Mechanisms of Regulation of Transporters of Amino Acid Absorption in Inflammatory Bowel Diseases

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Mechanisms of Regulation of Transporters of Amino Acid Absorption in Inflammatory Bowel Diseases

Soudamani Singh, Subha Arthur, Uma Sundaram

10.1002/cphy.c190016

Source: Volume 10, Issue 2, April 2020

Published online: March 2020

Full Article on Wiley Online Library

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Abstract

Intestinal absorption of dietary amino acids/peptides is essential for protein homeostasis, which in turn is crucial for maintaining health as well as restoration of health from significant diseases. Dietary amino acids/peptides are absorbed by unique transporter processes present in the brush border membrane of absorptive villus cells, which line the entire length of the intestine. To date, the only nutrient absorptive system described in the secretory crypt cells in the mammalian intestine is the one that absorbs the amino acid glutamine. Majority of the amino acid transporters are sodium dependent and therefore require basolateral membrane Na‐K‐ATPase to maintain an efficient transcellular Na gradient for their activity. These transport processes are tightly regulated by various cellular and molecular mechanisms that facilitate their optimal activity during normal physiological processes. Malabsorption of amino acids, recently described in pathophysiological states such as in inflammatory bowel disease (IBD), is undoubtedly responsible for the debilitating symptoms of IBD such as malnutrition, weight loss and ultimately a failure to thrive. Also recently, in vivo models of IBD and in vitro studies have demonstrated that specific immune‐inflammatory mediators/pathways regulate specific amino acid transporters. This provides possibilities to derive novel nutrition and immune‐based treatment options for conditions such as IBD. © 2020 American Physiological Society. Compr Physiol 10:673‐686, 2020.

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Soudamani Singh, Subha Arthur, Uma Sundaram. Mechanisms of Regulation of Transporters of Amino Acid Absorption in Inflammatory Bowel Diseases. Compr Physiol 2020, 10: 673-686. doi: 10.1002/cphy.c190016

	Figure 1. Intestinal epithelium is lined by columnar epithelial cells that originate from the intestinal stem cells located in the crypt. These mature and differentiate into absorptive villus cells that express many amino acid transporters in their brush border membrane (BBM). The lone amino acid transporter expressed in the crypt BBM is SN2 which is a Na‐glutamine cotransporter. Intraepithelial lymphocytes are represented by cells shaded green.
	Figure 2. Proposed models for leptin‐mediated hormonal regulation of amino acid transporter activity in the mammalian intestine. (A) Leptin hormone activates PI3K‐mTOR1, which in turn activates SK6 leading to the increase in transcription of AAT. (B) Alternate pathway of leptin mediated AAT activation is through phosphorylation of STAT3, which increases the transcription of AAT. AAT, amino acid transporters; PI3K, phosphoinositide 3‐kinase; mTORC1, mechanistic target of rapamycin complex1; S6K1, ribosomal protein S6 kinase beta‐1; ERK, extracellular‐signal‐regulated kinase; AP1, activator protein 1; TYR, tyrosine; P, phosphorylated protein; JAK, Janus kinase (JAK); STAT3, signal transducer and activator of transcription.
	Figure 3. Regulation of glutamine absorption in small intestinal villus and crypt cells during chronic intestinal inflammation. Na‐glutamine cotransporter B0AT1 in villus cells was inhibited secondary to reduced cotransporter numbers and reduced Na‐K‐ATPase activity, while SNAT5/SN2 was stimulated secondary to increased transporter affinity and increased Na‐K‐ATPase activity.
	Figure 4. In a rabbit model of chronic intestinal inflammation, B0AT1‐mediated glutamine malabsorption was ameliorated by treatment by a broad spectrum immune modulator, methylprednisolone (MP), inhibition of inducible nitric oxide (iNO) production with LNIL, a specific inhibitor of iNO synthase; inhibition of activated mast cells with ketotifen, a mast cell membrane stabilizer; inhibition of prostaglandin production with Piroxicam (PRX) a cyclooxygenase (COX) pathway inhibitor. Treatment with each of these pharmaceutical agents restored the activity of the Na‐glutamine cotransporter B0AT1 and Na‐K‐ATPase, thereby reversing the malabsorption of glutamine during chronic enteritis. These observations indicate that reduction of production or release of immune‐inflammatory mediators by immunocytes such as mast cells and/or epithelial cells (e.g., prostaglandins) by specific agents reverses the inhibition of B0AT1 during chronic enteritis.
	Figure 5. Model of immune regulation of B0AT1 in villus and SN2 in crypt cells in the intestine. The two‐primary sodium‐glutamine cotransporters are not only unique to villus (B0AT1) and crypt (SN2) cells, but the mechanism of their alteration during chronic enteritis is also quite novel. During chronic intestinal inflammation, upstream, both B0AT1 and SN2 are regulated by common inflammatory pathways, namely, mast cells, nitric oxide (NO) and arachidonic acid from the plasma membrane released by phospholipase A2 (PLAP2). But downstream, the immune regulation of these two transporters is quite unique: SN2 in crypt cells is regulated by the lipoxygenase (LOX) pathway, most likely by leukotrieneD4 (LTD4), whereas, B0AT1 in villus cells is regulated by the cyclooxygenase (COX) pathway, most likely by prostaglandin E2 (PGE2).
	Figure 6. In intestinal epithelial cells (IEC‐18 cells), the mechanism of LTD4 mediated inhibition of Na‐alanine cotransporter, ASCT1, is via the activation of PKC and PKA pathways through the phosphorylation of an intermediate protein RKIP. LTD4, leukotriene D4; PKC, protein kinase C; RKIP, Raf kinase inhibitory protein; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A.

References
1.	Adibi SA, Fogel MR, Agrawal RM. Comparison of free amino acid and dipeptide absorption in the jejunum of sprue patients. Gastroenterology 67: 586‐591, 1974.
