabolites (e.g., taurine and glutathione) to improve intestinal homeostasis [65]. Abundant Met is crucial for intestinal integrity and intestinal antioxidant capacity [66]. Lys influences the digestion of food and the expressions of amino acid transporters in the intestine [68]. Poly-L-lysine (PL) is a homopolymer of L-lysine and reduces the production of IL-8 in the IECs induced by TNF-α; thus, PL supplementation inhibits the expressions of proinflammatory cytokines by activating CaSR in the intestine [69]. Glucose-lysine Maillard reaction products (Glc-Lys MRPs) ameliorate DSS-induced colitis, increase glutathione content as well as antioxidant activities, and suppress the inflammatory cytokines and NF-κB [70, 71]; thus they can be used for preventing or treating IBD. Thr is a primary ingredient of intestinal IgA and mucins; thus, malnutrition of Thr induces inflammation and affects the immune responses through the NF-κB pathway [72]. Dietary supplementation with Thr has a favorable regulatory function on the intestinal barrier and immunity of broiler chicks infected with Eimeria maxima [73]. Thr insufficiency impairs intestinal immune response and increases inflammation associating with NF-κB and mTOR pathways in young grass carp infected by Aeromonas hydrophila [74]. BCAAs (e.g., Leu, Val, and Ile) enhance intestinal immune defense system through improving morphological integrity and immunoglobulin production in the intestine [113]. Leu enhances cell proliferation and the expressions of amino acid transporters by the activation of mTOR [77, 78]. However, high concentration of BCAAs increases oxidative stress and inflammation by mTOR and NF-κB [114]; thus, diets with low Leu ameliorate symptoms of colitis and intestinal inflammation via the amino acid sensor GCN2 in colitis model [22]. Ile induces the expression of β-defensins via G-protein-coupling receptors (GPCRs) and ERK/MAPK signaling pathways [79]. And a recent study found that dietary Ile improves intestinal immune function, antioxidant capacity, and microbial population and regulates gene expression of antioxidant enzyme, tight junctions, Nrf2, p38, and ERK1 in the intestine of Jian carp [115]. The research of Val in intestinal inflammation is relatively rare, but γ-glutamyl Val diminishes inflammation in colitis via CaSR signaling and inhibits TNF-α pathways in IECs [76]. Moreover, Trp, Phe, and Tyr possess aromatic nucleus so they are named as aromatic amino acids (AAAs), which reduce intestinal inflammation by activating CaSR in piglets [23]. The CaSR is one of the GPCRs, which participates in nutrient sensing and ion homeostasis maintaining, hormone and fluid secretion, cell differentiation, and apoptosis in the intestine [116, 117]. The deficiency of epithelial CaSR leads to weak intestinal integrity, alteration of microbiota composition, and acceleration of proinflammatory immune responses [118]. The gene expression of CaSR may be regulated by vitamin D, extracellular Ca²⁺, and cytokines [119–123]. However, L-amino acids such as L-Ala, L-Phe, and L-Trp are the agonists of the CaSR; thus they are effective in preventing and treating IBD and other diarrheal diseases via CaSR [123–127]. CaSR activated by Trp exerts anti-inflammation roles via activating the complex of Β-arrestin 2 (β-arr2) and TAK1-binding protein 1 (TAB1) to inhibit NF-κB and MAPK pathway in IECs [58].

The best example for EAAs in intestinal inflammation comes from Trp. Trp has a vital role in intestinal inflammation via 5-HT signaling pathway [59]. 5-HT signaling is made up of tryptophan hydroxylase-1 (TPH-1), 5-HT receptors, and serotonin reuptake transporter (SERT) [128]. Intestinal mucosa is the prime position of 5-HT synthesis catalyzed by TPH-1 [129]. Released from enterochromaffin cells, 5-HT starts to play its regulative role in the intestine (e.g., intestinal motility, fluid secretion) [130]. Functions of 5-HT are excised through a variety of 5-HT receptors; thus, 5-HT3 receptor and 5-HT4 receptor are principally associated with IBS [131]. The 5-HT3 receptor is only a ligand-gated ion channel, and recent evidences demonstrated that 5-HT3 receptor antagonists exert anti-inflammatory functions via inhibiting the production of inflammatory cytokines in colitis [132]. 5-HT2B is one of the 5-HT2 receptors, which plays vital parts in IBS and has a remarkable effect in the human colon [133, 134]. 5-HT7 receptor, a member of the GPCRs, whose expression in IBS is upregulated [135], regulates the severity of intestinal inflammation in colitis or CD [14]. Evidence indicates that the expression of IL-10 receptor is regulated by AHR in the colon [136]. Mice lacking IL-10 or IL-10R are sensitive to colitis [137] because IL-10 is a significant anti-inflammatory cytokine that represses the production of proinflammatory mediators. Kynurenine (Kyn) from Trp metabolism binds to AHR to regulate systemic inflammation, and research found that levels of Kyn are increased during intestinal inflammation to induce the expression of IL-10R [138, 139]. Moreover, dietary Trp alleviates SDS-induced colitis by AHR in mice [60]. AHR contributes to the expressions of IL-22 and the development of T-helper type 17 (Th17) cells [140]. IL-22 has significant functions in maintaining intestinal homeostasis [141]. The metabolism of Trp modulates the production of IL-22 by AHR [13]. Furthermore, a recent research indicates that Card9, a susceptibility gene of IBD, promotes the recovery of colitis by metabolizing Trp into AHR ligands to activate IL-22 signaling pathway in innate immune response [11]. The supplementation of Trp inhibits Th1 differentiation in vivo [61]. And L-Trp supplementation decreases the destruction of intestinal barrier triggered by stress via modulating 5-HT metabolism in broilers [62]. Collectively, EAAs mainly exert anti-inflammatory roles by NF-κB, CaSR, MAPK, and mTOR signaling pathway to restrain the expressions of proinflammatory cytokines. The functions and signaling pathways of EAAs in the intestinal inflammation are showed in Table 1. Possible signaling mechanisms of EAAs on the intestinal inflammation in the ECs are showed in Figure 1. Specific signaling pathways of EAAs in intestinal inflammation are showed Figure 2.

Figure 1

Possible signaling mechanisms of amino acids in intestinal inflammation in the ECs are illustrated. Amino acids ameliorate intestinal inflammation by impressing NF-κB and MAPK pathway. Amino acids activate Nrf2 pathway to regulate intestinal inflammation via inhibiting oxidative stress and the expressions of proinflammatory cytokines. Amino acids activate iNOS to inhibit NF-κB pathway by the production of NO. ACE2 combines B0AT1 to regulate uptake of Trp in IECs, which activates expressions of antimicrobial peptides to regulate intestinal microbiota. ACE2 illuminate intestinal inflammation by regulating innate immune responses and intestinal microbiota is not shown in the figure. GCN2 regulates intestinal inflammation by inhibiting inflammasome activation, triggering autophagy, and preventing oxidative stress. CaSR activated by Trp exerts anti-inflammation roles via activating the complex of Β-arrestin 2 (β-arr2) to inhibit NF-κB and MAPK pathway in IECs. After being activated by amino acids, mTOR signaling could inhibit autophagy.

Figure 2

Specific signaling pathways of different amino acids in intestinal inflammation are showed. Thr, His, Arg, Leu, Asn, Cys, Gln, Met, and Gly inhibit NF-κB signaling pathway to ameliorate intestinal inflammation. Thr, Arg, Leu, Asn, Trp, Gln, and Ile inhibit MAPK signaling pathway to relieve intestinal inflammation; Leu, Ile, and Val activate GCN2 pathway to improve intestinal inflammation. Tyr, Lys, Trp, Val, and Phe activate CaSR pathway to attenuate intestinal inflammation. NEAAs, Thr, Gln, Leu, Cys, and Trp may promote intestinal inflammation through activating mTOR. Trp reduces intestinal inflammation via activating ACE2 pathway; Cys decreases intestinal inflammation through activating Nrf2 signaling pathway. Arg decreases intestinal inflammation by iNOS signaling pathway.

