Amino Acids

, Volume 47, Issue 10, pp 2143–2154

Glutamine and intestinal barrier function

  • Bin Wang
  • Guoyao Wu
  • Zhigang Zhou
  • Zhaolai Dai
  • Yuli Sun
  • Yun Ji
  • Wei Li
  • Weiwei Wang
  • Chuang Liu
  • Feng Han
  • Zhenlong Wu
Review Article


The intestinal barrier integrity is essential for the absorption of nutrients and health in humans and animals. Dysfunction of the mucosal barrier is associated with increased gut permeability and development of multiple gastrointestinal diseases. Recent studies highlighted a critical role for glutamine, which had been traditionally considered as a nutritionally non-essential amino acid, in activating the mammalian target of rapamycin cell signaling in enterocytes. In addition, glutamine has been reported to enhance intestinal and whole-body growth, to promote enterocyte proliferation and survival, and to regulate intestinal barrier function in injury, infection, weaning stress, and other catabolic conditions. Mechanistically, these effects were mediated by maintaining the intracellular redox status and regulating expression of genes associated with various signaling pathways. Furthermore, glutamine stimulates growth of the small intestinal mucosa in young animals and also enhances ion transport by the gut in neonates and adults. Growing evidence supports the notion that glutamine is a nutritionally essential amino acid for neonates and a conditionally essential amino acid for adults. Thus, as a functional amino acid with multiple key physiological roles, glutamine holds great promise in protecting the gut from atrophy and injury under various stress conditions in mammals and other animals.


Glutamine Intestinal barrier function Nutrition 



Neutral amino acid transporter type 2


Adenosine triphosphate


Buthionine sulfoximine




Essential amino acids


Eukaryotic translation initiation factor 4E-binding protein-1


Eukaryotic translation initiation factor 4E


Forkhead box O transcription factor


GlutaminaseGALT gut-associated lymphatic tissue


Glutamate cysteine ligase


Glutamine synthetase




Glutathione synthetase


Glutathione disulfide


γ-Glutamyl transpeptidase




Inhibitor of NF-κB




Intrauterine growth restriction


Mitogen-activated protein kinases


Methionine sulfoximine


Mammalian target of rapamycin


mTOR complex


Reduced form of nicotinamide adenine dinucleotide


Reduced form of nicotinamide adenine dinucleotide phosphate


Nuclear factor-κB


Nitric oxide


NO synthase


p70 Ribosomal protein S6 kinase


Phosphatidylinositol 3-kinase


Protein kinase B


Pentose phosphate pathway


Ras homologue enriched in brain


Reactive oxygen species


Receptor tyrosine kinase


Sodium coupled neutral amino acid transporter 2


Tricarboxylic acid cycle


Tumor necrosis factor-alpha


Total parenteral nutrition


Reduced thioredoxin


Oxidized thioredoxin


Tuberous sclerosis complex


Zonula occludens protein 1


The intestinal mucosal barrier is a single layer of cells lining the gut that mainly consists of the enterocyte membranes and tight junctions between enterocytes (Arrieta et al. 2006). This intestinal epithelium acts as a selective barrier, allowing the transcellular transport of essential dietary nutrients, electrolytes, and water from the intestinal lumen into the circulation and preventing the passage of harmful or unwanted substances (including food antigens, bile, hydrolytic enzymes, endotoxin, microorganisms and their toxins) from entering the internal environment, thereby maintaining the intracellular homeostasis (Jacobi and Odle 2012; Ruth and Field 2013). Dysregulation of the intestinal barrier (also known as loss of intestinal barrier integrity) due to stress, invasion of pathogenic organisms, infection and immunological challenges has been reported to be associated with multiple diseases, such as food allergy, inflammatory bowel disease, celiac disease, irritable bowel syndrome, and type I diabetes through yet unknown mechanisms (Arrieta et al. 2006; Camilleri et al. 2012; Groschwitz and Hogan 2009). Based on this scenario, understanding the molecular mechanisms responsible for alterations and regulation of intestinal barrier function will have important implications for the treatment and prevention of intestinal diseases. The last decade has witnessed accumulating evidence on the beneficial effects of glutamine (Gln) on gut function and health in humans and other animals (Wu et al. 2013). Gln is oxidized by the Krebs cycle to produce ATP for rapid dividing cells (including enterocytes and lymphocytes) (Wu et al. 1995; Wu 1996). Of note, Gln activates the mTOR signaling and increases protein synthesis in enterocytes (Xi et al. 2012), promotes intestinal development, regulates tight junction protein expression and intestinal immunity, inhibits apoptosis induced by oxidative stress or other stimuli (Wu et al. 2013), which are required for gastrointestinal homeostasis (Fig. 1). Also, Gln serves as a major shuttle for the inter-organ transport of both carbon and nitrogen in animals (Curi et al. 2005) and serves as an important precursor for the synthesis of other biological active molecules, such as glutathione (the major non-enzymatic cellular antioxidant), glutamate, proline, arginine and nucleotide synthesis (Wu et al. 2011) (Fig. 1). The main objective of this review is to highlight recent advances in the understanding of the role of Gln in intestinal barrier function and health. For the synthesis, absorption, transportation, and metabolism of Gln in intestinal cells, readers are referred to the comprehensive reviews (Wu et al. 2011; Xi et al. 2011).
Fig. 1

Glutamine plays important roles in intestinal epithelial cells (see text for detail). AKT protein kinase B, ASCT2 neutral amino acid transporter type 2, ATP adenosine triphosphate, mTOR mammalian target of rapamycin, NADH reduced nicotinamide adenine dinucleotide, NADPH reduced form of nicotinamide adenine dinucleotide phosphate, PI3K phosphoinositide 3 kinase, SNAT2 sodium coupled neutral amino acid transporter 2, ZO-1 zonula occludens protein 1

Gln and intestinal development

Both enterocytes and intestinal luminal bacteria degrade Gln (Dai et al. 2010, 2012; Wu and Knabe 1994). Approximately 70 % of Gln in the enteral diet is catabolized by the absorptive cells of the small intestine during the first pass (Wu 1998). However, Gln is abundant in plasma, skeletal muscle, fetal fluid and milk, due to endogenous synthesis from branched-chain amino acids and glucose (Wu et al. 2011). The concentration of free Gln in porcine milk markedly increases from <0.1 mM at day 1 of lactation to 4 mM on day 29 of lactation, becoming the most abundant amino acid in sow’s milk (Wu and Knabe 1994). The predominance of Gln in sow’s milk is consistent with the notion that Gln plays a vital role in the growth and development of the neonatal gastrointestinal tract (Sheard and Walker 1988). In addition, dietary Gln supplementation to early-weaned piglets prevents jejunal atrophy during the first week postweaning (Wu et al. 1996). Moreover, oral administration of Gln (0.5 g/kg of body weight, twice daily) to 7- to 21-day-old suckling piglets enhances intestinal and whole-body growth (Haynes et al. 2009). Thus, milk-borne Gln is insufficient for maximal growth of the neonate. Likewise, supplementing Gln to Gln-free total parenteral nutrition (TPN) solution prevents intestinal atrophy in humans and rats under catabolic conditions (Buchman et al. 1995; Schroder et al. 1995). Similarly, dietary supplementation with Gln or glycyl-Gln dipeptide improves growth performance, small intestinal morphology and immunity response in endotoxin-challenged weaning piglets (Jiang et al. 2009; Yi et al. 2005).

Neonates with intrauterine growth restriction (IUGR) have higher perinatal mortality and morbidity in both humans and animals, including pigs (D’Inca et al. 2011; Rezaei et al. 2011, 2013b). IUGR neonates are characterized by reduced concentrations of Gln in plasma and a relatively thin intestine in both preterm and term neonates of many species (D’Inca et al. 2011; Wu et al. 2011). Alterations in intestinal development impair nutrient absorption and utilization and contribute to IUGR-related high morbidity and mortality (D’Inca et al. 2010, 2011; Wang et al. 2008). Interestingly, oral administration of Gln (1.0 g/kg of body weight per day) between day 0 and day 21 of age enhances the growth of IUGR piglets and reduces post-weaning mortality (Wu et al. 2011). Similar observations have been reported in low-birth-weight infants (Neu et al. 1999), suggesting Gln provision as an effective nutritional strategy to enhance intestinal development in IUGR neonates. All these results indicate a beneficial effect of Gln on postnatal intestinal growth and development.