2.	Aledo JC. Glutamine breakdown in rapidly dividing cells: Waste or investment? Bioessays 26: 778‐785, 2004.
3.	Archampong EQ, Harris J, Clark CG. Water and electrolyte transfer by colonic mucosa studied in vitro. Br J Surg 59: 314, 1972.
4.	Arthur S, Coon S, Kekuda R, Sundaram U. Regulation of sodium glucose co‐transporter SGLT1 through altered glycosylation in the intestinal epithelial cells. Biochim Biophys Acta 1838: 1208‐1214, 2014.
5.	Arthur S, Manoharan P, Sundaram S, Rahman MM, Palaniappan B, Sundaram U. Unique regulation of enterocyte brush border membrane Na‐glutamine and Na‐alanine co‐transport by peroxynitrite during chronic intestinal inflammation. Int J Mol Sci 20: 1504, 2019.
6.	Arthur S, Saha P, Sundaram S, Kekuda R, Sundaram U. Regulation of sodium‐glutamine cotransport in villus and crypt cells by glucocorticoids during chronic enteritis. Inflamm Bowel Dis 18: 2149‐2157, 2012.
7.	Arthur S, Singh S, Sundaram U. Cyclooxygenase pathway mediates the inhibition of Na‐glutamine co‐transporter B0AT1 in rabbit villus cells during chronic intestinal inflammation. PLoS ONE 13: e0203552, 2018.
8.	Arthur S, Sundaram U. Protein kinase C‐mediated phosphorylation of RKIP regulates inhibition of Na‐alanine cotransport by leukotriene D(4) in intestinal epithelial cells. Am J Physiol Cell Physiol 307: C1010‐C1016, 2014.
9.	Arthur S, Sundaram U. Inducible nitric oxide regulates intestinal glutamine assimilation during chronic intestinal inflammation. Nitric Oxide Biol Chem 44: 98‐104, 2015.
10.	Ashkenazi SCT, Pickering LK. Bacterial toxins associated with diarrheal disease. In: Textbook of Secretory Diarrhea. New York: Raven Press, 1991.
11.	Banan A, Fields JZ, Zhang Y, Keshavarzian A. iNOS upregulation mediates oxidant‐induced disruption of F‐actin and barrier of intestinal monolayers. Am J Physiol Gastrointest Liver Physiol 280: G1234‐G1246, 2001.
12.	Bar‐Peled L, Sabatini DM. Regulation of mTORC1 by amino acids. Trends Cell Biol 24: 400‐406, 2014.
13.	Barrett KE, Dharmsathaphorn K. Mechanisms of Chloride Secretion in a Colonic Epithelial Cell Line. New York: Raven Press, 1991.
14.	Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA. Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A 87: 1620‐1624, 1990.
15.	Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: The good, the bad, and ugly. Am J Phys 271: C1424‐C1437, 1996.
16.	Beunk L, Verwoerd A, van Overveld FJ, Rijkers GT. Role of mast cells in mucosal diseases: Current concepts and strategies for treatment. Expert Rev Clin Immunol 9: 53‐63, 2013.
17.	Binder HJ, Ptak T. Jejunal absorption of water and electrolytes in inflammatory bowel disease. J Lab Clin Med 76: 915‐924, 1970.
18.	Blikslager A, Hunt E, Guerrant R, Rhoads M, Argenzio R. Glutamine transporter in crypts compensates for loss of villus absorption in bovine cryptosporidiosis. Am J Physiol Gastrointest Liver Physiol 281: G645‐G653, 2001.
19.	Bode BP. Recent molecular advances in mammalian glutamine transport. J Nutr 131: 2475S‐2485S; discussion 2486S‐2477S, 2001.
20.	Boll M, Foltz M, Rubio‐Aliaga I, Kottra G, Daniel H. Functional characterization of two novel mammalian electrogenic proton‐dependent amino acid cotransporters. J Biol Chem 277: 22966‐22973, 2002.
21.	Broer A, Klingel K, Kowalczuk S, Rasko JE, Cavanaugh J, Broer S. Molecular cloning of mouse amino acid transport system B0, a neutral amino acid transporter related to Hartnup disorder. J Biol Chem 279: 24467‐24476, 2004.
22.	Broer A, Tietze N, Kowalczuk S, Chubb S, Munzinger M, Bak LK, Broer S. The orphan transporter v7‐3 (slc6a15) is a Na+‐dependent neutral amino acid transporter (B0AT2). Biochem J 393: 421‐430, 2006.
23.	Broer S, Broer A. Amino acid homeostasis and signalling in mammalian cells and organisms. Biochem J 474: 1935‐1963, 2017.
24.	Broer S, Fairweather SJ. Amino acid transport across the mammalian intestine. Compr Physiol 9: 343‐373, 2018.
25.	Brown DR, Miller RJ. Neurohormonal Control of Fluid and Electrolyte Transport in Intestinal Mucosa. Bethesda, MD: American Physiological Society, 1990.
26.	Bussolati O, Laris PC, Rotoli BM, Dall'Asta V, Gazzola GC. Transport system ASC for neutral amino acids. An electroneutral sodium/amino acid cotransport sensitive to the membrane potential. J Biol Chem 267: 8330‐8335, 1992.
27.	Camargo SM, Makrides V, Virkki LV, Forster IC, Verrey F. Steady‐state kinetic characterization of the mouse B(0)AT1 sodium‐dependent neutral amino acid transporter. Pflugers Arch ‐ Eur J Physiol 451: 338‐348, 2005.
28.	Castro GA, Powell DW. The Physiology of the Mucosal Immune System and Immune‐Mediated Responses in the Gastrointestinal Tract. New York: Raven Press, 1994.
29.	Chang EB, Leung PS. Intestinal water and electrolyte transport. In: Leung P, ed. The Gastrointestinal System. Dordrecht: Springer, 2014, p. 107‐134.
