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Proton Coupled Oligopeptide Transporter 1 (PepT1) Function, Regulation, and Influence on the Intestinal Homeostasis

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ABSTRACT

As the organ with one of the largest surface areas facing the environment and responsible for nutrient uptake, the small intestine expresses numerous transport proteins in its brush‐border membrane for efficient absorption and supply of dietary macro‐ and micronutrients. The understanding of regulation and functional interplay of these nutrient transporters is of emerging interest in nutrition and medical physiology research in respect to development of diabetes, obesity, and inflammatory bowel disease worldwide. The peptide transporter 1 (PepT1, SLC15A1) is abundantly expressed particularly in the intestinal tract and provides highly effective transport of amino acids in the form of di‐ and tripeptides and features a substantial acceptance for structurally related compounds and drugs. These characteristics bring PepT1 into focus for nutritional and medical/pharmaceutical approaches, as it is the essential hub responsible for oral bioavailability of dietary protein/peptide supplements and peptide‐like drugs in eukaryotic organisms. Detailed analysis of molecular processes regulating PepT1 expression and function achieved in the last two decades has helped to define and use adjusting tools and to better integrate the transporter's role in cell and organ physiology. In this article, we provide an overview of the current knowledge on PepT1 function in health and disease, and on regulatory factors modulating its gene and protein expression as well as transport activity. © 2018 American Physiological Society. Compr Physiol 8:843‐869, 2018.

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Figure 1. Figure 1. Amino acid and di‐ and tripeptide transporters in the apical and basolateral membrane of mammalian enterocytes in small intestine. The brush‐border membrane contains transport proteins for acidic amino acids (EAAT3), for glycine/proline (PAT1, IMINO), for neutral amino acids (B0AT1/ACE2), for basic in exchange with neutral amino acids (b0,+AT/rBAT), and for di‐ and tripeptides (PepT1). All heterodimeric amino acid transporters only function in the presence of their heavy chain (ACE2, rBAT, or 4F2hc). Most transporters are electrogenic and couple substrate uptake with ion movement. The function of PAT1 and PepT1 is dependent on the pH gradient between gut lumen and cytoplasm, which is maintained by the sodium‐proton exchanger NHE3. The Na+ gradient on the other hand is stabilized by the Na+/K+‐ATPase. In the cytoplasm, most peptides are hydrolyzed by numerous cytosolic peptidases and the released amino acids will be exported via basolateral amino acid transporters. TAT1 exports aromatic amino acids, SNAT2 imports neutral amino acids, while LAT2/4F2hc and y + LAT1/4F2hc are responsible for exchange of neutral or basic amino acids against neutral ones. The postulated basolateral peptide transporter that allows release of small peptides and structurally related drugs into the blood stream has not been identified yet.
Figure 2. Figure 2. Tissue distribution of peptide transporters PepT1 and PepT2 in humans. The PepT1 protein is mainly expressed in the small intestine, with increasing expression from duodenum to ileum. It can also be found in low concentrations in the distal colon, in the proximal tubulus of the kidney and in bile duct, pancreas, and placenta. PepT2 is the renal isoform, predominantly expressed in the distal tubulus, but also present in brain, glia cells, lung, and mammary gland. The scheme of the human corpus is from an open source (https://pixabay.com).
Figure 3. Figure 3. Expression of PepT1 protein along the mouse small intestine and colon. Representative images of duodenum (A), jejunum (B), ileum (C), and proximal (D), middle (E), and distal (F) colon tissue. Nuclei are stained with DAPI (blue), and mouse PepT1 protein expression was detected by custom‐made anti‐mPepT1 antibody, which was used before (). PepT1 expression increases from proximal to distal colon.
Figure 4. Figure 4. The role of PepT1 in intestinal homeostasis. The wide variety of PepT1 substrates includes exogenous oligopeptides like the C‐terminal sequence of α‐melanocyte stimulating hormone (α‐MSH) Lys‐Pro‐Val (KPV) and the dietary soy tripeptide Val‐Pro‐Tyr (VPY), as well as endogenous bacterial oligopeptides. Uptake via PepT1 of bacterial products like L‐Ala‐γ‐D‐Glu‐meso‐diaminopimelic acid (Tri‐DAP) and muramyl dipeptide (MDP), a constituent of bacterial cell walls, is associated with the activation of mitogen‐activated protein (MAP) kinase pathway and NF‐κB, and subsequently an increase in proinflammatory cytokine expression in enterocytes. In intestinal macrophages, PepT1‐mediated uptake of bacterial products induces an increase in proinflammatory cytokine secretion that, together with the increased cytokine levels in enterocytes, may contribute to the pathogenesis or promotion of intestinal inflammation. PepT1‐mediated uptake of other bacterial peptides like N‐formyl‐Met‐Leu‐Phe (fMLF) as well as of aforementioned KPV and VPY on the other hand conveys anti‐inflammatory properties by inhibition of proinflammatory cytokine secretion due to reduced activation of NF‐κB and MAP kinase inflammatory signaling pathways. Besides these anti‐inflammatory effects associated with PepT1 transport activity, PepT1 may also directly affect bacterial‐epithelial interactions. Certain enteropathogenic bacteria attaching to enterocytes specifically via lipid rafts induce PepT1 expression in said lipid rafts. Increased intestinal PepT1 expression in turn reduces bacterial lipid raft attachment, while at the same time reducing activity of NF‐κB, MAP kinase and secretion of proinflammatory cytokines, implying an anti‐inflammatory role of PepT1 in intestinal host defense against pathogenic enterobacteria.