Gln and intestinal cell proliferation

The epithelium of the mammalian intestine undergoes rapid renewing and turnover every 3–5 days (Camilleri et al. 2012). This process is fulfilled by the fine-tune balance between cell proliferation and loss, thus constituting a homeostasis which is required for the physiological function of the intestinal mucosal barrier (Bach et al. 2000). The underlying regulatory mechanisms may involve multiple signaling and growth factors. It is generally accepted that intestinal stem cells located near the base of the crypts divide rapidly and migrate along the crypt/villus axis and differentiate into absorptive enterocytes, enteroendocrine cells, mucous-secreting goblet cells, tuft cells, and Paneth cells (Barker et al. 2008; Shaker and Rubin 2010).

Gln enhances intestinal cell proliferation through a number of mechanisms. First, oxidation of Gln provides ATP to support intestinal ion transport, cell growth and migration and to maintain intestinal integrity (Curi et al. 2005). Second, Gln is a precursor for the synthesis of purine and pyrimidine nucleotides, which are essential for DNA synthesis and the proliferation of cells (Wu 1998). Third, Gln is a major substrate used to produce glutathione, an antioxidant in cellular environment (Reeds et al. 1997). Fourth, Gln up-regulates the expression of ornithine decarboxylase, a key enzyme for converting ornithine into polyamines, which are required for DNA and protein synthesis (Wu 2013). Fifth, Gln stimulates expression of heat shock proteins (Marc Rhoads and Wu 2009) to promote cell survival. Sixth, Gln regulates cellular signaling pathways for cell proliferation. For example, addition of physiological levels of Gln (0.5 and 2 mM) increases protein synthesis and inhibits protein degradation in enterocytes, resulting in enhanced cell proliferation (Xi et al. 2012). Similarly, Gln has been reported to stimulate protein synthesis in the small intestinal mucosa of humans and rats (Deniel et al. 2007; Rhoads et al. 1997; Ziegler 1994). Finally, Gln enhances expression of genes for mitogen-activated protein kinases, including both ERK1/2 and JNK, resulting in activation of AP1-dependent gene transcription, thereby contributing to cell proliferation (Rhoads et al. 1997).

Growing evidence shows interactions between Gln and growth factors in intestinal cells. Of note, several growth factors, such as epidermal growth factor (EGF), transforming growth factor, and insulin-like growth factor 1 (IGF-1), may regulate proliferation and differentiation in various cell types, including enterocytes (Booth et al. 1995). It is known that the intestinal epithelium contains receptors for IGFs, including IGF-1 (Rhoads et al. 1997). Gln supplementation may increase protein abundances of these growth factors by modulating rates of protein turnover, and consequently promotes cell proliferation by activating downstream signaling cascades. It has also been reported that EGF up-regulates the activity of Gln transporter B0/ASCT2 and system B0,+ and ASCT2 expression in a multiple kinases (MAPK, PI3K, Rho)-dependent manner in human enterocytes (Avissar et al. 2008), indicating a feedback loop between growth factors and Gln-induced cell signaling. These signaling pathways contribute to Gln-mediated enhancement of intestinal cell proliferation (Rhoads 1999).

Gln and tight junction

Intestinal epithelial cells are tightly bound together by intercellular junctional complexes (Fig. 1) that regulate the paracellular permeability and are crucial for the integrity of the epithelial barrier (de Santa Barbara et al. 2003). To date, four types of junctional complexes have been identified, including tight junctions, adherens junctions, gap junctions, and desmosomes. Tight junctions are the most apical structure of the apical complex demarcating the border between apical and basolateral membrane domains, selectively regulate the passage of molecules and ions via the paracellular pathway, and also restrict the lateral movement of molecules across the cell membrane (Prasad et al. 2005). Adherens junctions are located beneath the tight junctions and are involved in cell–cell adhesion and intracellular signaling (Farhadi et al. 2003; Matter and Balda 2003). Desmosomes and gap junctions contribute to cell–cell adhesion and intracellular communication, respectively. Among the junctional complexes, tight junctions are extensively studied due to its critical role in regulating barrier function and preventing relocation of toxins and pathogens from the gut lumen into mucosal tissue and circulation (Chen et al. 2014; Zhang et al. 2013).

Three types of structural transmembrane components that are enriched at tight junctions include the IgG-like family of junctional adhesion molecules, the claudin, and occludin families of transmembrane proteins (Furuse and Tsukita 2006; Schneeberger and Lynch 2004). Regulation of the assembly, disassembly, and maintenance of tight junction structure are influenced by various physiological and pathological stimuli that activate several kinases, including protein kinase C, mitogen-activated protein kinases (MAPK), myosin light chain kinase, and the Rho family of small GTPases (Ulluwishewa et al. 2011). In general, the activation of protein kinase phosphorylates tight junction protein, leading to alterations of barrier integrity and permeability. It should be noted that the results from different research groups are not always consistent and need further clarification (Findley and Koval 2009). Although the beneficial effect of Gln on intestinal health was documented in the 1990s (Deniel et al. 2007), the regulation of tight junction protein by Gln was reported only in recent years. Gln deprivation or inhibition of Gln synthetase led to significant decreases in transepithelial resistance, an increased permeability, as well as reduced tight junction proteins, claudin-1 and occludin in Caco-2 cells, a classic human cell line model for gut barrier function (DeMarco et al. 2003; Li et al. 2004). Importantly, the dysfunction of gut barrier function can be rescued by Gln addition (DeMarco et al. 2003). Mechanistically, Gln deprivation up-regulates the PI3K/AKT pathway, which, in turn, reduces the abundance of tight junction protein claudin-1, resulting in barrier function breakdown (Li and Neu 2009). It is unknown whether rates of claudin-1 synthesis, degradation, or both processes are affected in the gut. These observations suggest that Gln can directly or indirectly function as regulator of signal pathways associated with gut function. In addition, the protective effect of Gln on tight junction protein is also observed under stress response. For example, it has been reported that Gln prevented the acetaldehyde (a carcinogenic metabolite of ethanol)-induced increase in permeability to endotoxin by ameliorating the disruption of tight junction, adherence junction, and redistributing the tight junction proteins, ZO-1, occludin, E-cadherin, and β-catenin from the intracellular junction complex in Caco-2 cell monolayer (Basuroy et al. 2005; Seth et al. 2004), indicating a therapeutic potential of Gln on carcinoma progression. It should be noted that several lines of studies indicated that endogenous Gln synthesis by Gln synthetase is critical for the beneficial effect on protein expression of tight junction in human Caco-2 monolayer (DeMarco et al. 2003; Li and Neu 2009). However, in our recent study, we found that deprivation of Gln decreased monolayer transepithelial resistance which can be reversed by the provision of Gln to the culture medium in the absence of the Gln synthetase inhibitor in intestinal porcine epithelial cells. This suggests that the amount of endogenous Gln synthesized by Gln synthetase is much less than that of the Caco-2 cells used in the previous study (DeMarco et al. 2003; Li and Neu 2009). Indeed, Gln synthetase activity is negligible in enterocytes of neonatal pigs (Haynes et al. 2009) and lactating sows (Li et al. 2009). Another reason for this discrepancy might be due to metabolic, genetic, or epigenetic differences between cancer cells and normal intestinal epithelial cells (Meadows et al. 2008). In a recent study, Noth and his colleague demonstrated that oral Gln supplementation ameliorated intestinal permeability dysfunction as shown by increased occludin expression, reduced gastrointestinal permeability and reduced apoptotic cells in the crypt (Noth et al. 2013). All these in vivo and in vitro data suggest an important role for tight junction in the maintenance of gut function. Regulation of tight junction proteins by Gln is responsible, at least partially, for the beneficial effect of Gln on gut barrier function in humans and animals.