30.	Chaudhry FA, Reimer RJ, Krizaj D, Barber D, Storm‐Mathisen J, Copenhagen DR, Edwards RH. Molecular analysis of system N suggests novel physiological roles in nitrogen metabolism and synaptic transmission. Cell 99: 769‐780, 1999.
31.	Chen C, Yin Y, Tu Q, Yang H. Glucose and amino acid in enterocyte: Absorption, metabolism and maturation. Frontiers in Bioscience (Landmark Edition) 23: 1721‐1739, 2018.
32.	Chow A, Zhang R. Glutamine reduces heat shock‐induced cell death in rat intestinal epithelial cells. J Nutr 128: 1296‐1301, 1998.
33.	Christensen HN, Liang M, Archer EG. A distinct Na+‐requiring transport system for alanine, serine, cysteine, and similar amino acids. J Biol Chem 242: 5237‐5246, 1967.
34.	Powell DW. Neuro‐Immuno‐Physiology of the gastrointestinal mucosa. New York: Academy of Science, 1992, p. 1‐455
35.	Clark EC, Patel SD, Chadwick PR, Warhurst G, Curry A, Carlson GL. Glutamine deprivation facilitates tumour necrosis factor induced bacterial translocation in Caco‐2 cells by depletion of enterocyte fuel substrate. Gut 52: 224‐230, 2003.
36.	Coburn LA, Gong X, Singh K, Asim M, Scull BP, Allaman MM, Williams CS, Rosen MJ, Washington MK, Barry DP, Piazuelo MB, Casero RA Jr, Chaturvedi R, Zhao Z, Wilson KT. L‐arginine supplementation improves responses to injury and inflammation in dextran sulfate sodium colitis. PLoS ONE 7: e33546, 2012.
37.	Coburn LA, Horst SN, Allaman MM, Brown CT, Williams CS, Hodges ME, Druce JP, Beaulieu DB, Schwartz DA, Wilson KT. L‐arginine availability and metabolism is altered in ulcerative colitis. Inflamm Bowel Dis 22: 1847‐1858, 2016.
38.	Coeffier M, Marion‐Letellier R, Dechelotte P. Potential for amino acids supplementation during inflammatory bowel diseases. Inflamm Bowel Dis 16: 518‐524, 2010.
39.	Cooke HJ. Neural Regulation of Intestinal Electrolyte Transport. New York: Raven Press, 1994.
40.	Coon S, Kim J, Shao G, Sundaram U. Na‐glucose and Na‐neutral amino acid cotransport are uniquely regulated by constitutive nitric oxide in rabbit small intestinal villus cells. Am J Physiol Gastrointest Liver Physiol 289: G1030‐G1035, 2005.
41.	Coon S, Kim JK, Sundaram U. Inhibition of inducible nitric oxide production reverses the inhibition of Na‐glucose Co‐transport in the chronically inflamed rabbit intestine. Gastroenterology 124(4): A40‐G1035, 2003.
42.	Crespo I, San‐Miguel B, Prause C, Marroni N, Cuevas MJ, Gonzalez‐Gallego J, Tunon MJ. Glutamine treatment attenuates endoplasmic reticulum stress and apoptosis in TNBS‐induced colitis. PLoS ONE 7: e50407, 2012.
43.	Daniel H. Molecular and integrative physiology of intestinal peptide transport. Annu Rev Physiol 66: 361‐384, 2004.
44.	DeMarco V, Dyess K, Strauss D, West CM, Neu J. Inhibition of glutamine synthetase decreases proliferation of cultured rat intestinal epithelial cells. J Nutr 129: 57‐62, 1999.
45.	Dhillon SS, Mastropaolo LA, Murchie R, Griffiths C, Thoni C, Elkadri A, Xu W, Mack A, Walters T, Guo C, Mack D, Huynh H, Baksh S, Silverberg MS, Brumell JH, Snapper SB, Muise AM. Higher activity of the inducible nitric oxide synthase contributes to very early onset inflammatory bowel disease. Clin Transl Gastroenterol 5: e46, 2014.
46.	Dias RRF, de ECQ C, da CC SL, Tedesco RC, da K SC, Silva AC, RA DM, de Fatima Sarro‐Silva M. Toxoplasma gondii oral infection induces intestinal inflammation and retinochoroiditis in mice genetically selected for immune oral tolerance resistance. PLoS ONE 9: e113374, 2014.
47.	Epler MJ, Souba WW, Meng Q, Lin C, Karinch AM, Vary TC, Pan M. Metabolic acidosis stimulates intestinal glutamine absorption. J Gastrointest Surg 7: 1045‐1052, 2003.
48.	Erickson RH, Kim YS. Digestion and absorption of dietary protein. Annu Rev Med 41: 133‐139, 1990.
49.	Faure M, Moennoz D, Montigon F, Mettraux C, Breuille D, Ballevre O. Dietary threonine restriction specifically reduces intestinal mucin synthesis in rats. J Nutr 135: 486‐491, 2005.
50.	Fei YJ, Sugawara M, Nakanishi T, Huang W, Wang H, Prasad PD, Leibach FH, Ganapathy V. Primary structure, genomic organization, and functional and electrogenic characteristics of human system N 1, a Na+‐ and H+‐coupled glutamine transporter. J Biol Chem 275: 23707‐23717, 2000.
51.	Fraga S, Pinho MJ, Soares‐da‐Silva P. Expression of LAT1 and LAT2 amino acid transporters in human and rat intestinal epithelial cells. Amino Acids 29: 229‐233, 2005.
52.	Ganapathy V, Brandsch M, Leibach FH. Intestinal transport of amino acids and peptides. In: Johnson LR, ed. Physiology of gastrointestinal tract. 3rd ed. New York: Raven Press, 1994, p. 1773–1794.
53.	Gardner ML. Absorption of amino acids and peptides from a complex mixture in the isolated small intestine of the rat. J Physiol 253: 233‐256, 1975.