2.2. CEAAs and Intestinal Inflammation

Arg plays crucial roles in regulating intestinal inflammation via immune response, oxidative system, tight junction, and intestinal metabolism [142]. Arg as a nutritional supplement reduces the expressions of IL-1β and IL-6, as well as delaying the onset of colitis when the colitis is not very serious, and inhibits the increase of intestinal epithelial permeability by preventing inflammatory neutrophil recruitment and oxidative stress in the DSS-induced colitis [31]. Besides, Arg reduces the activation of IL-1β-induced NF-κB signaling pathway [80]. Nitric oxide (NO) also inhibits the activation of NF-κB signaling [143], and Arg decreases production of IL-8 during the intestinal inflammation which may occur through increasing the production of NO via inducible nitric oxide synthase (iNOS) [144]. L-Arg improves survival rate as well as antineoplastic properties and regulates the metabolism of T cells [81]. Our previous reports indicated that dietary supplementation of Arg partly alters the progression of porcine circovirus type 2 (PCV2) infection [82]. Dietary supplementation of Arg has significant influence in colitis treated with dextran sulfate sodium (DSS) via NF-κB signaling pathways [83]. Arg supplementation increases immune responses, growth characteristics, and morphology of small intestine in weaned piglets [84]. Arg supplementation changes the intestinal microbiota, which is conducive to activate intestinal innate immune responses by NF-κB signaling pathway [145]. His is another CEAAs and an important anti-inflammatory factor, which inhibits the production of IL-8 induced by oxidative stress or TNF-α through controlling the activation of NF-κB in the IECs [3]. His supplement alleviates colitis of murine by suppressing the generation of proinflammatory mediators; thus it may have therapeutic utility for CD by inhibiting the activation of NF-κB [85]. Moreover, the decrease of His increases relapsing risk in the emission of UC patients; thus His may be a noninvasive predictive marker in the intestinal inflammation [86]. Thus taking advantage of Arg or His supplementation to prevent or treat intestinal inflammation is a kind of new adjuvant treatment strategy for intestinal diseases associating with inflammation. The functions and signaling pathways of CEAAs in the intestinal inflammation are showed in Table 1. In conclusion, CEAAs play a critical anti-inflammatory role in the intestine through its regulatory functions in immune responses, NF-κB pathway. Possible signaling mechanisms of CEAAs on the intestinal inflammation in the ECs are showed in Figure 1. Specific signaling pathways of CEAAs in intestinal inflammation are showed Figure 2.

2.3. NEAAs and Intestinal Inflammation

NEAAs play beneficial roles in the intestinal inflammation. The deficiency of NEAAs damages intestinal barrier and expressions of TJPs (e.g., claudin-1, ZO-1) in IECs, which triggers protective autophagy via mTOR pathway [146]. Cys supplementation suppresses intestinal inflammation through increasing the expressions of TJPs and decreasing the expressions of proinflammatory factors in colitis [45]. Cys exerts protective functions in the intestinal barrier that involves anti-inflammation and antioxidation by suppressing the NF-κB pathway and activating the Nrf2 signaling pathway [25]. N-Acetylcysteine (NAC) protects intestinal barrier in piglets induced by LPS via mTOR, NF-κB, and MAPK signaling pathway [95, 96]. Accumulating evidence indicates that Gly enhances intestinal mucosal barrier and inhibits oxidative stress via suppressing the activation of NF-κB and the production of TNF-α, IL-1, and IL-6 [97–101]. Several lines of evidence have indicated that dietary supplementation of Glu has significant roles in the proliferation of IECs, the function of mucosal barrier, and the increase of antioxidative capacity to control intestinal permeability and decrease proinflammatory cytokines production [102, 103]. Glu effectively regulates oxidative stress and intestinal injury in piglets treated with the mycotoxin deoxynivalenol (DNO) [104]. Pro supplementation has crucial roles in regulating the proliferation and differentiation of IECs, increasing superoxide dismutase (SOD) activities, and expressions of TJPs [105, 106]. Dietary supplementation of Pro exerts advantageous immune-stimulatory functions in the mice immunized with inactivated Pasteurella multocida (Pm) [107]. Asp or Asn has important functions in stimulating the proliferation of IECs and triggering immune response to attenuate intestinal injury and restore intestinal morphology as well as barrier function impaired with lipopolysaccharide (LPS) via inhibiting NF-κB signaling pathway [55, 108, 109]. Dietary supplementation of Asp alleviates growth suppression and oxidative stress of piglets treated by H₂O₂ [110]. Ser promotes the synthesis of mucins and improves the composition of gut microbiota in the rats induced by DSS [75]. Ser immediately regulates adaptive immunity via modulating T cell proliferation [111]. Tyr and alanine (Ala) are necessary ingredients of protein synthesis and immunity, which also have advantageous functions in the intestinal inflammation [63]. However, their molecular mechanism and signaling pathways are still unclear; thus further numerous investigations are needed to be done to address these issues.

Gln, the richest amino acid in plasma, plays an important role in maintaining the integrity of intestinal barrier. Studies showed that deficiency of Gln can lead to villus atrophy, reduction in expression of TJPs, and increase in permeability of intestine, but Gln supplement can improve gut barrier function in IBS [87]. A lot of evidence shows that Gln plays an anti-inflammatory role by affecting the NF-κB as well as STAT signaling pathways [88]. IκB proteins are phosphorylated by IκB kinase to release NF-κB to activate the immune responses. Activated NF-κB complex triggers the expressions of IL-6 and TNF-α, which activates T cells and antigen-presenting cells (APCs) [147]. Gln inhibits NF-κB pathway by increasing the expression of heat shock proteins (HSPs) mediated by HSF-1 to suppress the expressions of inflammatory cytokines [17, 89]. STAT proteins are transcription factors regulating intestinal inflammation by mediating the expression of IL-6 [148]. Gln influences the activation of STAT signaling that was proved by reducing the phosphorylation of STAT1 as well as STAT5 [90]. When Gln is deficient, the expression of STAT4 is increased; nevertheless, the expression of STAT4 and IL-8 is reduced after supplementing Gln [149]. From the above studies, Gln may play anti-inflammatory role via preventing the activity of STAT and NF-κB to regulate the production of IL-6 as well as IL-8 in the intestinal inflammation. Moreover, Gln has protective effects in colitis by mTOR signaling pathway [91]. Deficiency of Gln triggers autophagy and hinders amino acid metabolism in IECs by inactivating mTOR and MAPK/ERK signaling pathways, but Gln supplementation recovers the phenomenon [18]. And another study found that the growth of enterocyte is induced by Gln via mTOR without AMPK signaling pathway [92]. Furthermore, Gln affects the production of intestinal SIgA to protect IECs from harmful factors [93]. The supplementation of dietary Gln may suppress intestinal enterotoxigenic Escherichia coli infection by innate immunity [94]. Collectively, NEAAs exert anti-inflammatory roles associating with NF-κB, MAPK, mTOR, and Nrf2 pathways. The functions and signaling pathway of NEAAs in the intestinal inflammation are showed in Table 2. Possible signaling mechanisms of amino acids on the intestinal inflammation in the ECs are showed in Figure 1. Specific signaling pathways of CEAAs in intestinal inflammation are showed in Figure 2.

3. Amino Acid Sensor GCN2 Regulates Intestinal Inflammation

GCN2 is a key sensor of integrated stress response (ISR) and can sense amino acid depletion [54, 150]. Previous, study reported that GCN2 deficient mice cannot effectively deal with the starvation of EAAs, leading to change in nutrition intake and increase in death [151]. A recent study found that GCN2 deficiency increases intestinal inflammation in IECs as well as APCs and Th17 cells responses in colitis [22]. Thus intestinal inflammation may be associated with amino acid sensing pathway GCN2, which may suppress intestinal inflammation by inhibiting inflammasome activation, triggering autophagy, and preventing oxidative stress and Th17 cells differentiation in colitis [22]. When amino acids are insufficient, the homeostasis of amino acids is recovered by arresting translational after the translation initiator eukaryotic initiation factor 2 (eIF2) phosphorylated by GCN2 [54, 152]. When amino acids are redundant, amino acids could lead to intestinal inflammation on account of lacking GCN2 stimulation [21]. Another research indicates that GCN2 is essential for regulating the expressions of inflammatory cytokines and immune responses in myeloid cells [153]. Therefore, GCN2 may be a fine target to manage inflammatory illness.

4. ACE2 Connects Amino Acid Malnutrition and Intestinal Inflammation

A series of evidence suggests that malnutrition is related to intestinal inflammation [154]. A study indicates that amino acid malnutrition is always related to intestinal inflammation via angiotensin-converting enzyme 2 (ACE2), which plays significant roles in amino acids homeostasis, innate immune responses, and intestinal microbiota [155]. ACE2 is an important enzyme of renin-angiotensin system (angiotensin 1–7), which is expressed on various organs including small intestine, and has a crucial function in controlling intestinal inflammation as a stabilizer of neutral amino acid transporters [156]. Angiotensin 1–7 treatment has an anti-inflammatory effect on IBD by reducing the activity of MAPK and NF-κB [157]. ACE2 regulates innate immune response and intestinal microbiota, which illuminates intestinal inflammation under conditions of severe malnutrition [158]. Mice with ACE2 knockout and ACE2 mutation show the decline in the uptake of Trp, leading to the decrease of expressions of antimicrobial peptides and the change of intestinal microbiota, resulting in the high sensitivity to intestinal inflammation, which is restored by Trp supplementation [155]. The acquisition and uptake of Trp primarily rely on B0AT1, whose expression is provoked by ACE2 in the IECs [159]. ACE2 provides a new way for the therapy of intestinal inflammation.