Gln and stress response

It has become increasingly clear that environmental factors, including stress and diets, play a crucial role in gastrointestinal health and defense against important intestinal disorders in both humans and animals (Arrieta et al. 2006; Wijtten et al. 2011). Several lines of evidence from epidemiological and basic animal research studies showed an important role of stress in disruption of intestinal barrier function, as well as the development and clinical onset of many gastrointestinal disorders (Smith et al. 2010; Wijtten et al. 2011). The inverse correlation between plasma concentration of Gln and intestinal barrier function upon weaning stress (Wang et al. 2008) or endotoxin challenge (Haynes et al. 2009) suggests a beneficial effect of Gln on improving intestinal mucosal integrity. Moreover, stresses occurring early life can have a long-lasting effect on gastrointestinal health in adult life (Gareau et al. 2007; Moeser et al. 2007; Soderholm et al. 2002). For example, the process of weaning is one of the most stressful events in the life of pigs, which contributes to intestinal and immune system dysfunction (Campbell et al. 2013; Wijtten et al. 2011). Early-weaned pigs commonly experience diarrhea, reduced food intake during the first 7–14 day postweaning, and impaired mucosal barrier function, as indicated by reductions in jejunal transepithelial electrical resistance and elevations in paracellular permeability (Campbell et al. 2013). The intestinal dysfunction is associated with increased concentrations of corticotrophin-releasing factor and adrenal cortisol (the major glucocorticoid in swine) in plasma (Smith et al. 2010), as well as abnormal activation of mast cells in the intestinal mucosa (Crowe and Perdue 1992). Appropriate activation of mast cell contributes to innate and acquired immunity and is important for host defense, by releasing such mediators as histamine, cytokines, proteoglycans, and proteases (Ramsay et al. 2010). However, over-activation of mast cells and related bioactive mediators exerts a profound influence on intestinal function, including increased intestinal permeability and visceral hypersensitivity (Ramsay et al. 2010). Further studies have identified mast cell-derived proteases Mcpt4 as a critical factor that regulate intestinal epithelial migration and barrier function (Groschwitz et al. 2009). Gln supplementation reduces the production of cortisol and ameliorates mucosal barrier dysfunction in weaning pigs (Wu et al. 2011). Moreover, cells have evolved a cellular mechanism of “self-eating” process (hereafter referred to as autophagy) for surviving under nutrient shortage in extracellular environment. Under normal conditions, autophagy allows cells to break down long-lived proteins for homeostasis. Autophagy is rapidly up-regulated and functions as a pro-survival process in response to different forms of stresses such as nutrient starvation, growth factor depletion, and endoplasmic reticulum (ER) stress (Kourtis and Tavernarakis 2009). Autophagy is negatively regulated by mTOR, a central regulator of cell growth and survival in responses to extracellular amino acids and growth factors. In an amino acid-rich environment, mTOR is active and regulates protein translation but also inhibits autophagy (Fig. 2). When extracellular amino acids are limited, autophagy recycles intracellular constituents to provide an alternative source of amino acids (Nicklin et al. 2009). Considering that amino acid is an activator of mTOR signaling, it is plausible that intracellular Gln status might be potential regulator of autophagy. Consistent with the hypothesis, it has been reported that Gln can inhibit the mTOR and p38 MAP kinase pathways under basal and stressed conditions, thus inducing autophagy which can contribute to cell survival during physiologic stress in intestinal epithelial cells (Sakiyama et al. 2009). Importantly, Kristan and colleagues recently demonstrated that transcription factor FOXOs can induce autophagy by trans-activation of Gln synthetase activity under conditions of growth factor deprivation (Sandri 2012; van der Vos et al. 2012). The FOXO family (FOXO1, 3, 4 and 6) is downstream of the insulin pathway and is negatively regulated by PI3K/AKT signaling. In the absence of growth factors, PI3K/AKT is inactived and FOXOs translocate into the nucleus and turn on the expression of Gln synthetase, a rate-limiting enzyme for Gln synthesis, thus leads to an increased level of Gln production (Sandri 2012; van der Vos et al. 2012). Interestingly, the FOXO-induced expression of Gln synthetase results in autophagy due to the inhibition of mTORC1 activity as evidenced by the lack of phosphorylation of the S6K1 kinase, and re-localization of mTOR from the lysosomes to the cytoplasm. These findings provide an intriguing link between FOXO transcription factors and autophagy, in which Gln production is a key mediator between these two processes (Sandri 2012). The autophagic effect induced by Gln is a critical survival mechanism for cells in response to growth factors or nutrition deprivation; thereby enhancing stress resistance.
Fig. 2

Proposed signaling pathway of glutamine-mediated cell growth and autophagy by mTOR pathway (see text for details). α-KG α-ketoglutarate, ASCT2 neutral amino acid transporter type 2, SNAT2 sodium coupled neutral amino acid transporter 2, EAA essential amino acids, 4EBP1 eukaryotic translation initiation factor 4E-binding protein-1, eIF4E eukaryotic translation initiation factor 4E, FOXO forkhead box O transcription factor, GS glutamine synthetase, IGFs insulin-like growth factors, mTORC1 mammalian target of rapamycin complex 1, mTORC2 mammalian target of rapamycin complex 2, p70S6K p70 ribosomal protein S6 kinase, PKB protein kinase B, PI3K phosphoinositide 3 kinase, Rheb Ras homologue enriched in brain, RTK receptor tyrosine kinase, TSC tuberous sclerosis comple

Preventive effects of Gln against apoptosis

The main function of the intestinal epithelial barrier is to separate the hostile external environment from the internal milieu. As the first line defensive system, the intestinal epithelial is exposed to various pathogens (commensal bacteria or pathogenic bacteria), toxin, damaged cells, and nutrient metabolites. The physical and chemical barriers created by the intestinal epithelium protect the intestinal mucosa from attack by potentially harmful enteric microorganisms (Ren et al. 2013a, b). To function properly, the epithelium has evolved to possess a relatively short life of 3–5 days. This rapid turnover of the enterocytes is maintained by the well-controlled balance between cell proliferation and apoptosis (Bach et al. 2000; Mates et al. 2006; Rhoads et al. 1997). Breakdown of this balance will lead to dysfunction of intestinal barrier which is associated with the development of diseases or an inflammatory response (Radtke and Clevers 2005). Various stresses, such as nutrient and growth factor deprivation, pathogenic bacteria toxins (e.g., endotoxin), and inflammatory cytokines, have been reported to induce apoptosis in intestinal epithelial cells, thus resulting in abnormal structure and function of the gut (Mates et al. 2006). It has been reported that Gln starvation-induced apoptosis is caspase 3-dependent, which can be prevented by Gln supplementation in small intestinal epithelial cells in which the activation of MAP kinase ERK and PI3K/AKT signaling plays an important role in limiting apoptosis (Larson et al. 2007; Papaconstantinou et al. 1998). In addition to intestinal cells, the apoptotic effect induced by Gln deprivation was observed in other cell types, including both normal and cancerous cells through mitochondrial or death receptor-mediated apoptotic pathway (Mates et al. 2006). The anti-apoptotic effect of Gln is also found in cytokine-treated cells. For example, Gln protects against apoptosis induced by the TNF-α related apoptosis inducing ligand (known as TRAIL) through a mechanism involving the pyrimidine pathway in human intestinal cells (Evans et al. 2003, 2005). Gln or alanyl-Gln also prevents Clostridium difficile toxin A-induced caspase 8 activation, and thus attenuates apoptosis in human intestinal epithelial T84 cells (Carneiro et al. 2006). Also, Gln significantly suppressed the release of cytochrome c from mitochondria [an indicator of apoptosis (Yang et al. 2013)] and diminished activities of caspases induced by sodium laurate, thus protected cell from undergoing apoptosis (Takayama et al. 2009). Comparative functional proteomics demonstrated that Gln significantly influences the protein expression profile in response to the mouse agonistic Fas antibody treatment in human epithelial HCT-8 cells (Deniel et al. 2007). Of the proteins, they noted that pro-apoptotic proteins, such as caspase 3 was down-regulated, whereas the cell death regulator Aven, a novel anti-apoptotic member, was up-regulated, suggesting the existence of other regulators that contribute to the anti-apoptotic effect of Gln (Deniel et al. 2007). In addition to the inactivation of caspase involved in apoptosis cascade, regulation of redox status can also contribute to anti-apoptosis. The cellular reducing environment is provided by two mutually interconnected systems; the TRX system and the glutathione (GSH) system (Fig. 3). Under physiological conditions, the intracellular reducing environment is maintained by the disulfide/dithiol-reducing activity of the GSH and TRX systems which is required for cellular homeostasis and cell survival (Circu and Aw 2011; Franco and Cidlowski 2009). Studies have shown a correlation between GSH depletion and the induction of apoptosis triggered by stimuli that activate the mitochondrial or death receptor-mediated apoptosis in various cell types (Franco and Cidlowski 2009; Kern and Kehrer 2005). Consistently, Gln has been reported to be responsible for the anti-apoptotic effect in epithelial cells due to its implication in the production of intracellular GSH, one of the potent antioxidants that contribute to the elimination of intracellular reactive oxygen species (ROS) and maintenance of redox status (Circu and Aw 2011, 2012). Thirdly, Gln treatment can induce heat shock protein 72 at transcriptional levels, thus contributing to the anti-apoptotic effect and reduced cellular damage (Musch et al. 1998; Ropeleski et al. 2005; Wischmeyer 2002). We recently found that addition of 0.5 mM H2O2 to culture media induced apoptosis in porcine intestinal epithelial cells and an increase in permeability, which could be attenuated by Gln supplementation (Data not shown).The anti-apoptotic effect of Gln on oxidative damage might involve several signaling pathways, such as reduced expression of Toll-like receptor and caspase 3 in neonatal pig enterocytes (Haynes et al. 2009), attenuated synthesis of NO by inducible NOS (Wu et al. 2011), enhanced abundance of anti-oxidative proteins including glutathione S-transferase (Mates et al. 2002; Wang et al. 2008), and increased expression of heme oxygenase-1 (Coeffier et al. 2002). In a recent study, Gln supplementation via rectal route has been reported to reduce endoplasmic reticulum stress markers such as, CHOP, BIP, ATF6, and apoptotic markers, including cytochrome c release, caspase activation, further expanding our understanding of the anti-apoptotic function of Gln in response to stresses (Crespo et al. 2012). It should be noted that most of the cell lines used on the anti-apoptotic effect of Gln are transformed or carcinoma cells with multiple genetic or epigenetic alterations which are associated with high rates of cell proliferation and apoptosis resistance. Cautions should be taken in interpreting these results from in vitro studies (Mates et al. 2006).
Fig. 3