54.	Gehart H, Clevers H. Tales from the crypt: New insights into intestinal stem cells. Nat Rev Gastroenterol Hepatol 16: 19‐34, 2019.
55.	Ghishan FK, Kiela PR. Epithelial transport in inflammatory bowel diseases. Inflamm Bowel Dis 20: 1099‐1109, 2014.
56.	Gilbert ER, Li H, Emmerson DA, Webb KE Jr, Wong EA. Dietary protein quality and feed restriction influence abundance of nutrient transporter mRNA in the small intestine of broiler chicks. J Nutr 138: 262‐271, 2008.
57.	Griffin BW, Klimko P, Crider JY, Sharif NA. AL‐8810: A novel prostaglandin f2α analog with selective antagonist effects at the prostaglandin f2α (fp) receptor. J Pharmacol Exp Ther 290: 1278‐1284, 1999.
58.	Hamberg M, Svensson J, Samuelsson B. Prostaglandin endoperoxides. A new concept concerning the mode of action and release of prostaglandins. Proc Natl Acad Sci U S A 71: 3824‐3828, 1974.
59.	Hara K, Yonezawa K, Weng QP, Kozlowski MT, Belham C, Avruch J. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF‐4E BP1 through a common effector mechanism. J Biol Chem 273: 14484‐14494, 1998.
60.	He SH. Key role of mast cells and their major secretory products in inflammatory bowel disease. World J Gastroenterol 10: 309‐318, 2004.
61.	Hogaboam CM, Jacobson K, Collins SM, Blennerhassett MG. The selective beneficial effects of nitric oxide inhibition in experimental colitis. Am J Phys 268: G673‐G684, 1995.
62.	Hosoi T, Goto H, Arisawa T, Niwa Y, Okada N, Ohmiya N, Hayakawa T. Role of nitric oxide synthase inhibitor in experimental colitis induced by 2,4,6‐trinitrobenzene sulphonic acid in rats. Clin Exp Pharmacol Physiol 28: 9‐12, 2001.
63.	Hsiung Y‐C, Liu J‐J, Hou Y‐C, Yeh C‐L, Yeh S‐L. Effects of dietary glutamine on the homeostasis of CD4+ T cells in mice with dextran sulfate sodium‐induced acute colitis. PLoS ONE 9: e84410, 2014.
64.	Hu D, Yan H, He XC, Li L. Recent advances in understanding intestinal stem cell regulation. F1000Research: 8, 2019.
65.	Hu X, Deng J, Yu T, Chen S, Ge Y, Zhou Z, Guo Y, Ying H, Zhai Q, Chen Y, Yuan F, Niu Y, Shu W, Chen H, Ma C, Liu Z, Guo F. ATF4 deficiency promotes intestinal inflammation in mice by reducing uptake of glutamine and expression of antimicrobial peptides. Gastroenterology 156: 1098‐1111, 2019.
66.	Inoue Y, Copeland EM, Souba WW. Growth hormone enhances amino acid uptake by the human small intestine. Ann Surg 219: 715‐722; discussion 722‐714, 1994.
67.	Jahnel J, Fickert P, Hauer AC, Högenauer C, Avian A, Trauner M. Inflammatory bowel disease alters intestinal bile acid transporter expression. Drug Metab Dispos 42: 1423‐1431, 2014.
68.	Jando J, Camargo SMR, Herzog B, Verrey F. Expression and regulation of the neutral amino acid transporter B0AT1 in rat small intestine. PLoS ONE 12: e0184845, 2017.
69.	Jewell JL, Guan KL. Nutrient signaling to mTOR and cell growth. Trends Biochem Sci 38: 233‐242, 2013.
70.	Jiang ZY, Sun LH, Lin YC, Ma XY, Zheng CT, Zhou GL, Chen F, Zou ST. Effects of dietary glycyl‐glutamine on growth performance, small intestinal integrity, and immune responses of weaning piglets challenged with lipopolysaccharide. J Anim Sci 87: 4050‐4056, 2009.
71.	Jiminez JA, Uwiera TC, Douglas Inglis G, Uwiera RR. Animal models to study acute and chronic intestinal inflammation in mammals. Gut Pathog 7: 29, 2015.
72.	Karinch AM, Pan M, Lin C‐M, Strange R, Souba WW. Glutamine metabolism in sepsis and infection. J Nutr 131: 2535S‐2538S, 2001.
73.	Kaunitz JD, Barrett KE, McRoberts JA. Electrolytes Secretions and Absorption: Small Intestine and Colon. Philadelphia: Lippincott‐Raven, 1995.
74.	Kekuda R, Prasad PD, Fei YJ, Torres‐Zamorano V, Sinha S, Yang‐Feng TL, Leibach FH, Ganapathy V. Cloning of the sodium‐dependent, broad‐scope, neutral amino acid transporter Bo from a human placental choriocarcinoma cell line. J Biol Chem 271: 18657‐18661, 1996.
75.	Kiela PR, Ghishan FK. Physiology of intestinal absorption and secretion. Best Pract Res Clin Gastroenterol 30: 145‐159, 2016.
76.	Kiesler P, Fuss IJ, Strober W. Experimental models of inflammatory bowel diseases. Cell Mol Gastroenterol Hepatol 1: 154‐170, 2015.
77.	Kim E, Goraksha‐Hicks P, Li L, Neufeld TP, Guan KL. Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 10: 935‐945, 2008.
78.	Kim M‐H, Kim H. The roles of glutamine in the intestine and its implication in intestinal diseases. Int J Mol Sci 18: 1051, 2017.
79.	Kleta R, Romeo E, Ristic Z, Ohura T, Stuart C, Arcos‐Burgos M, Dave MH, Wagner CA, Camargo SR, Inoue S, Matsuura N, Helip‐Wooley A, Bockenhauer D, Warth R, Bernardini I, Visser G, Eggermann T, Lee P, Chairoungdua A, Jutabha P, Babu E, Nilwarangkoon S, Anzai N, Kanai Y, Verrey F, Gahl WA, Koizumi A. Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder. Nat Genet 36: 999‐1002, 2004.