Figure 5. Figure 5. Functions of peptide transporter PepT1. In the last decade it became more and more obvious, that next to the transport of di‐ and tripeptides and peptidomimetic drugs, the activity pattern of PepT1 is much more complex. In distal ileum and in the colon the uptake of bacterial‐derived peptides plays a role in inflammatory processes and in the development of diseases. For stabilization of the intestinal homeostasis PepT1 is embedded in a network consisting of protein hydrolysis (peptidases), amino acid supply, mTOR signaling, protein de novo synthesis, and unfolded protein response (UPR). The analysis of its transceptor function, its regulation by micro RNAs (miRNA), and its direct protein‐protein interactions are relatively novel fields and they will improve the understanding of the peptide transporters.


Figure 1. Amino acid and di‐ and tripeptide transporters in the apical and basolateral membrane of mammalian enterocytes in small intestine. The brush‐border membrane contains transport proteins for acidic amino acids (EAAT3), for glycine/proline (PAT1, IMINO), for neutral amino acids (B0AT1/ACE2), for basic in exchange with neutral amino acids (b0,+AT/rBAT), and for di‐ and tripeptides (PepT1). All heterodimeric amino acid transporters only function in the presence of their heavy chain (ACE2, rBAT, or 4F2hc). Most transporters are electrogenic and couple substrate uptake with ion movement. The function of PAT1 and PepT1 is dependent on the pH gradient between gut lumen and cytoplasm, which is maintained by the sodium‐proton exchanger NHE3. The Na+ gradient on the other hand is stabilized by the Na+/K+‐ATPase. In the cytoplasm, most peptides are hydrolyzed by numerous cytosolic peptidases and the released amino acids will be exported via basolateral amino acid transporters. TAT1 exports aromatic amino acids, SNAT2 imports neutral amino acids, while LAT2/4F2hc and y + LAT1/4F2hc are responsible for exchange of neutral or basic amino acids against neutral ones. The postulated basolateral peptide transporter that allows release of small peptides and structurally related drugs into the blood stream has not been identified yet.


Figure 2. Tissue distribution of peptide transporters PepT1 and PepT2 in humans. The PepT1 protein is mainly expressed in the small intestine, with increasing expression from duodenum to ileum. It can also be found in low concentrations in the distal colon, in the proximal tubulus of the kidney and in bile duct, pancreas, and placenta. PepT2 is the renal isoform, predominantly expressed in the distal tubulus, but also present in brain, glia cells, lung, and mammary gland. The scheme of the human corpus is from an open source (https://pixabay.com).


Figure 3. Expression of PepT1 protein along the mouse small intestine and colon. Representative images of duodenum (A), jejunum (B), ileum (C), and proximal (D), middle (E), and distal (F) colon tissue. Nuclei are stained with DAPI (blue), and mouse PepT1 protein expression was detected by custom‐made anti‐mPepT1 antibody, which was used before (). PepT1 expression increases from proximal to distal colon.


Figure 4. The role of PepT1 in intestinal homeostasis. The wide variety of PepT1 substrates includes exogenous oligopeptides like the C‐terminal sequence of α‐melanocyte stimulating hormone (α‐MSH) Lys‐Pro‐Val (KPV) and the dietary soy tripeptide Val‐Pro‐Tyr (VPY), as well as endogenous bacterial oligopeptides. Uptake via PepT1 of bacterial products like L‐Ala‐γ‐D‐Glu‐meso‐diaminopimelic acid (Tri‐DAP) and muramyl dipeptide (MDP), a constituent of bacterial cell walls, is associated with the activation of mitogen‐activated protein (MAP) kinase pathway and NF‐κB, and subsequently an increase in proinflammatory cytokine expression in enterocytes. In intestinal macrophages, PepT1‐mediated uptake of bacterial products induces an increase in proinflammatory cytokine secretion that, together with the increased cytokine levels in enterocytes, may contribute to the pathogenesis or promotion of intestinal inflammation. PepT1‐mediated uptake of other bacterial peptides like N‐formyl‐Met‐Leu‐Phe (fMLF) as well as of aforementioned KPV and VPY on the other hand conveys anti‐inflammatory properties by inhibition of proinflammatory cytokine secretion due to reduced activation of NF‐κB and MAP kinase inflammatory signaling pathways. Besides these anti‐inflammatory effects associated with PepT1 transport activity, PepT1 may also directly affect bacterial‐epithelial interactions. Certain enteropathogenic bacteria attaching to enterocytes specifically via lipid rafts induce PepT1 expression in said lipid rafts. Increased intestinal PepT1 expression in turn reduces bacterial lipid raft attachment, while at the same time reducing activity of NF‐κB, MAP kinase and secretion of proinflammatory cytokines, implying an anti‐inflammatory role of PepT1 in intestinal host defense against pathogenic enterobacteria.