5. Conclusion

In conclusion, the functions of amino acids in intestinal inflammation are mainly associated with improving intestinal barrier, attenuating intestinal injury, suppressing oxidative stress, and inhibiting the expressions of proinflammatory cytokines. These functions are finished by a series of signaling mechanisms, including NF-κB, MAPK, Nrf2, mTOR, iNOS, CaSR, ACE2, and GCN2. However, the exact molecular mechanism of some amino acids is not unclear, such as Ala and Ser. Therefore, there is still much work to be done to explore the relevant signaling pathways. Future studies also should concentrate on the functions and signaling pathways of amino acids to explore safe and effective therapeutic schedule for human and animals in the intestinal inflammation.

Abbreviations

Arg:	Arginine
Ala:	Alanine
Asp:	Aspartate
Asn:	Asparagine
AHR:	Aryl hydrocarbon receptor
AAAs:	Aromatic amino acids
APCs:	Antigen-presenting cells
AJPAS:	Adherent junction proteins
BCAAs:	Branched chain amino acids
CEAAs:	Conditionally essential amino acids
CD:	Crohn’s disease
Card9:	Caspase recruitment domain family member 9
CaSR:	Calcium-sensing receptor
Cys:	Cysteine
ER:	Endoplasmic reticulum
eIF2:	Eukaryotic initiation factor 2
EAAs:	Essential amino acids
Glu:	Glutamate
Gln:	Glutamine
Gly:	Glycine
GCN2:	General controlled nonrepressed 2 kinase
GPCRs:	G-protein-coupling receptors
His:	Histidine
HSPs:	Heat shock proteins
IBD:	Inflammatory bowel disease
IBS:	Irritable bowel syndrome
iNOS:	Inducible nitric oxide synthase
IL-10R:	IL-10 receptor
IECs:	Intestinal epithelial cells
Ile:	Isoleucine
Kyn:	Kynurenine
Leu:	Leucine
mTOR:	Mechanistic target of rapamycin
Met:	Methionine
MAPK:	Mitogen-activated protein kinase
NEAAs:	Nonessential amino acids
NF-κB:	Nuclear factor-kappa-B
Nrf2:	Transcription factor NF-E2-related factor 2
Phe:	Phenylalanine
Pro:	Proline
Pm:	Pasteurella multocida
PL:	Poly-L-lysine
ROS:	Reactive oxygen species
Ser:	Serine
SERT:	Serotonin reuptake transporter
Ser:	Serine
SCFAs:	Short chain fatty acids
Trp:	Tryptophan
Thr:	Threonine
Tyr:	Tyrosine
Lys:	Lysine
Th17:	T-helper type 17
Tyr:	Tyrosine
TPH-1:	Tryptophan hydroxylase-1
TLR4:	Toll-like receptor 4
TJPs:	Tight junction proteins
UC:	Ulcerative colitis
Val:	Valine
5-HT:	5-Hydroxytryptophan.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

This work is supported by the earmarked fund of China Agriculture Research System (Beef/Yak Cattle, CARS-37).