Glutamine and intracellular redox homeostasis (see text for details). α-KG α-ketoglutarate, acivicin an irreversible inhibitor of γ-glutamyl transpeptidase, BSO buthionine sulfoximine, an inhibitor of glutamate cysteine ligase, DP dipeptidase, GSH glutathione, GSSG glutathione disulfide, γ-GT γ-glutamyl transpeptidase, NO nitric oxide, NOS NO synthase, GA glutaminase, GCL glutamate cysteine ligase, GS glutamine synthetase, GSS glutathione synthetase, MS methionine sulfoximine, PPP pentose phosphate pathway, TCA tricarboxylic acid cycle, Trx reduced thioredoxin, TrxSS oxidized thioredoxin

Gln, bacterial translocation and intestinal immunity

In addition to its role in digestion and absorption of nutrients, the small intestine is also viewed as the largest immune organ in the body to protect the internal milieu from potentially hostile pathogens which is required for the maintenance of normal intestinal epithelial barrier function (Menard et al. 2010; Veldhoen and Brucklacher-Waldert 2012). The normal intestinal barrier to bacteria invasion mainly depends on specific IgA antibody secreted from the gut-associated lymphatic tissue (GALT) with which several types of specialized cells, such as macrophages, natural killer cells, mast cells, and intraepithelial lymphocytes, are involved (Ruth and Field 2013). Under physiological conditions, IgA is secreted into the intestinal tract and has an ability to prevent the adherence of bacteria to the mucosal cell, which is the initiating and prerequisite step for colonization and invasion of bacteria to the deeper layers of the intestine (Artis 2008; Jacobi and Odle 2012). Abnormal regulation of secretory lgA (s-IgA) production due to pathologic invasion, stress exposure, or perturbation of the components of GALT, will impair the mucosal immune system, while leading to bacterial translocation and defective barrier integrity (Alverdy et al. 1988; Mestecky et al. 1986). The beneficial effect of Gln addition on mucosal during provision of standard total parenteral nutrition (Grant and Snyder 1988) promoted Burke and colleagues to elucidate immune function of Gln on the gastrointestine (Burke et al. 1989). These authors reported that addition of Gln to TPN reversed the decrease of s-IgA production, bacterial adherence to the intestinal mucosa, and bacterial translocation, suggesting a critical role of Gln in gut immune function (Alverdy 1990; Li et al. 2007). Experimental studies support the role of intestinal s-IgA as a significant component of the intestinal barrier function and that impaired production of s-IgA is associated with increased adherence of bacteria to the intestinal mucosa and breakdown of barrier function (Spitz et al. 1995). To demonstrate the role for Gln in bacterial translocation, rats exposed to a single dose of abdominal radiation were supplemented with Gln or isonitrogenous control in their drinking water for 4 days. The results indicated that provision of Gln blunts mucosal injury and the incidence of bacterial translocation (Souba et al. 1990). It has also been demonstrated that administration of Gln improves gut barrier function and reduces bacterial translocation in both in vivo (Chen et al. 1994; Souba et al. 1990) and in vitro (Scheppach et al. 1996) models of gut disorder. Furthermore, Gln deprivation facilitates TNF-α-induced bacterial translocation in Caco-2 cells, and the sensitization of TNF-α-induced bacterial translocation was blocked by an inhibition of the conversion of Gln to α-ketoglutarate (α-KG), a key step in oxidative metabolism of Gln (Clark et al. 2003). α-KG can activate mTOR and stimulate protein synthesis in enterocytes (Yao et al. 2012), thereby improving intestinal function (Hou et al. 2011). ATP depletion following Gln deprivation may be responsible, in part, for the sensitization effect of Gln on bacterial translocation (Clark et al. 2003). This view is supported by the observation showing that Gln is the major fuel energy for fast-dividing cells, including intestinal epithelial cell and lymphoma cells (Mates et al. 2006; Wu 1998).

Growing evidence shows that Gln inhibits intestinal expression and activation of nuclear factor-κB (NF-κB) (Haynes et al. 2009; Mondello et al. 2010) which is a pleiotropic transcription factor present in almost all cell types (Pasparakis 2012). NF-κB has been recognized as a critical regulator of immune responses and implications in the pathogenesis of diverse inflammatory diseases (Pasparakis 2009). While early studies mainly focused on the role of NF-κB in the development and function of immune cells, accumulating experimental evidence indicates that NF-κB signaling in epithelial cells is important for the maintenance of immune homeostasis in barrier tissues such as the skin and the intestine (Pasparakis 2012). Under normal conditions, NF-κB is located in the cytosol and complexed with the inhibitory protein IκB-α, and thus exists in an inactive state. Extracellular signals, such as cell stress and inflammatory signal, can activate the enzyme IκB kinase (IKK). IKK, in turn, phosphorylates the IκBα protein, which results in ubiquitination, dissociation of IκB-α from NF-κB, and eventual degradation of IκB-α by the proteasome. The activated NF-κB is then translocated into the nucleus where it binds to the promoter region of specific genes and results in their functional change (Li and Verma 2002). It becomes clear that the immune homeostasis of intestine depends on the interactions of the bacteria with the mucosal immune system. Activation of NF-κB has been observed in stress-induced or bacteria-induced disruption of barrier integrity (Banan et al. 2007; Han et al. 2009), suggesting that NF-κB signaling might contribute to disease pathogenesis. Pharmacological inhibition of NF-κB had protective effects in gut disease, including colitis, supporting a pathogenic role for NF-κB in intestinal inflammation. Commensal bacteria are believed to activate NF-κB in epithelial cells by stimulating pattern recognition receptors including Toll-like receptors and NOD-like receptors, which are expressed to allow sensing of commensal bacteria in intestinal epithelial cells (Abreu 2010). In additional to the classic activation of NF-κB signaling, including IκB degradation and direct modifications on NF-κB protein (Li and Verma 2002), the activity of NF-κB can also be regulated by Gln under stress condition or critical illness. Experimental in vitro studies show that Gln deprivation modulates endotoxin-induced IL-8 production via decreasing IκB protein in both human fetal and adult enterocytes, with the immature intestine showing the greatest response (Liboni et al. 2005). A recent study also demonstrated that, in addition to modulating IKK activity, Gln can induce nuclear degradation of the NF-κB p65 subunit via the ubiquitin–proteasome pathway, thus diminishing inflammatory response (Lesueur et al. 2012). These results clearly indicate a repressing effect of Gln on intestinal inflammation, which might be another mechanism responsible for its beneficial effect on barrier function as observed from the in vivo studies (Wu et al. 1996).