Figure 5. Functions of peptide transporter PepT1. In the last decade it became more and more obvious, that next to the transport of di‐ and tripeptides and peptidomimetic drugs, the activity pattern of PepT1 is much more complex. In distal ileum and in the colon the uptake of bacterial‐derived peptides plays a role in inflammatory processes and in the development of diseases. For stabilization of the intestinal homeostasis PepT1 is embedded in a network consisting of protein hydrolysis (peptidases), amino acid supply, mTOR signaling, protein de novo synthesis, and unfolded protein response (UPR). The analysis of its transceptor function, its regulation by micro RNAs (miRNA), and its direct protein‐protein interactions are relatively novel fields and they will improve the understanding of the peptide transporters.
References
 1. Abousaab A , Warsi J , Salker MS , Lang F . Beta‐Klotho as a negative regulator of the peptide transporters PEPT1 and PEPT2. Cell Physiol Biochem 40: 874‐882, 2016.
 2. Adibi SA. The oligopeptide transporter (Pept‐1) in human intestine: Biology and function. Gastroenterology 113: 332‐340, 1997.
 3. Adibi SA , Mercer DW . Protein digestion in human intestine as reflected in luminal, mucosal, and plasma amino acid concentrations after meals. J Clin Invest 52: 1586‐1594, 1973.
 4. Anderle P , Nielsen CU , Pinsonneault J , Krog PL , Brodin B , Sadee W . Genetic variants of the human dipeptide transporter PEPT1. J Pharmacol Exp Ther 316: 636‐646, 2006.
 5. Arakawa H , Ohmachi T , Ichiba K , Kamioka H , Tomono T , Kanagawa M , Idota Y , Hatano Y , Yano K , Morimoto K , Ogihara T . Interaction of peptide transporter 1 with D‐glucose and L‐glutamic acid; possible involvement of taste receptors. J Pharm Sci 105: 339‐342, 2016.
 6. Arakawa H , Saito S , Kanagawa M , Kamioka H , Yano K , Morimoto K , Ogihara T . Evaluation of a thiodipeptide, L‐phenylalanyl‐Psi[CS‐N]‐L‐alanine, as a novel probe for peptide transporter 1. Drug Metab Pharmacokinet 29: 470‐474, 2014.
 7. Ashrafi K , Chang FY , Watts JL , Fraser AG , Kamath RS , Ahringer J , Ruvkun G . Genome‐wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature 421: 268‐272, 2003.
 8. Ayyadurai S , Charania MA , Xiao B , Viennois E , Merlin D . PepT1 expressed in immune cells has an important role in promoting the immune response during experimentally induced colitis. Lab Invest 93: 888‐899, 2013.
 9. Ayyadurai S , Charania MA , Xiao B , Viennois E , Zhang Y , Merlin D . Colonic miRNA expression/secretion, regulated by intestinal epithelial PepT1, plays an important role in cell‐to‐cell communication during colitis. PLoS One 9: e87614, 2014.
 10. Bartel DP . MicroRNAs: Target recognition and regulatory functions. Cell 136: 215‐233, 2009.
 11. Beale JH , Parker JL , Samsudin F , Barrett AL , Senan A , Bird LE , Scott D , Owens RJ , Sansom MS , Tucker SJ , Meredith D , Fowler PW , Newstead S . Crystal structures of the extracellular domain from PepT1 and PepT2 provide novel insights into mammalian peptide transport. Structure 23: 1889‐1899, 2015.
 12. Benner J , Daniel H , Spanier B . A glutathione peroxidase, intracellular peptidases and the TOR complexes regulate peptide transporter PEPT‐1 in C. elegans . PLoS One 6: e25624, 2011.
 13. Berezikov E , Guryev V , van de Belt J , Wienholds E , Plasterk RH , Cuppen E . Phylogenetic shadowing and computational identification of human microRNA genes. Cell 120: 21‐24, 2005.
 14. Berthelsen R , Nielsen CU , Brodin B . Basolateral glycylsarcosine (Gly‐Sar) transport in Caco‐2 cell monolayers is pH dependent. J Pharm Pharmacol 65: 970‐979, 2013.