References

J. A. Jiminez, T. C. Uwiera, G. D. Inglis, and R. R. E. Uwiera, “Animal models to study acute and chronic intestinal inflammation in mammals,” Gut Pathogens, vol. 7, no. 1, article no. 29, 2015.
View at: Publisher Site | Google Scholar
R. D. Berg, “The indigenous gastrointestinal microflora,” Trends in Microbiology, vol. 4, no. 11, pp. 430–435, 1996.
View at: Publisher Site | Google Scholar
M. Shimizu, “Multifunctions of dietary polyphenols in the regulation of intestinal inflammation,” Journal of Food and Drug Analysis, vol. 25, no. 1, pp. 93–99, 2017.
View at: Publisher Site | Google Scholar
M. Camilleri, K. Madsen, R. Spiller, B. G. van Meerveld, and G. N. Verne, “Intestinal barrier function in health and gastrointestinal disease,” Neurogastroenterology & Motility, vol. 24, no. 6, pp. 503–512, 2012.
View at: Publisher Site | Google Scholar
L. Biancone, S. Zuzzi, M. Ranieri et al., “Fistulizing pattern in Crohn's disease and pancolitis in ulcerative colitis are independent risk factors for cancer: a single-center cohort study,” Journal of Crohn's and Colitis, vol. 6, no. 5, pp. 578–587, 2012.
View at: Publisher Site | Google Scholar
Y.-Z. Zhang and Y.-Y. Li, “Inflammatory bowel disease: pathogenesis,” World Journal of Gastroenterology, vol. 20, no. 1, pp. 91–99, 2014.
View at: Publisher Site | Google Scholar
V. Yadav, F. Varum, R. Bravo, E. Furrer, D. Bojic, and A. W. Basit, “Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets,” Translational Research, vol. 176, pp. 38–68, 2016.
View at: Publisher Site | Google Scholar
M. Martin-Subero, G. Anderson, B. Kanchanatawan, M. Berk, and M. Maes, “Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut-brain pathways,” CNS Spectrums, vol. 21, no. 2, pp. 184–198, 2016.
View at: Publisher Site | Google Scholar
L. Xin, N. Li, and W. Zhu, “An analysis of amino acid metabolic profile and its clinical significance in ulcerative colitis,” Zhonghua Nei Ke Za Zhi, vol. 54, no. 3, pp. 210–213, 2015.
View at: Google Scholar
M. D. Gershon, “5-Hydroxytryptamine (serotonin) in the gastrointestinal tract,” Current Opinion in Endocrinology, Diabetes and Obesity, vol. 20, no. 1, pp. 14–21, 2013.
View at: Publisher Site | Google Scholar
B. Lamas, M. L. Richard, and V. Leducq, “CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands,” Nature Medicine, vol. 22, no. 6, pp. 598–605, 2016.
View at: Publisher Site | Google Scholar
L. Etienne-Mesmin, B. Chassaing, and A. T. Gewirtz, “Tryptophan: A gut microbiota-derived metabolites regulating inflammation,” World Journal of Gastrointestinal Pharmacology and Therapeutics, vol. 8, no. 1, pp. 7–9, 2017.
View at: Publisher Site | Google Scholar
F.-Y. Yu, S.-G. Huang, H.-Y. Zhang et al., “Comparison of 5-hydroxytryptophan signaling pathway characteristics in diarrhea-predominant irritable bowel syndrome and ulcerative colitis,” World Journal of Gastroenterology, vol. 22, no. 12, pp. 3451–3459, 2016.
View at: Publisher Site | Google Scholar
D. Guseva, K. Holst, B. Kaune et al., “Serotonin 5-HT7 receptor is critically involved in acute and chronic inflammation of the gastrointestinal tract,” Inflammatory Bowel Diseases, vol. 20, no. 9, pp. 1516–1529, 2014.
View at: Publisher Site | Google Scholar
T. Sakiyama, M. W. Musch, M. J. Ropeleski, H. Tsubouchi, and E. B. Chang, “Glutamine Increases Autophagy Under Basal and Stressed Conditions in Intestinal Epithelial Cells,” Gastroenterology, vol. 136, no. 3, pp. 924–932, 2009.
View at: Publisher Site | Google Scholar
B. Wang, G. Wu, Z. Zhou et al., “Glutamine and intestinal barrier function,” Amino Acids, vol. 47, no. 10, pp. 2143–2154, 2015.
View at: Publisher Site | Google Scholar
Y.-C. Hou, C.-C. Chu, T.-L. Ko, C.-L. Yeh, and S.-L. Yeh, “Effects of alanyl-glutamine dipeptide on the expression of colon-inflammatory mediators during the recovery phase of colitis induced by dextran sulfate sodium,” European Journal of Nutrition, vol. 52, no. 3, pp. 1089–1098, 2013.
View at: Publisher Site | Google Scholar
Y. Zhu, G. Lin, Z. Dai et al., “L-Glutamine deprivation induces autophagy and alters the mTOR and MAPK signaling pathways in porcine intestinal epithelial cells,” Amino Acids, vol. 47, no. 10, pp. 2185–2197, 2015.
View at: Publisher Site | Google Scholar
W. Ren, L. Zou, N. Li et al., “Dietary arginine supplementation enhances immune responses to inactivated Pasteurella multocida vaccination in mice,” British Journal of Nutrition, vol. 109, no. 5, pp. 867–872, 2013.
View at: Publisher Site | Google Scholar
G. Wu, “Amino acids: metabolism, functions, and nutrition,” Amino Acids, vol. 37, no. 1, pp. 1–17, 2009.
View at: Publisher Site | Google Scholar
X. S. Revelo, S. Winer, and D. A. Winer, “Starving Intestinal Inflammation with the Amino Acid Sensor GCN2,” Cell Metabolism, vol. 23, no. 5, pp. 763–765, 2016.
View at: Publisher Site | Google Scholar
R. Ravindran, J. Loebbermann, H. I. Nakaya et al., “The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation,” Nature, vol. 531, no. 7595, pp. 523–527, 2016.
View at: Publisher Site | Google Scholar
B. Tan, B. Huang, J. Wang, G. P. Guang, C. B. Yang, and Y. Yin, “Aromatic amino acids alleviate intestinal inflammation in piglets through calcium-sensing receptor activation,” Journal of Animal Science, vol. 95, supplement 4, no. supplement4, pp. 201-202, 2017.
View at: Publisher Site | Google Scholar
A. Izcue and F. Powrie, “Immunology: Malnutrition promotes rogue bacteria,” Nature, vol. 487, no. 7408, pp. 437–439, 2012.
View at: Publisher Site | Google Scholar
Z. H. Song, G. Tong, K. Xiao, L. F. Jiao, Y. L. Ke, and C. H. Hu, “L -Cysteine protects intestinal integrity, attenuates intestinal inflammation and oxidant stress, and modulates NF-kB and Nrf2 pathways in weaned piglets after LPS challenge,” Journal of Innate Immunity, vol. 22, no. 3, pp. 152–161, 2016.
View at: Publisher Site | Google Scholar
L. Zhou, H. Zhang, K. J. Davies, and H. J. Forman, “Aging-related decline in the induction of Nrf2-regulated antioxidant genes in human bronchial epithelial cells,” Redox Biology, vol. 14, pp. 35–40, 2017.
View at: Publisher Site | Google Scholar
C. H. Hu, Z. H. Song, K. Xiao, J. Song, L. F. Jiao, and Y. L. Ke, “Zinc oxide influences intestinal integrity, the expressions of genes associated with inflammation and TLR4-myeloid differentiation factor 88 signaling pathways in weanling pigs,” Journal of Innate Immunity, vol. 20, no. 5, pp. 478–486, 2014.
View at: Publisher Site | Google Scholar
H. Satsu, E. Chidachi, Y. Hiura, H. Ogiwara, Y. Gondo, and M. Shimizu, “Induction of NAD(P)H: Quinone oxidoreductase 1 expression by cysteine via Nrf2 activation in human intestinal epithelial LS180 cells,” Amino Acids, vol. 43, no. 4, pp. 1547–1555, 2012.
View at: Publisher Site | Google Scholar
Z. Chen, Y. Zhang, L. Ma, Y. Ni, and H. Zhao, “Nrf2 plays a pivotal role in protection against burn trauma-induced intestinal injury and death,” Oncotarget , vol. 7, no. 15, pp. 19272–19283, 2016.
View at: Publisher Site | Google Scholar
S. Nagarjun, S. B. Dhadde, V. P. Veerapur, B. S. Thippeswamy, and B. N. Chandakavathe, “Ameliorative effect of chromium-D-phenylalanine complex on indomethacin-induced inflammatory bowel disease in rats,” Biomedicine & Pharmacotherapy, vol. 89, pp. 1061–1066, 2017.
View at: Publisher Site | Google Scholar
H. V. Robles, K. F. Castro Ochoa, P. Nava, A. Silva Olivares, M. Shibayama, and M. Schnoor, “Analyzing beneficial effects of nutritional supplements on intestinal epithelial barrier functions during experimental colitis,” Journal of Visualized Experiments, vol. 2017, no. 119, Article ID e55095, 2017.
View at: Publisher Site | Google Scholar
C. Wu, X. Qin, H. Du, and etal., “The immunological function of GABAergic system,” Frontiers in Bioscience, vol. 22, no. 7, pp. 1162–1172, 2017.
View at: Publisher Site | Google Scholar
J. Landy, E. Ronde, N. English et al., “Tight junctions in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer,” World Journal of Gastroenterology, vol. 22, no. 11, pp. 3117–3126, 2016.
View at: Publisher Site | Google Scholar