Conclusion and perspectives

Gln is a truly functional amino acid in nutrition (Wu et al. 2013). Dietary Gln has been shown to be important for maintenance of the intestinal mucosal barrier by regulating expression of genes and proteins involved in cell proliferation, differentiation and apoptosis, protein turnover, anti-oxidative property, and immunity responses. The critical dependence of gut function on the provision of dietary Gln is observed under physiological and stress conditions, such as weaning, lactation, gestation, and various gastrointestinal disorders (Wu 2014). This beneficial effect of Gln continues to stimulate research on basic and clinical studies involving animal models and humans. Compelling evidence showed that Gln is a nutritionally essential amino acid for neonates and a conditionally essential nutrient for adults (Rezaei et al. 2013a; Wu et al. 2014). Despite much progress in this research area, the underlying mechanisms for the actions of Gln remain largely unknown and should be addressed in future studies involving in vitro and in vivo experiments. It should be borne in mind that in vitro studies can provide useful information about the biochemistry, nutrition and physiology of Gln, but cannot fully mimic conditions in intact animals which require coordination of multiple systems for maintenance of homeostasis. For example, Gln regulates metabolism of intestinal bacteria (Dai et al. 2013), which is expected to have profound impacts on the health of the gut and the whole body. Cautions should be taken to interpret and extrapolate in vitro data to in vivo models, particularly with regard to concentrations of Gln and other amino acids in cell culture medium. Integration of results from all studies is necessary to better understand how Gln functions in animals and humans and how to develop new means to improve Gln nutrition in the organisms.



This work was supported by National Key Basic Research Program (2013CB127302), the Natural Science Foundation of China (31172217, 31272450, 31301979, and 31272451), the Chinese Universities Scientific Fund (2013RC002), the Program for New Century Excellent Talents in University (NCET-12-0522), and the Program for Beijing Municipal Excellent Talents, and Texas A&M AgriLife Research (H-8200).

Conflict of interest

The authors declare no conflicts of interest.