 15. Biegel A , Gebauer S , Hartrodt B , Brandsch M , Neubert K , Thondorf I . Three‐dimensional quantitative structure‐activity relationship analyses of beta‐lactam antibiotics and tripeptides as substrates of the mammalian H+/peptide cotransporter PEPT1. J Med Chem 48: 4410‐4419, 2005.
 16. Bikhazi AB , Skoury MM , Zwainy DS , Jurjus AR , Kreydiyyeh SI , Smith DE , Audette K , Jacques D . Effect of diabetes mellitus and insulin on the regulation of the PepT 1 symporter in rat jejunum. Mol Pharm 1: 300‐308, 2004.
 17. Bockman DE , Ganapathy V , Oblak TG , Leibach FH . Localization of peptide transporter in nuclei and lysosomes of the pancreas. Int J Pancreatol 22: 221‐225, 1997.
 18. Boehmer C , Palmada M , Klaus F , Jeyaraj S , Lindner R , Laufer J , Daniel H , Lang F . The peptide transporter PEPT2 is targeted by the protein kinase SGK1 and the scaffold protein NHERF2. Cell Physiol Biochem 22: 705‐714, 2008.
 19. Boggavarapu R , Jeckelmann JM , Harder D , Ucurum Z , Fotiadis D . Role of electrostatic interactions for ligand recognition and specificity of peptide transporters. BMC Biol 13: 58, 2015.
 20. Boll M , Markovich D , Weber WM , Korte H , Daniel H , Murer H . Expression cloning of a cDNA from rabbit small intestine related to proton‐coupled transport of peptides, beta‐lactam antibiotics and ACE‐inhibitors. Pflugers Arch 429: 146‐149, 1994.
 21. Börner V. Einfluss von Strukturparametern auf die Interaktion von Aminosäure‐ und Peptidderivaten mit dem intestinalen H+/Peptidsymporter PEPT1. (PhD thesis): Martin‐Luther‐Universität Halle‐Wittenberg, 2002.
 22. Boudry G , Rome V , Perrier C , Jamin A , Savary G , Le Huerou‐Luron I . A high‐protein formula increases colonic peptide transporter 1 activity during neonatal life in low‐birth‐weight piglets and disturbs barrier function later in life. Br J Nutr 112: 1073‐1080, 2014.
 23. Brandsch M. Transport of L‐proline, L‐proline‐containing peptides and related drugs at mammalian epithelial cell membranes. Amino Acids 31: 119‐136, 2006.
 24. Brandsch M. Transport of drugs by proton‐coupled peptide transporters: Pearls and pitfalls. Expert Opin Drug Metab Toxicol 5: 887‐905, 2009.
 25. Brandsch M , Knutter I , Leibach FH . The intestinal H+/peptide symporter PEPT1: Structure‐affinity relationships. Eur J Pharm Sci 21: 53‐60, 2004.
 26. Brandsch M , Knutter I , Thunecke F , Hartrodt B , Born I , Borner V , Hirche F , Fischer G , Neubert K . Decisive structural determinants for the interaction of proline derivatives with the intestinal H+/peptide symporter. Eur J Biochem 266: 502‐508, 1999.
 27. Bray GA , York DA. Obesity (legacy). Compr Physiol, 2010. DOI: 10.1002/cphy.cp070234.
 28. Bretschneider B , Brandsch M , Neubert R . Intestinal transport of beta‐lactam antibiotics: Analysis of the affinity at the H+/peptide symporter (PEPT1), the uptake into Caco‐2 cell monolayers and the transepithelial flux. Pharm Res 16: 55‐61, 1999.
 29. Broer S , Broer A . Amino acid homeostasis and signalling in mammalian cells and organisms. Biochem J 474: 1935‐1963, 2017.
 30. Brooks KK , Liang B , Watts JL . The influence of bacterial diet on fat storage in C. elegans . PLoS One 4: e7545, 2009.
 31. Bruckmueller H , Martin P , Kahler M , Haenisch S , Ostrowski M , Drozdzik M , Siegmund W , Cascorbi I , Oswald S . Clinically relevant multidrug transporters are regulated by microRNAs along the human intestine. Mol Pharm 14: 2245‐2253, 2017.
 32. Buyse M , Charrier L , Sitaraman S , Gewirtz A , Merlin D . Interferon‐gamma increases hPepT1‐mediated uptake of di‐tripeptides including the bacterial tripeptide fMLP in polarized intestinal epithelia. Am J Pathol 163: 1969‐1977, 2003.
 33. Calapai G , Corica F , Corsonello A , Sautebin L , Di Rosa M , Campo GM , Buemi M , Mauro VN , Caputi AP . Leptin increases serotonin turnover by inhibition of brain nitric oxide synthesis. J Clin Invest 104: 975‐982, 1999.