V. Garcia-Hernandez, M. Quiros, and A. Nusrat, “Intestinal epithelial claudins: expression and regulation in homeostasis and inflammation,” Annals of the New York Academy of Sciences, vol. 1397, no. 1, pp. 66–79, 2017.
View at: Publisher Site | Google Scholar
T. Xing, R. Camacho Salazar, and Y. Chen, “Animal models for studying epithelial barriers in neonatal necrotizing enterocolitis, inflammatory bowel disease and colorectal cancer,” Tissue Barriers, p. e1356901, 2017.
View at: Publisher Site | Google Scholar
E. Martini, S. M. Krug, B. Siegmund, M. F. Neurath, and C. Becker, “Mend your fences: the epithelial barrier and its relationship with mucosal immunity in inflammatory bowel disease,” Cellular and Molecular Gastroenterology and Hepatology, vol. 4, no. 1, pp. 33–46, 2017.
View at: Publisher Site | Google Scholar
Y. Wang, J. B. Mumm, R. Herbst, R. Kolbeck, and Y. Wang, “IL-22 Increases Permeability of Intestinal Epithelial Tight Junctions by Enhancing Claudin-2 Expression,” The Journal of Immunology, vol. 199, no. 9, pp. 3316–3325, 2017.
View at: Publisher Site | Google Scholar
J. Luettig, R. Rosenthal, C. Barmeyer, and J. D. Schulzke, “Claudin-2 as a mediator of leaky gut barrier during intestinal inflammation,” Tissue Barriers, vol. 3, no. 1, 2015.
View at: Publisher Site | Google Scholar
W. Liu, S. Mi, Z. Ruan et al., “Dietary Tryptophan Enhanced the Expression of Tight Junction Protein ZO-1 in Intestine,” Journal of Food Science, vol. 82, no. 2, pp. 562–567, 2017.
View at: Publisher Site | Google Scholar
H. Wang, Y. Ji, G. Wu et al., “L-tryptophan activates mammalian target of rapamycin and enhances expression of tight junction proteins in intestinal porcine epithelial cells,” Journal of Nutrition, vol. 145, no. 6, pp. 1156–1162, 2015.
View at: Publisher Site | Google Scholar
S. Beutheu, I. Ghouzali, L. Galas, P. Déchelotte, and M. Coëffier, “Glutamine and arginine improve permeability and tight junction protein expression in methotrexate-treated Caco-2 cells,” Clinical Nutrition, vol. 32, no. 5, pp. 863–869, 2013.
View at: Publisher Site | Google Scholar
M. N. Zuhl, K. R. Lanphere, L. Kravitz et al., “Effects of oral glutamine supplementation on exercise-induced gastrointestinal permeability and tight junction protein expression,” Journal of Applied Physiology, vol. 116, no. 2, pp. 183–191, 2014.
View at: Publisher Site | Google Scholar
M. Kim and H. Kim, “The Roles of Glutamine in the Intestine and Its Implication in Intestinal Diseases,” International Journal of Molecular Sciences, vol. 18, no. 5, p. 1051, 2017.
View at: Publisher Site | Google Scholar
F. R. Demehri, M. Barrett, M. W. Ralls, E. A. Miyasaka, Y. Feng, and D. H. Teitelbaum, “Intestinal epithelial cell apoptosis and loss of barrier function in the setting of altered microbiota with enteral nutrient deprivation,” Frontiers in Cellular and Infection Microbiology, vol. 3, Article ID 00105, 2013.
View at: Publisher Site | Google Scholar
C. J. Kim, J. Kovacs-Nolan, C. Yang, T. Archbold, M. Z. Fan, and Y. Mine, “L-cysteine supplementation attenuates local inflammation and restores gut homeostasis in a porcine model of colitis,” Biochimica et Biophysica Acta, vol. 1790, no. 10, pp. 1161–1169, 2009.
View at: Publisher Site | Google Scholar
T. Saitoh, N. Fujita, M. H. Jang et al., “Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production,” Nature, vol. 456, no. 7219, pp. 264–268, 2008.
View at: Publisher Site | Google Scholar
B. Ekim, B. Magnuson, H. A. Acosta-Jaquez, J. A. Keller, E. P. Feener, and D. C. Fingar, “mTOR kinase domain phosphorylation promotes mTORC1 signaling, cell growth, and cell cycle progression,” Molecular and Cellular Biology, vol. 31, no. 14, pp. 2787–2801, 2011.
View at: Publisher Site | Google Scholar
H. Yang, X. Xiong, T. Li, and Y. Yin, “Ethanolamine enhances the proliferation of intestinal epithelial cells via the mTOR signaling pathway and mitochondrial function,” In Vitro Cellular & Developmental Biology - Animal, vol. 52, no. 5, pp. 562–567, 2016.
View at: Publisher Site | Google Scholar
M. Coskun, J. Olsen, J. B. Seidelin, and O. H. Nielsen, “MAP kinases in inflammatory bowel disease,” Clinica Chimica Acta, vol. 412, no. 7-8, pp. 513–520, 2011.
View at: Publisher Site | Google Scholar
B. H. You, H. Chae, J. Song, H. W. Ko, Y. Chin, and Y. H. Choi, “α-Mangostin ameliorates dextran sulfate sodium-induced colitis through inhibition of NF-κB and MAPK pathways,” International Immunopharmacology, vol. 49, pp. 212–221, 2017.
View at: Publisher Site | Google Scholar
G. Docena, L. Rovedatti, L. Kruidenier et al., “Down-regulation of p38 mitogen-activated protein kinase activation and proinflammatory cytokine production by mitogen-activated protein kinase inhibitors in inflammatory bowel disease,” Clinical & Experimental Immunology, vol. 162, no. 1, pp. 108–115, 2010.
View at: Publisher Site | Google Scholar
A. Raza, J. W. Crothers, M. M. McGill, G. M. Mawe, C. Teuscher, and D. N. Krementsov, “Anti-inflammatory roles of p38α MAPK in macrophages are context dependent and require IL-10,” Journal of Leukocyte Biology, vol. 102, no. 5, pp. 1219–1227, 2017.
View at: Publisher Site | Google Scholar
J. P. Shellhammer, E. Morin-Kensicki, J. P. Matson et al., “Amino acid metabolites that regulate G protein signaling during osmotic stress,” PLoS Genetics, vol. 13, no. 5, p. e1006829, 2017.
View at: Publisher Site | Google Scholar
J. Shan, W. Donelan, J. N. Hayner, F. Zhang, E. E. Dudenhausen, and M. S. Kilberg, “MAPK signaling triggers transcriptional induction of cFOS during amino acid limitation of HepG2 cells,” Biochimica et Biophysica Acta, vol. 1853, no. 3, pp. 539–548, 2015.
View at: Publisher Site | Google Scholar
S. Chen, Y. Liu, X. Wang et al., “Asparagine improves intestinal integrity, inhibits TLR4 and NOD signaling, and differently regulates p38 and ERK1/2 signaling in weanling piglets after LPS challenge,” Journal of Innate Immunity, vol. 22, no. 8, pp. 577–587, 2016.
View at: Publisher Site | Google Scholar
J. Jiang, D. Shi, X.-Q. Zhou et al., “In vitro and in vivo protective effect of arginine against lipopolysaccharide induced inflammatory response in the intestine of juvenile Jian carp (Cyprinus carpio var. Jian),” Fish & Shellfish Immunology, vol. 42, no. 2, pp. 457–464, 2015.
View at: Publisher Site | Google Scholar
S. Lecleire, A. Hassan, R. Marion-Letellier et al., “Combined glutamine and arginine decrease proinflammatory cytokine production by biopsies from Crohn's patients in association with changes in nuclear factor-κB and p38 mitogen-activated protein kinase pathways,” Journal of Nutrition, vol. 138, no. 12, pp. 2481–2486, 2008.
View at: Publisher Site | Google Scholar
Y. Mine and H. Zhang, “Calcium-sensing receptor (CaSR)-mediated anti-inflammatory effects of L-amino acids in intestinal epithelial cells,” Journal of Agricultural and Food Chemistry, vol. 63, no. 45, pp. 9987–9995, 2015.
View at: Publisher Site | Google Scholar
J. Zhang, J. Bi, S. Liu et al., “5-HT Drives Mortality in Sepsis Induced by Cecal Ligation and Puncture in Mice,” Mediators of Inflammation, vol. 2017, Article ID 6374283, 12 pages, 2017.
View at: Publisher Site | Google Scholar
J. Islam, S. Sato, K. Watanabe et al., “Dietary tryptophan alleviates dextran sodium sulfate-induced colitis through aryl hydrocarbon receptor in mice,” The Journal of Nutritional Biochemistry, vol. 42, pp. 43–50, 2017.
View at: Publisher Site | Google Scholar
T. V. Lanz, S. Becker, S. R. Mohapatra, C. A. Opitz, W. Wick, and M. Platten, “Suppression of Th1 differentiation by tryptophan supplementation in vivo,” Amino Acids, vol. 49, no. 7, pp. 1169–1175, 2017.
View at: Publisher Site | Google Scholar
Y. Yue, Y. Guo, and Y. Yang, “Effects of dietary l-tryptophan supplementation on intestinal response to chronic unpredictable stress in broilers,” Amino Acids, vol. 49, no. 7, pp. 1227–1236, 2017.
View at: Publisher Site | Google Scholar
P. Li, Y. Yin, D. Li, W. S. Kim, and G. Wu, “Amino acids and immune function,” British Journal of Nutrition, vol. 98, no. 2, pp. 237–252, 2007.
View at: Publisher Site | Google Scholar