80.	Kolios G, Valatas V, Ward SG. Nitric oxide in inflammatory bowel disease: A universal messenger in an unsolved puzzle. Immunology 113: 427‐437, 2004.
81.	Kong S, Zhang YH, Zhang W. Regulation of intestinal epithelial cells properties and functions by amino acids. Biomed Res Int 2018: 2819154‐2819154, 2018.
82.	Kosiewicz MM, Nast CC, Krishnan A, Rivera‐Nieves J, Moskaluk CA, Matsumoto S, Kozaiwa K, Cominelli F. Th1‐type responses mediate spontaneous ileitis in a novel murine model of Crohn's disease. J Clin Invest 107: 695‐702, 2001.
83.	Kubes P, McCafferty DM. Nitric oxide and intestinal inflammation. Am J Med 109: 150‐158, 2000.
84.	Kuhl AA, Pawlowski NN, Grollich K, Loddenkemper C, Zeitz M, Hoffmann JC. Aggravation of intestinal inflammation by depletion/deficiency of gammadelta T cells in different types of IBD animal models. J Leukoc Biol 81: 168‐175, 2007.
85.	Leibach FH, Ganapathy V. Peptide transporters in the intestine and the kidney. Annu Rev Nutr 16: 99‐119, 1996.
86.	Li YS, Li JS, Jiang JW, Liu FN, Li N, Qin WS, Zhu H. Glycyl‐glutamine‐enriched long‐term total parenteral nutrition attenuates bacterial translocation following small bowel transplantation in the pig. J Surg Res 82: 106‐111, 1999.
87.	Liboni K, Li N, Neu J. Mechanism of glutamine‐mediated amelioration of lipopolysaccharide‐induced IL‐8 production in Caco‐2 cells. Cytokine 26: 57‐65, 2004.
88.	Liboni KC, Li N, Scumpia PO, Neu J. Glutamine modulates LPS‐induced IL‐8 production through IkappaB/NF‐kappaB in human fetal and adult intestinal epithelium. J Nutr 135: 245‐251, 2005.
89.	Lin L, Yee SW, Kim RB, Giacomini KM. SLC transporters as therapeutic targets: Emerging opportunities. Nat Rev Drug Discov 14: 543‐560, 2015.
90.	Liu Y, Wang X, Hu CA. Therapeutic potential of amino acids in inflammatory bowel disease. Nutrients 9: E920, 2017.
91.	Ma K, Hu Y, Smith DE. Peptide transporter 1 is responsible for intestinal uptake of the dipeptide glycylsarcosine: Studies in everted jejunal rings from wild‐type and Pept1 null mice. J Pharm Sci 100: 767‐774, 2011.
92.	Mackenzie B, Erickson JD. Sodium‐coupled neutral amino acid (System N/A) transporters of the SLC38 gene family. Pflugers Arch ‐ Eur J Physiol 447: 784‐795, 2004.
93.	Maenz DD, Patience JF. L‐threonine transport in pig jejunal brush border membrane vesicles. Functional characterization of the unique system B in the intestinal epithelium. J Biol Chem 267: 22079‐22086, 1992.
94.	Manifava M, Smith M, Rotondo S, Walker S, Niewczas I, Zoncu R, Clark J, Ktistakis NT. Dynamics of mTORC1 activation in response to amino acids. elife 5: e19960, 2016.
95.	Manoharan P, Sundaram S, Singh S, Sundaram U. Inducible nitric oxide regulates brush border membrane Na‐glucose Co‐transport, but not Na:H exchange via p38 MAP kinase in intestinal epithelial cells. Cell 7: 111, 2018.
96.	Mates JM, Perez‐Gomez C, Nunez de Castro I, Asenjo M, Marquez J. Glutamine and its relationship with intracellular redox status, oxidative stress and cell proliferation/death. Int J Biochem Cell Biol 34: 439‐458, 2002.
97.	McCafferty DM. Peroxynitrite and inflammatory bowel disease. Gut 46: 436‐439, 2000.
98.	Meier Y, Eloranta JJ, Darimont J, Ismair MG, Hiller C, Fried M, Kullak‐Ublick GA, Vavricka SR. Regional distribution of solute carrier mRNA expression along the human intestinal tract. Drug Metab Dispos 35: 590‐594, 2007.
99.	Merlin D, Si‐Tahar M, Sitaraman SV, Eastburn K, Williams I, Liu X, Hediger MA, Madara JL. Colonic epithelial hPepT1 expression occurs in inflammatory bowel disease: Transport of bacterial peptides influences expression of MHC class 1 molecules. Gastroenterology 120: 1666‐1679, 2001.
100.	Miller MJ, Sadowska‐Krowicka H, Chotinaruemol S, Kakkis JL, Clark DA. Amelioration of chronic ileitis by nitric oxide synthase inhibition. J Pharmacol Exp Ther 264: 11‐16, 1993.
101.	Munck BG. Transport of imino acids and non‐alpha‐amino acids across the brush‐border membrane of the rabbit ileum. J Membr Biol 83: 15‐24, 1985.
102.	Munck BG. Transport of neutral and cationic amino acids across the brush‐border membrane of the rabbit ileum. J Membr Biol 83: 1‐13, 1985.
103.	Munck LK, Munck BG. Chloride‐dependence of amino acid transport in rabbit ileum. Biochim Biophys Acta 1027: 17‐20, 1990.
104.	Munck LK, Munck BG. Amino acid transport in the small intestine. Physiol Res 43: 335‐345, 1994.
105.	Murakami M, Kudo I. Phospholipase A2. J Biochem 131: 285‐292, 2002.
106.	Murnin M, Kumar A, Li GD, Brown M, Sumpio BE, Basson MD. Effects of glutamine isomers on human (Caco‐2) intestinal epithelial proliferation, strain‐responsiveness, and differentiation. J Gastrointest Surg 4: 435‐442, 2000.