 34. Carlson RM , Vavricka SR , Eloranta JJ , Musch MW , Arvans DL , Kles KA , Walsh‐Reitz MM , Kullak‐Ublick GA , Chang EB . fMLP induces Hsp27 expression, attenuates NF‐kappaB activation, and confers intestinal epithelial cell protection. Am J Physiol Gastrointest Liver Physiol 292: G1070‐G1078, 2007.
 35. Chappell VL , Thompson MD , Jeschke MG , Chung DH , Thompson JC , Wolf SE . Effects of incremental starvation on gut mucosa. Dig Dis Sci 48: 765‐769, 2003.
 36. Chen HQ , Yang J , Zhang M , Zhou YK , Shen TY , Chu ZX , Zhang M , Hang XM , Jiang YQ , Qin HL . Lactobacillus plantarum ameliorates colonic epithelial barrier dysfunction by modulating the apical junctional complex and PepT1 in IL‐10 knockout mice. Am J Physiol Gastrointest Liver Physiol 299: G1287‐G1297, 2010.
 37. Chen M , Singh A , Xiao F , Dringenberg U , Wang J , Engelhardt R , Yeruva S , Rubio‐Aliaga I , Nassl AM , Kottra G , Daniel H , Seidler U . Gene ablation for PEPT1 in mice abolishes the effects of dipeptides on small intestinal fluid absorption, short‐circuit current, and intracellular pH. Am J Physiol Gastrointest Liver Physiol 299: G265‐G274, 2010.
 38. Consortium TCeS. Genome sequence of the nematode C. elegans: A platform for investigating biology. Science 282: 2012‐2018, 1998.
 39. Coon SD , Rajendran VM , Schwartz JH , Singh SK . Glucose‐dependent insulinotropic polypeptide‐mediated signaling pathways enhance apical PepT1 expression in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 308: G56‐G62, 2015.
 40. Coon SD , Schwartz JH , Rajendran VM , Jepeal L , Singh SK . Glucose‐dependent insulinotropic polypeptide regulates dipeptide absorption in mouse jejunum. Am J Physiol Gastrointest Liver Physiol 305: G678‐G684, 2013.
 41. Dai X , Chen X , Chen Q , Shi L , Liang H , Zhou Z , Liu Q , Pang W , Hou D , Wang C , Zen K , Yuan Y , Zhang CY , Xia L . MicroRNA‐193a‐3p reduces intestinal inflammation in response to microbiota via down‐regulation of colonic PepT1. J Biol Chem 290: 16099‐16115, 2015.
 42. Dalmasso G , Charrier‐Hisamuddin L , Nguyen HT , Yan Y , Sitaraman S , Merlin D . PepT1‐mediated tripeptide KPV uptake reduces intestinal inflammation. Gastroenterology 134: 166‐178, 2008.
 43. Dalmasso G , Nguyen HT , Charrier‐Hisamuddin L , Yan Y , Laroui H , Demoulin B , Sitaraman SV , Merlin D . PepT1 mediates transport of the pro‐inflammatory bacterial tripeptide L‐Ala‐{gamma}‐D‐Glu‐meso‐DAP in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 299(3): G687‐G696, 2010.
 44. Dalmasso G , Nguyen HT , Ingersoll SA , Ayyadurai S , Laroui H , Charania MA , Yan Y , Sitaraman SV , Merlin D . The PepT1‐NOD2 signaling pathway aggravates induced colitis in mice. Gastroenterology 141: 1334‐1345, 2011.
 45. Dalmasso G , Nguyen HT , Yan Y , Charrier‐Hisamuddin L , Sitaraman SV , Merlin D . Butyrate transcriptionally enhances peptide transporter PepT1 expression and activity. PLoS One 3: e2476, 2008.
 46. Dalmasso G , Nguyen HT , Yan Y , Laroui H , Charania MA , Obertone TS , Sitaraman SV , Merlin D . MicroRNA‐92b regulates expression of the oligopeptide transporter PepT1 in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 300: G52‐G59, 2011.
 47. Daniel H , Kottra G . The proton oligopeptide cotransporter family SLC15 in physiology and pharmacology. Pflugers Arch 447: 610‐618, 2004.
 48. Daniel H , Morse EL , Adibi SA . Determinants of substrate affinity for the oligopeptide/H+ symporter in the renal brush border membrane. J Biol Chem 267: 9565‐9573, 1992.
 49. Daniel H , Spanier B , Kottra G , Weitz D . From bacteria to man: Archaic proton‐dependent peptide transporters at work. Physiology (Bethesda) 21: 93‐102, 2006.
 50. Daniel H , Zietek T . Taste and move: Glucose and peptide transporters in the gastrointestinal tract. Exp Physiol 100: 1441‐1450, 2015.
 51. de Souza HS , Fiocchi C . Immunopathogenesis of IBD: Current state of the art. Nat Rev Gastroenterol Hepatol 13: 13‐27, 2016.