A. Alamshah, E. Spreckley, M. Norton et al., “l-phenylalanine modulates gut hormone release and glucose tolerance, and suppresses food intake through the calcium-sensing receptor in rodents,” International Journal of Obesity, vol. 41, no. 11, pp. 1693–1701, 2017.
View at: Publisher Site | Google Scholar
R. Martín-Venegas, M. Teresa Brufau, A. M. Guerrero-Zamora, Y. Mercier, P.-A. Geraert, and R. Ferrer, “The methionine precursor DL-2-hydroxy-(4-methylthio)butanoic acid protects intestinal epithelial barrier function,” Food Chemistry, vol. 141, no. 3, pp. 1702–1709, 2013.
View at: Publisher Site | Google Scholar
Y. Chen, D. F. Li, Z. L. Dai et al., “L-methionine supplementation maintains the integrity and barrier function of the small-intestinal mucosa in post-weaning piglets,” Amino Acids, vol. 46, no. 4, pp. 1131–1142, 2014.
View at: Publisher Site | Google Scholar
G. Liu, L. Yu, J. Fang et al., “Methionine restriction on oxidative stress and immune response in dss-induced colitis mice,” Oncotarget, vol. 8, no. 27, pp. 44511–44520, 2017.
View at: Publisher Site | Google Scholar
X.-Q. Wang, P.-L. Zeng, Y. Feng et al., “Effects of dietary lysine levels on apparent nutrient digestibility and cationic amino acid transporter mRNA abundance in the small intestine of finishing pigs, Sus scrofa,” Animal Science Journal, vol. 83, no. 2, pp. 148–155, 2012.
View at: Publisher Site | Google Scholar
Y. Mine and H. Zhang, “Anti-inflammatory Effects of Poly-L-lysine in Intestinal Mucosal System Mediated by Calcium-Sensing Receptor Activation,” Journal of Agricultural and Food Chemistry, vol. 63, no. 48, pp. 10437–10447, 2015.
View at: Publisher Site | Google Scholar
J. G. Oh, S. H. Chun, D. H. Kim et al., “Anti-inflammatory effect of sugar-amino acid Maillard reaction products on intestinal inflammation model in vitro and in vivo,” Carbohydr Res, vol. 449, pp. 47–58, 2017.
View at: Google Scholar
C. Hong, C. H. Rhee, M. C. Pyo, and K. Lee, “Anti-inflammatory effect of glucose-lysine Maillard reaction products on intestinal inflammation model in vivo,” International Immunopharmacology, vol. 52, pp. 324–332, 2017.
View at: Publisher Site | Google Scholar
Q. Zhang, X. Chen, S. D. Eicher, K. M. Ajuwon, and T. J. Applegate, “Effect of threonine on secretory immune system using a chicken intestinal ex vivo model with lipopolysaccharide challenge,” Poultry Science, vol. 96, no. 9, pp. 3043–3051, 2017.
View at: Publisher Site | Google Scholar
E. L. Wils-Plotz, M. C. Jenkins, and R. N. Dilger, “Modulation of the intestinal environment, innate immune response, and barrier function by dietary threonine and purified fiber during a coccidiosis challenge in broiler chicks,” Poultry Science, vol. 92, no. 3, pp. 735–745, 2013.
View at: Publisher Site | Google Scholar
Y. Dong, W. Jiang, Y. Liu et al., “Threonine deficiency decreased intestinal immunity and aggravated inflammation associated with NF-κB and target of rapamycin signalling pathways in juvenile grass carp (Ctenopharyngodon idella) after infection with Aeromonas hydrophila,” British Journal of Nutrition, vol. 118, no. 02, pp. 92–108, 2017.
View at: Publisher Site | Google Scholar
M. Faure, C. Mettraux, D. Moennoz et al., “Specific amino acids increase mucin synthesis and microbiota in dextran sulfate sodium-treated rats,” Journal of Nutrition, vol. 136, no. 6, pp. 1558–1564, 2006.
View at: Google Scholar
H. Zhang, J. Kovacs-Nolan, T. Kodera, Y. Eto, and Y. Mine, “γ-Glutamyl cysteine and γ-glutamyl valine inhibit TNF-α signaling in intestinal epithelial cells and reduce inflammation in a mouse model of colitis via allosteric activation of the calcium-sensing receptor,” Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, vol. 1852, no. 5, pp. 792–804, 2015.
View at: Publisher Site | Google Scholar
S. Zhang, M. Ren, X. Zeng, P. He, X. Ma, and S. Qiao, “Leucine stimulates ASCT2 amino acid transporter expression in porcine jejunal epithelial cell line (IPEC-J2) through PI3K/Akt/mTOR and ERK signaling pathways,” Amino Acids, vol. 46, no. 12, pp. 2633–2642, 2015.
View at: Publisher Site | Google Scholar
M. Coëffier, S. Claeyssens, M. Bensifi et al., “Influence of leucine on protein metabolism, phosphokinase expression, and cell proliferation in human duodenum,” American Journal of Clinical Nutrition, vol. 93, no. 6, pp. 1255–1262, 2011.
View at: Publisher Site | Google Scholar
Y. Konno, T. Ashida, and Y. Inaba, “Isoleucine, an Essential Amino Acid, Induces the Expression of Human Defensin 2 through the Activation of the G-Protein Coupled Receptor-ERK Pathway in the Intestinal Epithelia,” Food & Nutrition Sciences, pp. 548–555, 2012.
View at: Google Scholar
Q. Meng, M. Cooney, N. Yepuri, and R. N. Cooney, “L-arginine attenuates Interleukin-1β (IL-1β) induced nuclear factor kappa-beta (NF-κB) activation in Caco-2 cells,” PLoS ONE, vol. 12, no. 3, Article ID e0174441, 2017.
View at: Publisher Site | Google Scholar
R. Geiger, J. C. Rieckmann, T. Wolf et al., “L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity,” Cell, vol. 167, no. 3, pp. 829–842.e13, 2016.
View at: Publisher Site | Google Scholar
W. Ren, Y. Yin, G. Liu et al., “Effect of dietary arginine supplementation on reproductive performance of mice with porcine circovirus type 2 infection,” Amino Acids, vol. 42, no. 6, pp. 2089–2094, 2012.
View at: Publisher Site | Google Scholar
W. Ren, J. Yin, M. Wu et al., “Serum amino acids profile and the beneficial effects of L-arginine or L-glutamine supplementation in dextran sulfate sodium colitis,” PLoS ONE, vol. 9, no. 2, article e88335, 2014.
View at: Publisher Site | Google Scholar
B. Tan, X. G. Li, X. Kong et al., “Dietary l-arginine supplementation enhances the immune status in early-weaned piglets,” Amino Acids, vol. 37, no. 2, pp. 323–331, 2009.
View at: Publisher Site | Google Scholar
A. Andou, T. Hisamatsu, S. Okamoto et al., “Dietary histidine ameliorates murine colitis by inhibition of proinflammatory cytokine production from macrophages,” Gastroenterology, vol. 136, no. 2, pp. 564–574.e2, 2009.
View at: Publisher Site | Google Scholar
T. Hisamatsu, N. Ono, A. Imaizumi et al., “Decreased plasma histidine level predicts risk of relapse in patients with ulcerative colitis in remission,” PLoS ONE, vol. 10, no. 10, Article ID e0140716, 2015.
View at: Publisher Site | Google Scholar
N. Achamrah, P. Dechelotte, and M. Coeffier, “Glutamine and the regulation of intestinal permeability: From bench to bedside,” Current Opinion in Clinical Nutrition & Metabolic Care, vol. 20, no. 1, pp. 86–91, 2017.
View at: Publisher Site | Google Scholar
J. Marc Rhoads and G. Wu, “Glutamine, arginine, and leucine signaling in the intestine,” Amino Acids, vol. 37, no. 1, pp. 111–122, 2009.
View at: Publisher Site | Google Scholar
H. Xue, A. J. D. Sufit, and P. E. Wischmeyer, “Glutamine therapy improves outcome of in vitro and in vivo experimental colitis models,” Journal of Parenteral and Enteral Nutrition, vol. 35, no. 2, pp. 188–197, 2011.
View at: Publisher Site | Google Scholar
N. A. Kretzmann, H. Fillmann, J. L. Mauriz, C. A. Marroni, J. González-Gallego, and M. J. Tuñón, “Effects of glutamine on proinflammatory gene expression and activation of nuclear factor Kappa B and signal transducers and activators of transcription in TNBS-induced colitis,” Inflammatory Bowel Diseases, vol. 14, no. 11, pp. 1504–1513, 2008.
View at: Publisher Site | Google Scholar
Y. Tian, K. Wang, Y. Fan et al., “Chemopreventive effect of dietary glutamineon colitis-associated colorectal cancer is associated with modulation of the DEPTOR/mTOR signaling pathway,” Nutrients, vol. 8, no. 5, article no. 261, 2016.
View at: Publisher Site | Google Scholar
D. Yi, Y. Hou, L. Wang et al., “L-Glutamine enhances enterocyte growth via activation of the mTOR signaling pathway independently of AMPK,” Amino Acids, vol. 47, no. 1, pp. 65–78, 2015.
View at: Publisher Site | Google Scholar
W. Ren, K. Wang, J. Yin et al., “Glutamine-induced secretion of intestinal secretory immunoglobulin A: A mechanistic perspective,” Frontiers in Immunology, vol. 7, article no. 503, 2016.