107.	Na EJ, Nam HY, Park J, Chung MA, Woo HA, Kim H‐J. PI3K‐mTOR‐S6K signaling mediates neuronal viability via collapsin response mediator protein‐2 expression. Front Mol Neurosci 10: 288, 2017.
108.	Nakanishi T, Hatanaka T, Huang W, Prasad PD, Leibach FH, Ganapathy ME, Ganapathy V. Na+‐ and Cl‐‐coupled active transport of carnitine by the amino acid transporter ATB(0,+) from mouse colon expressed in HRPE cells and Xenopus oocytes. J Physiol 532: 297‐304, 2001.
109.	Nakanishi T, Kekuda R, Fei YJ, Hatanaka T, Sugawara M, Martindale RG, Leibach FH, Prasad PD, Ganapathy V. Cloning and functional characterization of a new subtype of the amino acid transport system N. Am J Physiol Cell Physiol 281: C1757‐C1768, 2001.
110.	Nakaya M, Xiao Y, Zhou X, Chang J‐H, Chang M, Cheng X, Blonska M, Lin X, Sun S‐C. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 40: 692‐705, 2014.
111.	Nemirovsky MS, Hugon JS. Immunopathology of guinea pig autoimmune enterocolitis induced by alloimmunisation with an intestinal protein. Gut 27: 1434‐1442, 1986.
112.	Nepal N, Arthur S, Sundaram U. Unique regulation of Na‐K‐ATPase during growth and maturation of intestinal epithelial cells. Cells 8: E593, 2019.
113.	Oishi AJ, Inoue Y, Souba WW, Sarr MG. Alterations in carrier‐mediated glutamine transport after a model of canine jejunal autotransplantation. Dig Dis Sci 41: 1915‐1924, 1996.
114.	Papaconstantinou HT, Hwang KO, Rajaraman S, Hellmich MR, Townsend CM Jr, Ko TC. Glutamine deprivation induces apoptosis in intestinal epithelial cells. Surgery 124: 152‐159; discussion 159‐160, 1998.
115.	Pochini L, Scalise M, Galluccio M, Indiveri C. Membrane transporters for the special amino acid glutamine: Structure/function relationships and relevance to human health. Front Chem 2: 61, 2014.
116.	Powell DW. Immunophysiology of intestinal electrolyte transport. In: Schultz SG, sec. ed., Absorptive and secretory processes of the intestine. Frizzell RA and Field M, vol eds. Handbook of Physiology: The Gastrointestinal System IV. Rockville, MD: American Physiological Society, 1991, p. 591–641.
117.	Rachmilewitz D, Stamler JS, Bachwich D, Karmeli F, Ackerman Z, Podolsky DK. Enhanced colonic nitric oxide generation and nitric oxide synthase activity in ulcerative colitis and Crohn's disease. Gut 36: 718‐723, 1995.
118.	Reimer RJ, Chaudhry FA, Gray AT, Edwards RH. Amino acid transport system A resembles system N in sequence but differs in mechanism. Proc Natl Acad Sci U S A 97: 7715‐7720, 2000.
119.	Ren W, Liu G, Yin J, Tan B, Wu G, Bazer FW, Peng Y, Yin Y. Amino‐acid transporters in T‐cell activation and differentiation. Cell Death Dis 8: e2655‐e2655, 2017.
120.	Rhoads JM, Argenzio RA, Chen W, Rippe RA, Westwick JK, Cox AD, Berschneider HM, Brenner DA. L‐glutamine stimulates intestinal cell proliferation and activates mitogen‐activated protein kinases. Am J Phys 272: G943‐G953, 1997.
121.	Robert A. Antisecretory, antiulcer, cytoprotective and diarrheogenic properties of prostaglandins. Adv Prostaglandin Thromboxane Res 2: 507‐520, 1976.
122.	Robert A. Prostaglandins: Effects on the gastrointestinal tract. Clin Physiol Biochem 2: 61‐69, 1984.
123.	Saha P, Arthur S, Kekuda R, Sundaram U. Na‐glutamine co‐transporters B(0)AT1 in villus and SN2 in crypts are differentially altered in chronically inflamed rabbit intestine. Biochim Biophys Acta 1818: 434‐442, 2012.
124.	Sakiyama T, Musch MW, Ropeleski MJ, Tsubouchi H, Chang EB. Glutamine increases autophagy under basal and stressed conditions in intestinal epithelial cells. Gastroenterology 136: 924‐932, 2009.
125.	Salloum RM, Souba WW, Fernandez A, Stevens BR. Dietary modulation of small intestinal glutamine transport in intestinal brush border membrane vesicles of rats. J Surg Res 48: 635‐638, 1990.
126.	Salloum RM, Stevens BR, Schultz GS, Souba WW. Regulation of small intestinal glutamine transport by epidermal growth factor. Surgery 113: 552‐559, 1993.
127.	Salloum RM, Stevens BR, Souba WW. Adaptive regulation of brush‐border amino acid transport in a chronic excluded jejunal limb. Am J Phys 261: G22‐G27, 1991.
128.	Sartor RB, Cromartie WJ, Powell DW, Schwab JH. Granulomatous enterocolitis induced in rats by purified bacterial cell wall fragments. Gastroenterology 89: 587‐595, 1985.
129.	Sartor RB, Powell DW. Mechanisms of Diarrhea in Inflammation and Hypersensitivity: Immune System Modulation of Intestinal Transport. New York: Elsevier Science Publishing Co, 1991.
130.	Satoh O, Kudo Y, Shikata H, Yamada K, Kawasaki T. Characterization of amino‐acid transport systems in guinea‐pig intestinal brush‐border membrane. Biochim Biophys Acta 985: 120‐126, 1989.