 52. Der‐Boghossian AH , Saad SR , Perreault C , Provost C , Jacques D , Kadi LN , Issa NG , Sibai AM , El‐Majzoub NW , Bikhazi AB . Role of insulin on jejunal PepT1 expression and function regulation in diabetic male and female rats. Can J Physiol Pharmacol 88: 753‐759, 2010.
 53. Diakogiannaki E , Pais R , Tolhurst G , Parker HE , Horscroft J , Rauscher B , Zietek T , Daniel H , Gribble FM , Reimann F . Oligopeptides stimulate glucagon‐like peptide‐1 secretion in mice through proton‐coupled uptake and the calcium‐sensing receptor. Diabetologia 56: 2688‐2696, 2013.
 54. Doki S , Kato HE , Solcan N , Iwaki M , Koyama M , Hattori M , Iwase N , Tsukazaki T , Sugita Y , Kandori H , Newstead S , Ishitani R , Nureki O . Structural basis for dynamic mechanism of proton‐coupled symport by the peptide transporter POT. Proc Natl Acad Sci U S A 110: 11343‐11348, 2013.
 55. Donowitz M , Ming Tse C , Fuster D . SLC9/NHE gene family, a plasma membrane and organellar family of Na(+)/H(+) exchangers. Mol Aspects Med 34: 236‐251, 2013.
 56. Durchschein F , Petritsch W , Hammer HF . Diet therapy for inflammatory bowel diseases: The established and the new. World J Gastroenterol 22: 2179‐2194, 2016.
 57. Eaden JA , Abrams KR , Mayberry JF . The risk of colorectal cancer in ulcerative colitis: A meta‐analysis. Gut 48: 526‐535, 2001.
 58. Eddy EP , Wood C , Miller J , Wilson G , Hidalgo IJ . A comparison of the affinities of dipeptides and antibiotics for the di‐/tripeptide transporter in Caco‐2 cells. Int J Pharm 115: 79‐86, 1995.
 59. Elvira B , Blecua M , Luo D , Yang W , Shumilina E , Munoz C , Lang F . SPAK‐sensitive regulation of glucose transporter SGLT1. J Membr Biol 247: 1191‐1197, 2014.
 60. Erickson RH , Gum JR, Jr. , Lindstrom MM , McKean D , Kim YS . Regional expression and dietary regulation of rat small intestinal peptide and amino acid transporter mRNAs. Biochem Biophys Res Commun 216: 249‐257, 1995.
 61. Eriksson AH , Varma MV , Perkins EJ , Zimmerman CL . The intestinal absorption of a prodrug of the mGlu2/3 receptor agonist LY354740 is mediated by PEPT1: In situ rat intestinal perfusion studies. J Pharm Sci 99: 1574‐1581, 2010.
 62. Fei YJ , Kanai Y , Nussberger S , Ganapathy V , Leibach FH , Romero MF , Singh SK , Boron WF , Hediger MA . Expression cloning of a mammalian proton‐coupled oligopeptide transporter. Nature 368: 563‐566, 1994.
 63. Fei YJ , Sugawara M , Liu JC , Li HW , Ganapathy V , Ganapathy ME , Leibach FH . cDNA structure, genomic organization, and promoter analysis of the mouse intestinal peptide transporter PEPT1. Biochim Biophys Acta 1492: 145‐154, 2000.
 64. Felix MA , Braendle C . The natural history of Caenorhabditis elegans . Curr Biol 20: R965‐R969, 2010.
 65. Foster DR , Landowski CP , Zheng X , Amidon GL , Welage LS . Interferon‐gamma increases expression of the di/tri‐peptide transporter, h‐PEPT1, and dipeptide transport in cultured human intestinal monolayers. Pharmacol Res 59: 215‐220, 2009.
 66. Ganapathy V , Leibach FH. Is intestinal peptide transport energized by a proton gradient? Am J Physiol 249: G153‐G160, 1985.
 67. Ganapathy ME , Huang W , Wang H , Ganapathy V , Leibach FH . Valacyclovir: A substrate for the intestinal and renal peptide transporters PEPT1 and PEPT2. Biochem Biophys Res Commun 246: 470‐475, 1998.
 68. Ganapathy ME , Mahesh VB , Devoe LD , Leibach FH , Ganapathy V . Dipeptide transport in brush‐border membrane vesicles isolated from normal term human placenta. Am J Obstet Gynecol 153: 83‐86, 1985.
 69. Gangopadhyay A , Thamotharan M , Adibi SA . Regulation of oligopeptide transporter (Pept‐1) in experimental diabetes. Am J Physiol Gastrointest Liver Physiol 283: G133‐G138, 2002.
 70. Geillinger KE , Kipp AP , Schink K , Roder PV , Spanier B , Daniel H . Nrf2 regulates the expression of the peptide transporter PEPT1 in the human colon carcinoma cell line Caco‐2. Biochim Biophys Acta 1840: 1747‐1754, 2014.