View at: Publisher Site | Google Scholar
G. Liu, W. Ren, J. Fang et al., “L-Glutamine and L-arginine protect against enterotoxigenic Escherichia coli infection via intestinal innate immunity in mice,” Amino Acids, vol. 49, no. 12, pp. 1945–1954, 2017.
View at: Publisher Site | Google Scholar
D. Yi, Y. Hou, H. Xiao et al., “N-Acetylcysteine improves intestinal function in lipopolysaccharides-challenged piglets through multiple signaling pathways,” Amino Acids, pp. 1–15, 2017.
View at: Publisher Site | Google Scholar
L. Wang, J. Zhou, Y. Hou et al., “N-Acetylcysteine supplementation alleviates intestinal injury in piglets infected by porcine epidemic diarrhea virus,” Amino Acids, vol. 49, no. 12, pp. 1931–1943, 2017.
View at: Publisher Site | Google Scholar
W. Wang, Z. Wu, G. Lin et al., “Glycine Stimulates Protein Synthesis and Inhibits Oxidative Stress in Pig Small Intestinal Epithelial Cells,” Journal of Nutrition, vol. 144, no. 10, pp. 1540–1548, 2014.
View at: Publisher Site | Google Scholar
Z. Zhong, M. D. Wheeler, X. Li et al., “L-glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective agent,” Current Opinion in Clinical Nutrition & Metabolic Care, vol. 6, no. 2, pp. 229–240, 2003.
View at: Publisher Site | Google Scholar
W. Li, K. Sun, Y. Ji et al., “Glycine regulates expression and distribution of claudin-7 and Zo-3 proteins in intestinal porcine epithelial cells,” Journal of Nutrition, vol. 146, no. 5, pp. 964–969, 2016.
View at: Publisher Site | Google Scholar
P. Li and G. Wu, “Roles of dietary glycine, proline, and hydroxyproline in collagen synthesis and animal growth,” Amino Acids, 2017.
View at: Publisher Site | Google Scholar
H. Bruns, D. Kazanavicius, D. Schultze et al., “Glycine inhibits angiogenesis in colorectal cancer: role of endothelial cells,” Amino Acids, vol. 48, no. 11, pp. 2549–2558, 2016.
View at: Publisher Site | Google Scholar
X. Wu, Y. Zhang, Z. Liu, T. J. Li, and Y. L. Yin, “Effects of oral supplementation with glutamate or combination of glutamate and N-carbamylglutamate on intestinal mucosa morphology and epithelium cell proliferation in weanling piglets,” Journal of Animal Science, vol. 90, no. 4, pp. 337–339, 2012.
View at: Publisher Site | Google Scholar
N. Jiao, Z. Wu, Y. Ji, B. Wang, Z. Dai, and G. Wu, “L-Glutamate enhances barrier and antioxidative functions in intestinal porcine epithelial cells,” Journal of Nutrition, vol. 145, no. 10, pp. 2258–2264, 2015.
View at: Publisher Site | Google Scholar
M. Wu, H. Xiao, W. Ren et al., “Therapeutic effects of glutamic acid in piglets challenged with deoxynivalenol,” PLoS ONE, vol. 9, no. 7, article e100591, 2014.
View at: Publisher Site | Google Scholar
G. Wu, F. W. Bazer, R. C. Burghardt et al., “Proline and hydroxyproline metabolism: implications for animal and human nutrition,” Amino Acids, vol. 40, no. 4, pp. 1053–1063, 2011.
View at: Publisher Site | Google Scholar
P. Kang, L. Zhang, Y. Hou et al., “Effects of l-proline on the growth performance, and blood parameters in weaned lipopolysaccharide (LPS)-challenged pigs,” Asian-Australasian Journal of Animal Sciences, vol. 27, no. 8, pp. 1150–1156, 2014.
View at: Publisher Site | Google Scholar
W. Ren, L. Zou, Z. Ruan et al., “Dietary l-proline supplementation confers immunostimulatory effects on inactivated Pasteurella multocida vaccine immunized mice,” Amino Acids, vol. 45, no. 3, pp. 555–561, 2013.
View at: Publisher Site | Google Scholar
H. Wang, Y. Liu, H. Shi et al., “Aspartate attenuates intestinal injury and inhibits TLR4 and NODs/NF-κB and p38 signaling in weaned pigs after LPS challenge,” European Journal of Nutrition, vol. 56, no. 4, pp. 1433–1443, 2016.
View at: Publisher Site | Google Scholar
P. Bin, S. Liu, S. Chen et al., “The effect of aspartate supplementation on the microbial composition and innate immunity on mice,” Amino Acids, vol. 49, no. 12, pp. 2045–2051, 2017.
View at: Publisher Site | Google Scholar
J. Duan, J. Yin, W. Ren et al., “Dietary supplementation with l-glutamate and l-aspartate alleviates oxidative stress in weaned piglets challenged with hydrogen peroxide,” Amino Acids, vol. 48, no. 1, pp. 53–64, 2016.
View at: Publisher Site | Google Scholar
E. H. Ma, G. Bantug, T. Griss et al., “Serine Is an Essential Metabolite for Effector T Cell Expansion,” Cell Metabolism, vol. 25, no. 2, p. 482, 2017.
View at: Publisher Site | Google Scholar
Y. Martínez, X. Li, G. Liu et al., “The role of methionine on metabolism, oxidative stress, and diseases,” Amino Acids, vol. 49, no. 12, pp. 2091–2098, 2017.
View at: Publisher Site | Google Scholar
M. Ren, S. H. Zhang, X. F. Zeng, H. Liu, and S. Y. Qiao, “Branched-chain amino acids are beneficial to maintain growth performance and intestinal immune-related function in weaned piglets fed protein restricted diet,” Asian-Australasian Journal of Animal Sciences, vol. 28, no. 12, pp. 1742–1750, 2015.
View at: Publisher Site | Google Scholar
O. Zhenyukh, E. Civantos, M. Ruiz-Ortega et al., “High concentration of branched-chain amino acids promotes oxidative stress, inflammation and migration of human peripheral blood mononuclear cells via mTORC1 activation,” Free Radical Biology & Medicine, vol. 104, pp. 165–177, 2017.
View at: Publisher Site | Google Scholar
J. Zhao, L. Feng, Y. Liu et al., “Effect of dietary isoleucine on the immunity, antioxidant status, tight junctions and microflora in the intestine of juvenile Jian carp (Cyprinuscarpio var. Jian),” Fish and Shellfish Immunology, vol. 41, no. 2, pp. 663–673, 2014.
View at: Publisher Site | Google Scholar
F. Jouret, J. Wu, M. Hull et al., “Activation of the ca2+-sensing receptor induces deposition of tight junction components to the epithelial cell plasma membrane,” Journal of Cell Science, vol. 126, no. 22, pp. 5132–5142, 2013.
View at: Publisher Site | Google Scholar
T. I. Alfadda, A. M. A. Saleh, P. Houillier, and J. P. Geibel, “Calcium-sensing receptor 20 years later,” American Journal of Physiology-Cell Physiology, vol. 307, no. 3, pp. C221–C231, 2014.
View at: Publisher Site | Google Scholar
S. X. Cheng, Y. L. Lightfoot, T. Yang et al., “Epithelial CaSR deficiency alters intestinal integrity and promotes proinflammatory immune responses,” FEBS Letters, vol. 588, no. 22, pp. 4158–4166, 2014.
View at: Publisher Site | Google Scholar
G. N. Hendy and L. Canaff, “Calcium-sensing receptor gene: Regulation of expression,” Frontiers in Physiology, vol. 7, article no. 394, 2016.
View at: Publisher Site | Google Scholar
R. J. MacLeod, “CaSR function in the intestine: Hormone secretion, electrolyte absorption and secretion, paracrine non-canonical Wnt signaling and colonic crypt cell proliferation,” Best Practice & Research Clinical Endocrinology & Metabolism, vol. 27, no. 3, pp. 385–402, 2013.
View at: Publisher Site | Google Scholar
A. Aggarwal, J. Höbaus, S. Tennakoon et al., “Active Vitamin D potentiates the anti-neoplastic effects of calcium in the colon: A cross talk through the calcium-sensing receptor,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 155, pp. 231–238, 2016.
View at: Publisher Site | Google Scholar
C. Zhang, C. L. Miller, R. Gorkhali et al., “Molecular basis of the extracellular ligands mediated signaling by the calcium sensing receptor,” Frontiers in Physiology, vol. 7, article no. 441, 2016.
View at: Publisher Site | Google Scholar
W. Yang, L. Liu, Y. Masugi et al., “Calcium intake and risk of colorectal cancer according to expression status of calcium-sensing receptor (CASR),” Gut, 2017.
View at: Publisher Site | Google Scholar
J. L. Owen, S. X. Cheng, Y. Ge, B. Sahay, and M. Mohamadzadeh, “The role of the calcium-sensing receptor in gastrointestinal inflammation,” Seminars in Cell & Developmental Biology, vol. 49, pp. 44–51, 2016.
View at: Publisher Site | Google Scholar
Y. Geng, L. Mosyak, I. Kurinov et al., “Structural mechanism of ligand activation in human calcium-sensing receptor,” eLife, vol. 5, Article ID e13662, 2016.
View at: Publisher Site | Google Scholar
S. X. Cheng, “Calcium-sensing receptor: A new target for therapy of diarrhea,” World Journal of Gastroenterology, vol. 22, no. 9, pp. 2711–2724, 2016.