  1. Abreu MT (2010) Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol 10:131–144PubMedCrossRefGoogle Scholar
  2. Alverdy JC (1990) Effects of glutamine-supplemented diets on immunology of the gut. JPEN J Parenter Enteral Nutr 14:109S–113SPubMedCrossRefGoogle Scholar
  3. Alverdy JC, Aoys E, Moss GS (1988) Total parenteral nutrition promotes bacterial translocation from the gut. Surgery 104:185–190PubMedGoogle Scholar
  4. Arrieta MC, Bistritz L, Meddings JB (2006) Alterations in intestinal permeability. Gut 55:1512–1520PubMedGoogle Scholar
  5. Artis D (2008) Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat Rev Immunol 8:411–420PubMedCrossRefGoogle Scholar
  6. Avissar NE, Sax HC, Toia L (2008) In human entrocytes, GLN transport and ASCT2 surface expression induced by short-term EGF are MAPK, PI3 K, and Rho-dependent. Dig Dis Sci 53:2113–2125PubMedCrossRefGoogle Scholar
  7. Bach SP, Renehan AG, Potten CS (2000) Stem cells: the intestinal stem cell as a paradigm. Carcinogenesis 21:469–476PubMedCrossRefGoogle Scholar
  8. Banan A, Keshavarzian A, Zhang L, Shaikh M, Forsyth CB, Tang Y et al (2007) NF-kappaB activation as a key mechanism in ethanol-induced disruption of the F-actin cytoskeleton and monolayer barrier integrity in intestinal epithelium. Alcohol 41:447–460PubMedCrossRefGoogle Scholar
  9. Barker N, van de Wetering M, Clevers H (2008) The intestinal stem cell. Genes Dev 22:1856–1864PubMedCentralPubMedCrossRefGoogle Scholar
  10. Basuroy S, Sheth P, Mansbach CM, Rao RK (2005) Acetaldehyde disrupts tight junctions and adherens junctions in human colonic mucosa: protection by EGF and l-glutamine. Am J Physiol Gastrointest Liver Physiol 289:G367–G375PubMedCrossRefGoogle Scholar
  11. Booth C, Evans GS, Potten CS (1995) Growth factor regulation of proliferation in primary cultures of small intestinal epithelium. In Vitro Cell Dev Biol Anim 31:234–243PubMedCrossRefGoogle Scholar
  12. Buchman AL, Moukarzel AA, Bhuta S, Belle M, Ament ME, Eckhert CD et al (1995) Parenteral nutrition is associated with intestinal morphologic and functional changes in humans. JPEN J Parenter Enteral Nutr 19:453–460PubMedCrossRefGoogle Scholar
  13. Burke DJ, Alverdy JC, Aoys E, Moss GS (1989) Glutamine-supplemented total parenteral nutrition improves gut immune function. Arch Surg 124:1396–1399PubMedCrossRefGoogle Scholar
  14. Camilleri M, Madsen K, Spiller R, Greenwood-Van Meerveld B, Verne GN (2012) Intestinal barrier function in health and gastrointestinal disease. Neurogastroenterol Motil 24:503–512PubMedCrossRefGoogle Scholar
  15. Campbell JM, Crenshaw JD, Polo J (2013) The biological stress of early weaned piglets. J Anim Sci Biotechnol 4:19PubMedCentralPubMedCrossRefGoogle Scholar
  16. Carneiro BA, Fujii J, Brito GA, Alcantara C, Oria RB, Lima AA et al (2006) Caspase and bid involvement in Clostridium difficile toxin A-induced apoptosis and modulation of toxin A effects by glutamine and alanyl-glutamine in vivo and in vitro. Infect Immun 74:81–87PubMedCentralPubMedCrossRefGoogle Scholar
  17. Chen K, Okuma T, Okamura K, Torigoe Y, Miyauchi Y (1994) Glutamine-supplemented parenteral nutrition improves gut mucosa integrity and function in endotoxemic rats. JPEN J Parenter Enteral Nutr 18:167–171PubMedCrossRefGoogle Scholar
  18. Chen Y, Li DF, Dai ZL et al (2014) L-methionine supplementation maintains the integrity and barrier function of the small-intestinal mucosa in post-weaning pigs. Amino Acids 46:1131–1142PubMedCrossRefGoogle Scholar
  19. Circu ML, Aw TY (2011) Redox biology of the intestine. Free Radical Res 45:1245–1266CrossRefGoogle Scholar
  20. Circu ML, Aw TY (2012) Glutathione and modulation of cell apoptosis. Biochim Biophys Acta 1823:1767–1777PubMedCentralPubMedCrossRefGoogle Scholar
  21. Clark EC, Patel SD, Chadwick PR, Warhurst G, Curry A, Carlson GL (2003) Glutamine deprivation facilitates tumour necrosis factor induced bacterial translocation in Caco-2 cells by depletion of enterocyte fuel substrate. Gut 52:224–230PubMedCentralPubMedCrossRefGoogle Scholar
  22. Coeffier M, Le Pessot F, Leplingard A, Marion R, Lerebours E, Ducrotte P et al (2002) Acute enteral glutamine infusion enhances heme oxygenase-1 expression in human duodenal mucosa. J Nutr 132:2570–2573PubMedGoogle Scholar
  23. Crespo I, San-Miguel B, Prause C, Marroni N, Cuevas MJ, Gonzalez-Gallego J et al (2012) Glutamine treatment attenuates endoplasmic reticulum stress and apoptosis in TNBS-induced colitis. PLoS One 7:e50407PubMedCentralPubMedCrossRefGoogle Scholar
  24. Crowe SE, Perdue MH (1992) Functional abnormalities in the intestine associated with mucosal mast cell activation. Reg Immunol 4:113–117PubMedGoogle Scholar
  25. Curi R, Lagranha CJ, Doi SQ, Sellitti DF, Procopio J, Pithon-Curi TC et al (2005) Molecular mechanisms of glutamine action. J Cell Physiol 204:392–401PubMedCrossRefGoogle Scholar
  26. Dai ZL, Zhang J, Wu G, Zhu WY (2010) Utilization of amino acids by bacteria from the pig small intestine. Amino Acids 39:1201–1215PubMedCrossRefGoogle Scholar
  27. Dai ZL, Li XL, Xi PB, Zhang J, Wu G, Zhu WY (2012) Metabolism of select amino acids in bacteria from the pig small intestine. Amino Acids 42:1597–1608PubMedCrossRefGoogle Scholar
  28. Dai ZL, Li XL, Xi PB, Zhang J, Wu G, Zhu WY (2013) l-Glutamine regulates amino acid utilization by intestinal bacteria. Amino Acids 45:501–512PubMedCrossRefGoogle Scholar
  29. de Santa Barbara P, van den Brink GR, Roberts DJ (2003) Development and differentiation of the intestinal epithelium. Cell Mol Life Sci 60:1322–1332PubMedCentralPubMedCrossRefGoogle Scholar
  30. DeMarco VG, Li N, Thomas J, West CM, Neu J (2003) Glutamine and barrier function in cultured Caco-2 epithelial cell monolayers. J Nutr 133:2176–2179PubMedGoogle Scholar
  31. Deniel N, Marion-Letellier R, Charlionet R, Tron F, Leprince J, Vaudry H et al (2007) Glutamine regulates the human epithelial intestinal HCT-8 cell proteome under apoptotic conditions. Mol Cell Proteomics 6:1671–1679PubMedCrossRefGoogle Scholar
  32. D’Inca R, Kloareg M, Gras-Le Guen C, Le Huerou-Luron I (2010) Intrauterine growth restriction modifies the developmental pattern of intestinal structure, transcriptomic profile, and bacterial colonization in neonatal pigs. J Nutr 140:925–931PubMedCrossRefGoogle Scholar
  33. D’Inca R, Gras-Le Guen C, Che L, Sangild PT, Le Huerou-Luron I (2011) Intrauterine growth restriction delays feeding-induced gut adaptation in term newborn pigs. Neonatology 99:208–216PubMedCrossRefGoogle Scholar
  34. Evans ME, Jones DP, Ziegler TR (2003) Glutamine prevents cytokine-induced apoptosis in human colonic epithelial cells. J Nutr 133:3065–3071PubMedGoogle Scholar
  35. Evans ME, Jones DP, Ziegler TR (2005) Glutamine inhibits cytokine-induced apoptosis in human colonic epithelial cells via the pyrimidine pathway. Am J Physiol Gastrointest Liver Physiol 289:G388–G396PubMedCrossRefGoogle Scholar
  36. Farhadi A, Banan A, Fields J, Keshavarzian A (2003) Intestinal barrier: an interface between health and disease. J Gastroenterol Hepatol 18:479–497PubMedCrossRefGoogle Scholar
  37. Findley MK, Koval M (2009) Regulation and roles for claudin-family tight junction proteins. IUBMB Life 61:431–437PubMedCentralPubMedCrossRefGoogle Scholar
  38. Franco R, Cidlowski JA (2009) Apoptosis and glutathione: beyond an antioxidant. Cell Death Differ 16:1303–1314PubMedCrossRefGoogle Scholar
  39. Furuse M, Tsukita S (2006) Claudins in occluding junctions of humans and flies. Trends Cell Biol 16:181–188PubMedCrossRefGoogle Scholar
  40. Gareau MG, Jury J, Perdue MH (2007) Neonatal maternal separation of rat pups results in abnormal cholinergic regulation of epithelial permeability. Am J Physiol Gastrointest Liver Physiol 293:G198–G203PubMedCrossRefGoogle Scholar
  41. Grant JP, Snyder PJ (1988) Use of l-glutamine in total parenteral nutrition. J Surg Res 44:506–513PubMedCrossRefGoogle Scholar
  42. Groschwitz KR, Hogan SP (2009) Intestinal barrier function: molecular regulation and disease pathogenesis. J Allergy Clin Immunol 124:3–20 (quiz 21-22)PubMedCentralPubMedCrossRefGoogle Scholar
  43. Groschwitz KR, Ahrens R, Osterfeld H, Gurish MF, Han X, Abrink M et al (2009) Mast cells regulate homeostatic intestinal epithelial migration and barrier function by a chymase/Mcpt4-dependent mechanism. Proc Natl Acad Sci 106:22381–22386PubMedCentralPubMedCrossRefGoogle Scholar