 71. Geillinger KE , Kuhlmann K , Eisenacher M , Giesbertz P , Meyer HE , Daniel H , Spanier B . Intestinal amino acid availability via PEPT‐1 affects TORC1/2 signaling and the unfolded protein response. J Proteome Res 13: 3685‐3692, 2014.
 72. Gillingham MB , Dahly EM , Carey HV , Clark MD , Kritsch KR , Ney DM . Differential jejunal and colonic adaptation due to resection and IGF‐I in parenterally fed rats. Am J Physiol Gastrointest Liver Physiol 278: G700‐G709, 2000.
 73. Gilzad Kohan H , Kaur K , Jamali F . Synthesis and characterization of a new peptide prodrug of glucosamine with enhanced gut permeability. PLoS One 10: e0126786, 2015.
 74. Groneberg DA , Doring F , Eynott PR , Fischer A , Daniel H . Intestinal peptide transport: Ex vivo uptake studies and localization of peptide carrier PEPT1. Am J Physiol Gastrointest Liver Physiol 281: G697‐G704, 2001.
 75. Guettou F , Quistgaard EM , Tresaugues L , Moberg P , Jegerschold C , Zhu L , Jong AJ , Nordlund P , Low C . Structural insights into substrate recognition in proton‐dependent oligopeptide transporters. EMBO reports 14: 804‐810, 2013.
 76. Gupta D , Varghese Gupta S , Dahan A , Tsume Y , Hilfinger J , Lee KD , Amidon GL . Increasing oral absorption of polar neuraminidase inhibitors: A prodrug transporter approach applied to oseltamivir analogue. Mol Pharm 10: 512‐522, 2013.
 77. Hamilton JA. Fatty acid transport: Difficult or easy? J Lipid Res 39: 467‐481, 1998.
 78. Harder D , Stolz J , Casagrande F , Obrdlik P , Weitz D , Fotiadis D , Daniel H . DtpB (YhiP) and DtpA (TppB, YdgR) are prototypical proton‐dependent peptide transporters of Escherichia coli . FEBS J 275: 3290‐3298, 2008.
 79. Helander HF , Fandriks L . Surface area of the digestive tract—Revisited. Scand J Gastroenterol 49: 681‐689, 2014.
 80. Hindlet P , Bado A , Farinotti R , Buyse M . Long‐term effect of leptin on H+‐coupled peptide cotransporter 1 activity and expression in vivo: Evidence in leptin‐deficient mice. J Pharmacol Exp Ther 323: 192‐201, 2007.
 81. Hindlet P , Bado A , Kamenicky P , Delomenie C , Bourasset F , Nazaret C , Farinotti R , Buyse M . Reduced intestinal absorption of dipeptides via PepT1 in mice with diet‐induced obesity is associated with leptin receptor down‐regulation. J Biol Chem 284: 6801‐6808, 2009.
 82. Hosseinzadeh Z , Dong L , Bhavsar SK , Warsi J , Almilaji A , Lang F . Upregulation of peptide transporters PEPT1 and PEPT2 by Janus kinase JAK2. Cell Physiol Biochem 31: 673‐682, 2013.
 83. Hu Y , Chen X , Smith DE . Species‐dependent uptake of glycylsarcosine but not oseltamivir in Pichia pastoris expressing the rat, mouse, and human intestinal peptide transporter PEPT1. Drug Metab Dispos 40: 1328‐1335, 2012.
 84. Hu Y , Smith DE . Species differences in the pharmacokinetics of cefadroxil as determined in wildtype and humanized PepT1 mice. Biochem Pharmacol 107: 81‐90, 2016.
 85. Hu Y , Smith DE , Ma K , Jappar D , Thomas W , Hillgren KM . Targeted disruption of peptide transporter Pept1 gene in mice significantly reduces dipeptide absorption in intestine. Mol Pharm 5: 1122‐1130, 2008.
 86. Hu Y , Xie Y , Wang Y , Chen X , Smith DE . Development and characterization of a novel mouse line humanized for the intestinal peptide transporter PEPT1. Mol Pharm 11: 3737‐3746, 2014.
 87. Huang Q , Vera Delgado JM , Seni Pinoargote OD , Llaguno RA . Molecular evolution of the Slc15 family and its response to waterborne copper and mercury exposure in tilapia. Aquat Toxicol 163: 140‐147, 2015.
 88. Huo Y , Khatri N , Hou Q , Gilbert J , Wang G , Man HY . The deubiquitinating enzyme USP46 regulates AMPA receptor ubiquitination and trafficking. J Neurochem 134: 1067‐1080, 2015.
 89. Irie M , Terada T , Katsura T , Matsuoka S , Inui K . Computational modelling of H+‐coupled peptide transport via human PEPT1. J Physiol 565: 429‐439, 2005.