131.	Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell 168: 960‐976, 2017.
132.	Schioth HB, Roshanbin S, Hagglund MG, Fredriksson R. Evolutionary origin of amino acid transporter families SLC32, SLC36 and SLC38 and physiological, pathological and therapeutic aspects. Mol Asp Med 34: 571‐585, 2013.
133.	Sellin JH. Intestinal electrolyte absorption and secretion. In: Feldman M, Scharschmidt BH and Slesisenger MH, editors, Gastrointestinal and Liver Disease. 6th edn, Saunders WB: Philadelphia, 1997, p. 1451‐1470.
134.	Seow HF, Broer S, Broer A, Bailey CG, Potter SJ, Cavanaugh JA, Rasko JE. Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19. Nat Genet 36: 1003‐1007, 2004.
135.	Sharon P, Ligumsky M, Rachmilewitz D, Zor U. Role of prostaglandins in ulcerative colitis. Enhanced production during active disease and inhibition by sulfasalazine. Gastroenterology 75: 638‐640, 1978.
136.	Silva AC, Santos‐Neto MS, Soares AM, Fonteles MC, Guerrant RL, Lima AA. Efficacy of a glutamine‐based oral rehydration solution on the electrolyte and water absorption in a rabbit model of secretory diarrhea induced by cholera toxin. J Pediatr Gastroenterol Nutr 26: 513‐519, 1998.
137.	Singh K, Coburn LA, Barry DP, Asim M, Scull BP, Allaman MM, Lewis ND, Washington MK, Rosen MJ, Williams CS, Chaturvedi R, Wilson KT. Deletion of cationic amino acid transporter 2 exacerbates dextran sulfate sodium colitis and leads to an IL‐17‐predominant T cell response. Am J Physiol Gastrointest Liver Physiol 305: G225‐G240, 2013.
138.	Singh S, Arthur S, Sundaram U. Unique regulation of Na‐glutamine cotransporter SN2/SNAT5 in rabbit intestinal crypt cells during chronic enteritis. J Cell Mol Med 22: 1443‐1451, 2018.
139.	Singh S, Arthur S, Talukder J, Palaniappan B, Coon S, Sundaram U. Mast cell regulation of Na‐glutamine co‐transporters B0AT1 in villus and SN2 in crypt cells during chronic intestinal inflammation. BMC Gastroenterol 15: 47, 2015.
140.	Srinivas SR, Prasad PD, Umapathy NS, Ganapathy V, Shekhawat PS. Transport of butyryl‐L‐carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB(0,+). Am J Physiol Gastrointest Liver Physiol 293: G1046‐G1053, 2007.
141.	Stein A, Hinz M, Uncini T. Amino acid‐responsive Crohn's disease: A case study. Clin Exp Gastroenterol 3: 171‐177, 2010.
142.	Sugawara M, Nakanishi T, Fei YJ, Martindale RG, Ganapathy ME, Leibach FH, Ganapathy V. Structure and function of ATA3, a new subtype of amino acid transport system A, primarily expressed in the liver and skeletal muscle. Biochim Biophys Acta 1509: 7‐13, 2000.
143.	Sundaram U, Hassanain H, Suntres Z, Yu JG, Cooke HJ, Guzman J, Christofi FL. Rabbit chronic ileitis leads to up‐regulation of adenosine A1/A3 gene products, oxidative stress, and immune modulation. Biochem Pharmacol 65: 1529‐1538, 2003.
144.	Sundaram U, Knickelbein RG, Dobbins JW. Mechanism of intestinal secretion. Effect of serotonin on rabbit ileal crypt and villus cells. J Clin Invest 87: 743‐746, 1991.
145.	Sundaram U, Knickelbein RG, Dobbins JW. Mechanism of intestinal secretion: Effect of cyclic AMP on rabbit ileal crypt and villus cells. Proc Natl Acad Sci U S A 88: 6249‐6253, 1991.
146.	Sundaram U, Knickelbein RG, Dobbins JW. pH regulation in ileum: Na(+)‐H+ and Cl(‐)‐HCO3‐ exchange in isolated crypt and villus cells. Am J Phys 260: G440‐G449, 1991.
147.	Sundaram U, West AB. Effect of chronic inflammation on electrolyte transport in rabbit ileal villus and crypt cells. Am J Phys 272: G732‐G741, 1997.
148.	Sundaram U, Wisel S, Coon S. Mechanism of inhibition of proton: Dipeptide co‐transport during chronic enteritis in the mammalian small intestine. Biochim Biophys Acta 1714: 134‐140, 2005.
149.	Sundaram U, Wisel S, Coon S. Neutral Na‐amino acid cotransport is differentially regulated by glucocorticoids in the normal and chronically inflamed rabbit small intestine. Am J Physiol Gastrointest Liver Physiol 292: G467‐G474, 2007.
150.	Sundaram U, Wisel S, Fromkes JJ. Unique mechanism of inhibition of Na+‐amino acid cotransport during chronic ileal inflammation. Am J Phys 275: G483‐G489, 1998.
151.	Sundaram U, Wisel S, Rajendren VM, West AB. Mechanism of inhibition of Na+‐glucose cotransport in the chronically inflamed rabbit ileum. Am J Phys 273: G913‐G919, 1997.
152.	Sundaram U, Wisel S, Stengelin S, Kramer W, Rajendran V. Mechanism of inhibition of Na+‐bile acid cotransport during chronic ileal inflammation in rabbits. Am J Phys 275: G1259‐G1265, 1998.
153.	Talukder JR, Kekuda R, Saha P, Arthur S, Sundaram U. Identification and characterization of rabbit small intestinal villus cell brush border membrane Na‐glutamine cotransporter. Am J Physiol Gastrointest Liver Physiol 295: G7‐g15, 2008.