View at: Publisher Site | Google Scholar
L. Tang, C. Y. Cheng, X. Sun, A. J. Pedicone, M. Mohamadzadeh, and S. X. Cheng, “The extracellular calcium-sensing receptor in the intestine: Evidence for regulation of colonic absorption, secretion, motility, and immunity,” Frontiers in Physiology, vol. 7, no. 245, 2016.
View at: Google Scholar
C. Bailey, C. Ruaux, B. V. Stang, and B. A. Valentine, “Expression of serotonin, chromogranin-A, serotonin receptor-2B, tryptophan hydroxylase-1, and serotonin reuptake transporter in the intestine of dogs with chronic enteropathy,” Journal of Veterinary Diagnostic Investigation, vol. 28, no. 3, pp. 271–278, 2016.
View at: Publisher Site | Google Scholar
P. Saetre, P. Lundmark, A. Wang et al., “The Tryptophan Hydroxylase 1 (TPH1) gene, schizophrenia susceptibility, and suicidal behavior: A multi-centre case-control study and meta-analysis,” American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, vol. 153, no. 2, pp. 387–396, 2010.
View at: Publisher Site | Google Scholar
B. I. Gustafsson, L. Thommesen, A. K. Stunes, K. Tommeras et al., “Serotonin and fluoxetine modulate bone cell function in vitro,” Journal of Cellular Biochemistry, vol. 98, no. 1, pp. 139–151, 2006.
View at: Publisher Site | Google Scholar
M. El-Salhy, D. Gundersen, J. G. Hatlebakk, O. H. Gilja, and T. Hausken, “Abnormal rectal endocrine cells in patients with irritable bowel syndrome,” Regulatory Peptides, vol. 188, pp. 60–65, 2014.
View at: Publisher Site | Google Scholar
A. Motavallian-Naeini, M. Minaiyan, M. Rabbani, and P. Mahzuni, “Anti-inflammatory effect of ondansetron through 5-HT 3 receptors on TNBS-induced colitis in rat,” EXCLI Journal, vol. 11, pp. 30–44, 2012.
View at: Google Scholar
T.-E. Reid, K. Kumar, and X. S. Wang, “Predictive in silico studies of human 5-hydroxytryptamine receptor subtype 2B (5-HT2B) and valvular heart disease,” Current Topics in Medicinal Chemistry, vol. 13, no. 11, pp. 1353–1362, 2013.
View at: Publisher Site | Google Scholar
R. A. Borman, N. S. Tilford, D. W. Harmer et al., “5-HT2B receptors play a key role in mediating the excitatory effects of 5-HT in human colon in vitro,” British Journal of Pharmacology, vol. 135, no. 5, pp. 1144–1151, 2002.
View at: Publisher Site | Google Scholar
B. C. Zou, L. Dong, Y. Wang et al., “Expression and role of 5-HT7 receptor in brain and intestine in rats with irritable bowel syndrome,” Chinese Medical Journal, vol. 120, no. 23, pp. 2069–2074, 2007.
View at: Google Scholar
J. M. Lanis, E. E. Alexeev, V. F. Curtis et al., “Tryptophan metabolite activation of the aryl hydrocarbon receptor regulates IL-10 receptor expression on intestinal epithelia,” Mucosal Immunology, vol. 10, no. 5, pp. 1133–1144, 2017.
View at: Publisher Site | Google Scholar
K. R. Engelhardt and B. Grimbacher, “IL-10 in humans: lessons from the gut, IL-10/IL-10 receptor deficiencies, and IL-10 polymorphisms,” Current Topics in Microbiology and Immunology, vol. 380, pp. 1–18, 2014.
View at: Google Scholar
L. Stejskalova, Z. Dvorak, and P. Pavek, “Endogenous and exogenous ligands of aryl hydrocarbon receptor: current state of art,” Current Drug Metabolism, vol. 12, no. 2, pp. 198–212, 2011.
View at: Publisher Site | Google Scholar
A. Bessede, M. Gargaro, M. T. Pallotta et al., “Aryl hydrocarbon receptor control of a disease tolerance defence pathway,” Nature, vol. 511, no. 7508, pp. 184–190, 2014.
View at: Publisher Site | Google Scholar
I. Monteleone, A. Rizzo, M. Sarra et al., “Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract,” Gastroenterology, vol. 141, no. 1, pp. 237–248, 2011.
View at: Publisher Site | Google Scholar
B. Sovran, L. M. P. Loonen, P. Lu et al., “IL-22-STAT3 pathway plays a key role in the maintenance of ileal homeostasis in mice lacking secreted mucus barrier,” Inflammatory Bowel Diseases, vol. 21, no. 3, pp. 531–542, 2015.
View at: Publisher Site | Google Scholar
W. Ren, G. Liu, S. Chen et al., l -Arginine and Inflammatory Bowel Diseases (IBD), Springer International Publishing, 2017.
J. R. Matthews, C. H. Botting, M. Panico, H. R. Morris, and R. T. Hay, “Inhibition of NF-κB DNA binding by nitric oxide,” Nucleic Acids Research, vol. 24, no. 12, pp. 2236–2242, 1996.
View at: Publisher Site | Google Scholar
R. Marion, M. Coëffier, S. Lemoulan, G. Gargala, P. Ducrotté, and P. Déchelotte, “L-Arginine modulates CXC chemokines in the human intestinal epithelial cell line HCT-8 by the NO pathway,” Biochimie, vol. 87, no. 12, pp. 1048–1055, 2005.
View at: Publisher Site | Google Scholar
W. Ren, S. Chen, J. Yin et al., “Dietary arginine supplementation of mice alters the microbial population and activates intestinal innate immunity,” Journal of Nutrition, vol. 144, no. 6, pp. 988–995, 2014.
View at: Google Scholar
Y. Yang, W. Li, Y. Sun, F. Han, C.-A. A. Hu, and Z. Wu, “Amino acid deprivation disrupts barrier function and induces protective autophagy in intestinal porcine epithelial cells,” Amino Acids, vol. 47, no. 10, pp. 2177–2184, 2015.
View at: Publisher Site | Google Scholar
K. Ganeshan and A. Chawla, “Metabolic regulation of immune responses,” Annual Review of Immunology, vol. 32, pp. 609–634, 2014.
View at: Publisher Site | Google Scholar
M. H. Kaplan, “STAT signaling in inflammation,” Jakstat, vol. 2, no. 1, p. e24198, 2014.
View at: Publisher Site | Google Scholar
K. Liboni, N. Li, and J. Neu, “Mechanism of glutamine-mediated amelioration of lipopolysaccharide-induced IL-8 production in Caco-2 cells,” Cytokine, vol. 26, no. 2, pp. 57–65, 2004.
View at: Publisher Site | Google Scholar
N. Donnelly, A. M. Gorman, S. Gupta, and A. Samali, “The eIF2α kinases: Their structures and functions,” Cellular and Molecular Life Sciences, vol. 70, no. 19, pp. 3493–3511, 2013.
View at: Publisher Site | Google Scholar
P. Bunpo, J. K. Cundiff, R. B. Reinert, R. C. Wek, C. J. Aldrich, and T. G. Anthony, “The eIF2 kinase GCN2 is essential for the murine immune system to adapt to amino acid deprivation by asparaginase,” Journal of Nutrition, vol. 140, no. 11, pp. 2020–2027, 2010.
View at: Publisher Site | Google Scholar
K. M. Mazor and M. H. Stipanuk, “GCN2- and eIF2α-phosphorylation-independent, but ATF4-dependent, induction of CARE-containing genes in methionine-deficient cells,” Amino Acids, vol. 48, no. 12, pp. 2831–2842, 2016.
View at: Publisher Site | Google Scholar
B. Ravishankara, H. Liua, R. Shindea et al., “The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 112, no. 34, pp. 10774–10779, 2015.
View at: Publisher Site | Google Scholar
Y. Khan and Z. A. Bhutta, “Nutritional deficiencies in the developing world: Current status and opportunities for intervention,” Pediatric Clinics of North America, vol. 57, no. 6, pp. 1409–1441, 2010.
View at: Publisher Site | Google Scholar
T. Hashimoto, T. Perlot, A. Rehman et al., “ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation,” Nature, vol. 487, no. 7408, pp. 477–481, 2012.
View at: Publisher Site | Google Scholar
K. Kuba, Y. Imai, and J. M. Penninger, “Multiple functions of angiotensin-converting enzyme 2 and its relevance in cardiovascular diseases,” Circulation Journal, vol. 77, no. 2, pp. 301–308, 2013.
View at: Publisher Site | Google Scholar
M. A. Khajah, M. M. Fateel, K. V. Ananthalakshmi, and Y. A. Luqmani, “Anti-inflammatory action of angiotensin 1-7 in experimental colitis,” PLoS ONE, vol. 11, no. 3, Article ID e0150861, 2016.
View at: Publisher Site | Google Scholar
T. Perlot and J. M. Penninger, “ACE2 - From the renin-angiotensin system to gut microbiota and malnutrition,” Microbes and Infection, vol. 15, no. 13, pp. 866–873, 2013.
View at: Publisher Site | Google Scholar
S. Kowalczuk, A. Bröer, N. Tietze, J. M. Vanslambrouck, J. E. J. Rasko, and S. Bröer, “A protein complex in the brush-border membrane explains a Hartnup disorder allele,” The FASEB Journal, vol. 22, no. 8, pp. 2880–2887, 2008.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2018 Fang He et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

8634

Downloads

3338

Citations