  44. Han X, Ren X, Jurickova I, Groschwitz K, Pasternak BA, Xu H et al (2009) Regulation of intestinal barrier function by signal transducer and activator of transcription 5b. Gut 58:49–58PubMedCentralPubMedCrossRefGoogle Scholar
  45. Haynes TE, Li P, Li X, Shimotori K, Sato H, Flynn NE et al (2009) l-Glutamine or L-alanyl-l-glutamine prevents oxidant- or endotoxin-induced death of neonatal enterocytes. Amino Acids 37:131–142PubMedCrossRefGoogle Scholar
  46. Hou Y, Yao K, Wang L, Ding B, Fu D, Liu Y et al (2011) Effects of alpha-ketoglutarate on energy status in the intestinal mucosa of weaned piglets chronically challenged with lipopolysaccharide. Br J Nutr 106:357–363PubMedCrossRefGoogle Scholar
  47. Jacobi SK, Odle J (2012) Nutritional factors influencing intestinal health of the neonate. Adv Nutr 3:687–696PubMedCentralPubMedCrossRefGoogle Scholar
  48. Jiang ZY, Sun LH, Lin YC, Ma XY, Zheng CT, Zhou GL et al (2009) Effects of dietary glycyl-glutamine on growth performance, small intestinal integrity, and immune responses of weaning piglets challenged with lipopolysaccharide. J Anim Sci 87:4050–4056PubMedCrossRefGoogle Scholar
  49. Kern JC, Kehrer JP (2005) Free radicals and apoptosis: relationships with glutathione, thioredoxin, and the BCL family of proteins. Front Biosci 10:1727–1738PubMedCrossRefGoogle Scholar
  50. Kourtis N, Tavernarakis N (2009) Autophagy and cell death in model organisms. Cell Death Differ 16:21–30PubMedCrossRefGoogle Scholar
  51. Larson SD, Li J, Chung DH, Evers BM (2007) Molecular mechanisms contributing to glutamine-mediated intestinal cell survival. Am J Physiol Gastrointest Liver Physiol 293:G1262–G1271PubMedCentralPubMedCrossRefGoogle Scholar
  52. Lesueur C, Bole-Feysot C, Bekri S, Husson A, Lavoinne A, Brasse-Lagnel C (2012) Glutamine induces nuclear degradation of the NF-kappaB p65 subunit in Caco-2/TC7 cells. Biochimie 94:806–815PubMedCrossRefGoogle Scholar
  53. Li N, Neu J (2009) Glutamine deprivation alters intestinal tight junctions via a PI3-K/Akt mediated pathway in Caco-2 cells. J Nutr 139:710–714PubMedCentralPubMedCrossRefGoogle Scholar
  54. Li Q, Verma IM (2002) NF-kappaB regulation in the immune system. Nat Rev Immunol 2:725–734PubMedCrossRefGoogle Scholar
  55. Li N, Lewis P, Samuelson D, Liboni K, Neu J (2004) Glutamine regulates Caco-2 cell tight junction proteins. Am J Physiol Gastrointest Liver Physiol 287:G726–G733PubMedCrossRefGoogle Scholar
  56. Li P, Yin YL, Li D, Kim SW, Wu G (2007) Amino acids and immune function. Br J Nutr 98:237–252PubMedCrossRefGoogle Scholar
  57. Li P, Knabe DA, Kim SW et al (2009) Lactating porcine mammary tissue catabolizes branched-chain amino acids for glutamine and aspartate synthesis. J Nutr 139:1502–1509PubMedCentralPubMedCrossRefGoogle Scholar
  58. Liboni KC, Li N, Scumpia PO, Neu J (2005) Glutamine modulates LPS-induced IL-8 production through IkappaB/NF-kappaB in human fetal and adult intestinal epithelium. J Nutr 135:245–251PubMedGoogle Scholar
  59. Marc Rhoads J, Wu G (2009) Glutamine, arginine, and leucine signaling in the intestine. Amino Acids 37:111–122PubMedCrossRefGoogle Scholar
  60. Mates JM, Perez-Gomez C, Nunez de Castro I, Asenjo M, Marquez J (2002) Glutamine and its relationship with intracellular redox status, oxidative stress and cell proliferation/death. Int J Biochem Cell Biol 34:439–458PubMedCrossRefGoogle Scholar
  61. Mates JM, Segura JA, Alonso FJ, Marquez J (2006) Pathways from glutamine to apoptosis. Front Biosci 11:3164–3180PubMedCrossRefGoogle Scholar
  62. Matter K, Balda MS (2003) Signalling to and from tight junctions. Nat Rev Mol Cell Biol 4:225–236PubMedCrossRefGoogle Scholar
  63. Meadows AL, Kong B, Berdichevsky M, Roy S, Rosiva R, Blanch HW et al (2008) Metabolic and morphological differences between rapidly proliferating cancerous and normal breast epithelial cells. Biotechnol Prog 24:334–341PubMedCrossRefGoogle Scholar
  64. Menard S, Cerf-Bensussan N, Heyman M (2010) Multiple facets of intestinal permeability and epithelial handling of dietary antigens. Mucosal Immunol 3:247–259PubMedCrossRefGoogle Scholar
  65. Mestecky J, Russell MW, Jackson S, Brown TA (1986) The human IgA system: a reassessment. Clin Immunol Immunopathol 40:105–114PubMedCrossRefGoogle Scholar
  66. Moeser AJ, Ryan KA, Nighot PK, Blikslager AT (2007) Gastrointestinal dysfunction induced by early weaning is attenuated by delayed weaning and mast cell blockade in pigs. Am J Physiol Gastrointest Liver Physiol 293:G413–G421PubMedCrossRefGoogle Scholar
  67. Mondello S, Galuppo M, Mazzon E, Domenico I, Mondello P, Carmela A et al (2010) Glutamine treatment attenuates the development of ischaemia/reperfusion injury of the gut. Eur J Pharmacol 643:304–315PubMedCrossRefGoogle Scholar
  68. Musch MW, Hayden D, Sugi K, Straus D, Chang EB (1998) Cell-specific induction of hsp72-mediated protection by glutamine against oxidant injury in IEC18 cells. Proc Assoc Am Physicians 110:136–139PubMedGoogle Scholar
  69. Neu J, DeMarco V, Weiss M (1999) Glutamine supplementation in low-birth-weight infants: mechanisms of action. JPEN J Parenter Enteral Nutr 23:S49–S51PubMedCrossRefGoogle Scholar
  70. Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B et al (2009) Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136:521–534PubMedCentralPubMedCrossRefGoogle Scholar
  71. Noth R, Hasler R, Stuber E, Ellrichmann M, Schafer H, Geismann C et al (2013) Oral glutamine supplementation improves intestinal permeability dysfunction in a murine acute graft-vs.-host disease model. Am J Physiol Gastrointest Liver Physiol 304:G646–G654PubMedCrossRefGoogle Scholar
  72. Papaconstantinou HT, Hwang KO, Rajaraman S, Hellmich MR, Townsend CM Jr, Ko TC (1998) Glutamine deprivation induces apoptosis in intestinal epithelial cells. Surgery 124:152–159 (discussion 159-160)PubMedCrossRefGoogle Scholar
  73. Pasparakis M (2009) Regulation of tissue homeostasis by NF-kappaB signalling: implications for inflammatory diseases. Nat Rev Immunol 9:778–788PubMedCrossRefGoogle Scholar
  74. Pasparakis M (2012) Role of NF-kappaB in epithelial biology. Immunol Rev 246:346–358PubMedCrossRefGoogle Scholar
  75. Prasad S, Mingrino R, Kaukinen K, Hayes KL, Powell RM, MacDonald TT et al (2005) Inflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells. Lab Invest 85:1139–1162PubMedCrossRefGoogle Scholar
  76. Radtke F, Clevers H (2005) Self-renewal and cancer of the gut: two sides of a coin. Science 307:1904–1909PubMedCrossRefGoogle Scholar
  77. Ramsay DB, Stephen S, Borum M, Voltaggio L, Doman DB (2010) Mast cells in gastrointestinal disease. Gastroenterol Hepatol (N Y) 6:772–777Google Scholar
  78. Reeds PJ, Burrin DG, Stoll B, Jahoor F, Wykes L, Henry J et al (1997) Enteral glutamate is the preferential source for mucosal glutathione synthesis in fed piglets. Am J Physiol 273:E408–E415PubMedGoogle Scholar
  79. Ren WK, Luo W, Wu MM et al (2013a) Dietary L-glutamine supplementation improves pregnancy outcome in mice infected with type 2 porcine circovirus. Amino Acids 45:479–488PubMedCrossRefGoogle Scholar
  80. Ren WK, Liu SP, Chen S et al (2013b) Dietary L-glutamine supplementation increases pasteurella multocida burden and expression of major virulence factors. Amino Acids 45:947–955PubMedCrossRefGoogle Scholar
  81. Rezaei R, Knabe DA, Li XL et al (2011) Enhanced efficiency of milk utilization for growth in surviving low-birth-weight piglets. J Anim Sci Biotechnol 2:73–83Google Scholar
  82. Rezaei R, Wang WW, Wu ZL et al (2013a) Biochemical and physiological bases for utilization of dietary amino acids by young pigs. J Anim Sci Biotechnol 4:7PubMedCentralPubMedCrossRefGoogle Scholar
  83. Rezaei R, Knabe DA, Tekwe CD et al (2013b) Dietary supplementation with monosodium glutamate is safe and improves growth performance in postweaning pigs. Amino Acids 44:911–923PubMedCrossRefGoogle Scholar
  84. Rhoads M (1999) Glutamine signaling in intestinal cells. JPEN J Parenter Enteral Nutr 23:S38–S40PubMedCrossRefGoogle Scholar
  85. Rhoads JM, Argenzio RA, Chen W, Rippe RA, Westwick JK, Cox AD et al (1997) l-glutamine stimulates intestinal cell proliferation and activates mitogen-activated protein kinases. Am J Physiol 272:G943–G953PubMedGoogle Scholar