154.	Talukder JR, Kekuda R, Saha P, Prasad PD, Ganapathy V, Sundaram U. Functional characterization, localization, and molecular identification of rabbit intestinal N‐amino acid transporter. Am J Physiol Gastrointest Liver Physiol 294: G1301‐G1310, 2008.
155.	Talukder JR, Kekuda R, Saha P, Sundaram U. Mechanism of leukotriene D4 inhibition of Na‐alanine cotransport in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 295: G1‐G6, 2008.
156.	Taylor PM. Role of amino acid transporters in amino acid sensing. Am J Clin Nutr 99: 223s‐230s, 2014.
157.	Theoharides TC, Alysandratos KD, Angelidou A, Delivanis DA, Sismanopoulos N, Zhang B, Asadi S, Vasiadi M, Weng Z, Miniati A, Kalogeromitros D. Mast cells and inflammation. Biochim Biophys Acta 1822: 21‐33, 2012.
158.	Torres J, Mehandru S, Colombel JF, Peyrin‐Biroulet L. Crohn's disease. Lancet (London, England) 389: 1741‐1755, 2017.
159.	Torres‐Zamorano v, Kekuda R, Leibach FH, Ganapathy V. Tyrosine phosphorylation‐and epidermal growth factor‐dependent regulation of the sodium‐coupled amino acid transporter B0 in the human placental choriocarcinoma cell line JAR. Biochim Biophys Acta 1356: 258‐270, 1997.
160.	Tremel H, Kienle B, Weilemann LS, Stehle P, Furst P. Glutamine dipeptide‐supplemented parenteral nutrition maintains intestinal function in the critically ill. Gastroenterology 107: 1595‐1601, 1994.
161.	Tumer E, Broer A, Balkrishna S, Julich T, Broer S. Enterocyte‐specific regulation of the apical nutrient transporter SLC6A19 (B(0)AT1) by transcriptional and epigenetic networks. J Biol Chem 288: 33813‐33823, 2013.
162.	Sundaram U. The small intestine. In: Spiro HM, ed. Clinical Gastroenterology, Chapter 19. McGraw‐Hill Inc, 1993, p. 343–366.
163.	Umar S. Intestinal stem cells. Curr Gastroenterol Rep 12: 340‐348, 2010.
164.	Vallance BA, Dijkstra G, Qiu B, van der Waaij LA, van Goor H, Jansen PL, Mashimo H, Collins SM. Relative contributions of NOS isoforms during experimental colitis: Endothelial‐derived NOS maintains mucosal integrity. Am J Physiol Gastrointest Liver Physiol 287: G865‐G874, 2004.
165.	van Acker BA, Hulsewe KW, Wagenmakers AJ, Soeters PB, von Meyenfeldt MF. Glutamine appearance rate in plasma is not increased after gastrointestinal surgery in humans. J Nutr 130: 1566‐1571, 2000.
166.	van der Wielen N, Mensink M, Moughan PJ. Amino Acid Absorption in the Large Intestine of Humans and Porcine Models. J Nutr 147: 1493‐1498, 2017.
167.	Van Voorhis K, Said HM, Ghishan FK, Abumrad NN. Transport of glutamine in rat intestinal brush‐border membrane vesicles. Biochim Biophys Acta 978: 51‐55, 1989.
168.	Varanasi S, Coon S, Sundaram U. Mast cell membrane stabilization alleviated the inhibition of Na‐amino Co‐transport in the chronically inflamed intestine. Gastroenterlogy 122: W952, 2002.
169.	Varoqui H, Zhu H, Yao D, Ming H, Erickson JD. Cloning and functional identification of a neuronal glutamine transporter. J Biol Chem 275: 4049‐4054, 2000.
170.	Vicario M, Amat C, Rivero M, Moreto M, Pelegri C. Dietary glutamine affects mucosal functions in rats with mild DSS‐induced colitis. J Nutr 137: 1931‐1937, 2007.
171.	Vuille‐dit‐Bille RN, Camargo SM, Emmenegger L, Sasse T, Kummer E, Jando J, Hamie QM, Meier CF, Hunziker S, Forras‐Kaufmann Z, Kuyumcu S, Fox M, Schwizer W, Fried M, Lindenmeyer M, Gotze O, Verrey F. Human intestine luminal ACE2 and amino acid transporter expression increased by ACE‐inhibitors. Amino Acids 47: 693‐705, 2015.
172.	Wallace JL, Miller MJ. Nitric oxide in mucosal defense: A little goes a long way. Gastroenterology 119: 512‐520, 2000.
173.	Williams JM, Duckworth CA, Burkitt MD, Watson AJM, Campbell BJ, Pritchard DM. Epithelial cell shedding and barrier function: A matter of life and death at the small intestinal villus tip. Vet Pathol 52: 445‐455, 2015.
174.	Windmueller HG, Spaeth AE. Respiratory fuels and nitrogen metabolism in vivo in small intestine of fed rats. Quantitative importance of glutamine, glutamate, and aspartate. J Biol Chem 255: 107‐112, 1980.
175.	Wischmeyer PE. Glutamine and heat shock protein expression. Nutrition 18: 225‐228, 2002.
176.	Wischmeyer PE, Musch MW, Madonna MB, Thisted R, Chang EB. Glutamine protects intestinal epithelial cells: Role of inducible HSP70. Am J Phys 272: G879‐G884, 1997.
177.	Xue H, Sufit AJ, Wischmeyer PE. Glutamine therapy improves outcome of in vitro and in vivo experimental colitis models. JPEN J Parenter Enteral Nutr 35: 188‐197, 2011.
178.	Yang Z, Liao SF. Physiological effects of dietary amino acids on gut health and functions of swine. Front Vet Sci 6: 169, 2019.
179.	Yoon M‐S. The role of mammalian target of rapamycin (mTOR) in insulin signaling. Nutrients 9: 1176, 2017.

Article Title:	Mechanisms of Regulation of Transporters of Amino Acid Absorption in Inflammatory Bowel Diseases
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