  86. Ropeleski MJ, Riehm J, Baer KA, Musch MW, Chang EB (2005) Anti-apoptotic effects of l-glutamine-mediated transcriptional modulation of the heat shock protein 72 during heat shock. Gastroenterology 129:170–184PubMedCrossRefGoogle Scholar
  87. Ruth MR, Field CJ (2013) the immune modifying effects of the gut-associated lymphoid tissue. J Anim Sci Biotechnol 4:27PubMedCentralPubMedCrossRefGoogle Scholar
  88. Sakiyama T, Musch MW, Ropeleski MJ, Tsubouchi H, Chang EB (2009) Glutamine increases autophagy under basal and stressed conditions in intestinal epithelial cells. Gastroenterology 136:924–932PubMedCentralPubMedCrossRefGoogle Scholar
  89. Sandri M (2012) FOXOphagy path to inducing stress resistance and cell survival. Nat Cell Biol 14:786–788PubMedCrossRefGoogle Scholar
  90. Scheppach W, Dusel G, Kuhn T, Loges C, Karch H, Bartram HP et al (1996) Effect of l-glutamine and n-butyrate on the restitution of rat colonic mucosa after acid induced injury. Gut 38:878–885PubMedCentralPubMedCrossRefGoogle Scholar
  91. Schneeberger EE, Lynch RD (2004) The tight junction: a multifunctional complex. Am J Physiol Cell Physiol 286:C1213–C1228PubMedCrossRefGoogle Scholar
  92. Schroder J, Wardelmann E, Winkler W, Fandrich F, Schweizer E, Schroeder P (1995) Glutamine dipeptide-supplemented parenteral nutrition reverses gut atrophy, disaccharidase enzyme activity, and absorption in rats. JPEN J Parenter Enteral Nutr 19:502–506PubMedCrossRefGoogle Scholar
  93. Seth A, Basuroy S, Sheth P, Rao RK (2004) l-Glutamine ameliorates acetaldehyde-induced increase in paracellular permeability in Caco-2 cell monolayer. Am J Physiol Gastrointest Liver Physiol 287:G510–G517PubMedCrossRefGoogle Scholar
  94. Shaker A, Rubin DC (2010) Intestinal stem cells and epithelial-mesenchymal interactions in the crypt and stem cell niche. Transl Res 156:180–187PubMedCentralPubMedCrossRefGoogle Scholar
  95. Sheard NF, Walker WA (1988) The role of breast milk in the development of the gastrointestinal tract. Nutr Rev 46:1–8PubMedCrossRefGoogle Scholar
  96. Smith F, Clark JE, Overman BL, Tozel CC, Huang JH, Rivier JE et al (2010) Early weaning stress impairs development of mucosal barrier function in the porcine intestine. Am J Physiol Gastrointest Liver Physiol 298:G352–G363PubMedCentralPubMedCrossRefGoogle Scholar
  97. Soderholm JD, Yates DA, Gareau MG, Yang PC, MacQueen G, Perdue MH (2002) Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress. Am J Physiol Gastrointest Liver Physiol 283:G1257–G1263PubMedCrossRefGoogle Scholar
  98. Souba WW, Klimberg VS, Hautamaki RD, Mendenhall WH, Bova FC, Howard RJ et al (1990) Oral glutamine reduces bacterial translocation following abdominal radiation. J Surg Res 48:1–5PubMedCrossRefGoogle Scholar
  99. Spitz J, Yuhan R, Koutsouris A, Blatt C, Alverdy J, Hecht G (1995) Enteropathogenic Escherichia coli adherence to intestinal epithelial monolayers diminishes barrier function. Am J Physiol 268:G374–G379PubMedGoogle Scholar
  100. Takayama C, Mukaizawa F, Fujita T, Ogawara K, Higaki K, Kimura T (2009) Amino acids suppress apoptosis induced by sodium laurate, an absorption enhancer. J Pharm Sci 98:4629–4638PubMedCrossRefGoogle Scholar
  101. Ulluwishewa D, Anderson RC, McNabb WC, Moughan PJ, Wells JM, Roy NC (2011) Regulation of tight junction permeability by intestinal bacteria and dietary components. J Nutr 141:769–776PubMedCrossRefGoogle Scholar
  102. van der Vos KE, Eliasson P, Proikas-Cezanne T, Vervoort SJ, van Boxtel R, Putker M et al (2012) Modulation of glutamine metabolism by the PI(3)K-PKB-FOXO network regulates autophagy. Nat Cell Biol 14:829–837PubMedCrossRefGoogle Scholar
  103. Veldhoen M, Brucklacher-Waldert V (2012) Dietary influences on intestinal immunity. Nat Rev Immunol 12:696–708PubMedCrossRefGoogle Scholar
  104. Wang J, Chen L, Li P, Li X, Zhou H, Wang F et al (2008) Gene expression is altered in piglet small intestine by weaning and dietary glutamine supplementation. J Nutr 138:1025–1032PubMedCrossRefGoogle Scholar
  105. Wijtten PJ, van der Meulen J, Verstegen MW (2011) Intestinal barrier function and absorption in pigs after weaning: a review. Br J Nutr 105:967–981PubMedCrossRefGoogle Scholar
  106. Wischmeyer PE (2002) Glutamine and heat shock protein expression. Nutrition 18:225–228PubMedCrossRefGoogle Scholar
  107. Wu G (1996) Effects of concanavalin A and phorbol myristate acetate on glutamine metabolism and proliferation of porcine intestinal intraepithelial lymphocytes. Comp Biochem Physiol A Physiol 114:363–368PubMedCrossRefGoogle Scholar
  108. Wu G (1998) Intestinal mucosal amino acid catabolism. J Nutr 128:1249–1252PubMedGoogle Scholar
  109. Wu G (2013) Functional amino acids in nutrition and health. Amino Acids 45:407–411PubMedCrossRefGoogle Scholar
  110. Wu G (2014) Dietary requirements of synthesizable amino acids by animals: a paraddigm shift in protein nutrition. J Anim Sci Biotechnol 5:34PubMedCentralPubMedCrossRefGoogle Scholar
  111. Wu G, Knabe DA (1994) Free and protein-bound amino acids in sow’s colostrum and milk. J Nutr 124:415–424PubMedGoogle Scholar
  112. Wu G, Knabe DA, Yan W, Flynn NE (1995) Glutamine and glucose metabolism in enterocytes of the neonatal pig. Am J Physiol 268:R334–R342PubMedGoogle Scholar
  113. Wu G, Meier SA, Knabe DA (1996) Dietary glutamine supplementation prevents jejunal atrophy in weaned pigs. J Nutr 126:2578–2584PubMedGoogle Scholar
  114. Wu G, Bazer FW, Johnson GA, Knabe DA, Burghardt RC, Spencer TE et al (2011) Triennial Growth Symposium: important roles for l-glutamine in swine nutrition and production. J Anim Sci 89:2017–2030PubMedCrossRefGoogle Scholar
  115. Wu G, Wu Z, Dai Z, Yang Y, Wang W, Liu C et al (2013) Dietary requirements of “nutritionally non-essential amino acids” by animals and humans. Amino Acids 44:1107–1113PubMedCrossRefGoogle Scholar
  116. Wu G, Bazer FW, Dai ZL et al (2014) Amino acid nutrition in animals: protein synthesis and beyond. Annu Rev Anim Biosci 2:387–417PubMedCrossRefGoogle Scholar
  117. Xi P, Jiang Z, Zheng C, Lin Y, Wu G (2011) Regulation of protein metabolism by glutamine: implications for nutrition and health. Front Biosci (Landmark Ed) 16:578–597CrossRefGoogle Scholar
  118. Xi P, Jiang Z, Dai Z, Li X, Yao K, Zheng C et al (2012) Regulation of protein turnover by l-glutamine in porcine intestinal epithelial cells. J Nutr Biochem 23:1012–1017PubMedCrossRefGoogle Scholar
  119. Yang Y, Sun F, Zhang C et al (2013) Hypoxia promotes cell proliferation by modulating E2F1 in chicken pulmonary arterial smooth muscle cells. J Anim Sci Biotechnol 4:28PubMedCentralPubMedCrossRefGoogle Scholar
  120. Yao K, Yin Y, Li X, Xi P, Wang J, Lei J et al (2012) Alpha-ketoglutarate inhibits glutamine degradation and enhances protein synthesis in intestinal porcine epithelial cells. Amino Acids 42:2491–2500PubMedCrossRefGoogle Scholar
  121. Yi GF, Carroll JA, Allee GL, Gaines AM, Kendall DC, Usry JL et al (2005) Effect of glutamine and spray-dried plasma on growth performance, small intestinal morphology, and immune responses of Escherichia coli K88+ -challenged weaned pigs. J Anim Sci 83:634–643PubMedGoogle Scholar
  122. Zhang SH, Qiao SY, Ren M et al (2013) Supplementation with branched-chain amino acids to a low-protein diet regulates intestinal expression of amino acid and peptide transporters in weanling pigs. Amino Acids 45:1191–1205PubMedCrossRefGoogle Scholar
  123. Ziegler TR (1994) Glutamine is essential for epidermal growth factor-stimulated intestinal cell proliferation. JPEN J Parenter Enteral Nutr 18:84–86PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  • Bin Wang
    • 1
  • Guoyao Wu
    • 1
    • 2
  • Zhigang Zhou
    • 3
  • Zhaolai Dai
    • 1
  • Yuli Sun
    • 1
  • Yun Ji
    • 1
  • Wei Li
    • 1
  • Weiwei Wang
    • 1
  • Chuang Liu
    • 1
  • Feng Han
    • 1
  • Zhenlong Wu
    • 1
  1. 1.State Key Laboratory of Animal Nutrition, College of Animal Science and TechnologyChina Agricultural UniversityBeijingPeople’s Republic of China
  2. 2.Department of Animal ScienceTexas A&M UniversityCollege StationUSA
  3. 3.Key Laboratory for Feed Biotechnology of the Ministry of AgricultureFeed Research Institute, Chinese Academy of Agricultural SciencesBeijingChina

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