 90. Jappar D , Wu SP , Hu Y , Smith DE . Significance and regional dependency of peptide transporter (PEPT) 1 in the intestinal permeability of glycylsarcosine: In situ single‐pass perfusion studies in wild‐type and Pept1 knockout mice. Drug Metab Dispos 38: 1740‐1746, 2010.
 91. Jess T , Gamborg M , Matzen P , Munkholm P , Sorensen TI . Increased risk of intestinal cancer in Crohn's disease: A meta‐analysis of population‐based cohort studies. Am J Gastroenterol 100: 2724‐2729, 2005.
 92. Jin X , Zimmers TA , Zhang Z , Pierce RH , Koniaris LG . Interleukin‐6 is an important in vivo inhibitor of intestinal epithelial cell death in mice. Gut 59: 186‐196, 2010.
 93. Joly F , Mayeur C , Messing B , Lavergne‐Slove A , Cazals‐Hatem D , Noordine ML , Cherbuy C , Duee PH , Thomas M . Morphological adaptation with preserved proliferation/transporter content in the colon of patients with short bowel syndrome. Am J Physiol Gastrointest Liver Physiol 297: G116‐G123, 2009.
 94. Jostins L , Ripke S , Weersma RK , Duerr RH , McGovern DP , Hui KY , Lee JC , Schumm LP , Sharma Y , Anderson CA , Essers J , Mitrovic M , Ning K , Cleynen I , Theatre E , Spain SL , Raychaudhuri S , Goyette P , Wei Z , Abraham C , Achkar JP , Ahmad T , Amininejad L , Ananthakrishnan AN , Andersen V , Andrews JM , Baidoo L , Balschun T , Bampton PA , Bitton A , Boucher G , Brand S , Buning C , Cohain A , Cichon S , D'Amato M , De Jong D, Devaney KL , Dubinsky M , Edwards C , Ellinghaus D , Ferguson LR , Franchimont D , Fransen K , Gearry R , Georges M , Gieger C , Glas J , Haritunians T , Hart A , Hawkey C , Hedl M , Hu X , Karlsen TH , Kupcinskas L , Kugathasan S , Latiano A , Laukens D , Lawrance IC , Lees CW , Louis E , Mahy G , Mansfield J , Morgan AR , Mowat C , Newman W , Palmieri O , Ponsioen CY , Potocnik U , Prescott NJ , Regueiro M , Rotter JI , Russell RK , Sanderson JD , Sans M , Satsangi J , Schreiber S , Simms LA , Sventoraityte J , Targan SR , Taylor KD , Tremelling M , Verspaget HW , De Vos M, Wijmenga C , Wilson DC , Winkelmann J , Xavier RJ , Zeissig S , Zhang B , Zhang CK , Zhao H , Silverberg MS , Annese V , Hakonarson H , Brant SR , Radford‐Smith G , Mathew CG , Rioux JD , Schadt EE , Daly MJ , Franke A , Parkes M , Vermeire S , Barrett JC , Cho JH . Host‐microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491: 119‐124, 2012.
 95. Kennedy DJ , Leibach FH , Ganapathy V , Thwaites DT . Optimal absorptive transport of the dipeptide glycylsarcosine is dependent on functional Na+/H+ exchange activity. Pflugers Arch 445: 139‐146, 2002.
 96. Knütter I. Strukturelle Anforderungen an Substrate und Inhibitoren epithelialer H+/Peptidsymporter. (PhD thesis). http://d‐nb.info/969928610/34: Martin‐Luther‐Universität Halle‐Wittenberg, 2003.
 97. Knutter I , Hartrodt B , Theis S , Foltz M , Rastetter M , Daniel H , Neubert K , Brandsch M . Analysis of the transport properties of side chain modified dipeptides at the mammalian peptide transporter PEPT1. Eur J Pharm Sci 21: 61‐67, 2004.
 98. Knutter I , Hartrodt B , Toth G , Keresztes A , Kottra G , Mrestani‐Klaus C , Born I , Daniel H , Neubert K , Brandsch M . Synthesis and characterization of a new and radiolabeled high‐affinity substrate for H+/peptide cotransporters. Febs J 274: 5905‐5914, 2007.
 99. Knutter I , Kottra G , Fischer W , Daniel H , Brandsch M . High‐affinity interaction of sartans with H+/peptide transporters. Drug Metab Dispos 37: 143‐149, 2009.
 100. Knutter I , Rubio‐Aliaga I , Boll M , Hause G , Daniel H , Neubert K , Brandsch M . H+‐peptide cotransport in the human bile duct epithelium cell line SK‐ChA‐1. Am J Physiol Gastrointest Liver Physiol 283: G222‐G229, 2002.
 101. Knutter I , Wollesky C , Kottra G , Hahn MG , Fischer W , Zebisch K , Neubert RH , Daniel H , Brandsch M . Transport of angiotensin‐converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther 327: 432‐441, 2008.
 102. Kolodziejczak D , Spanier B , Pais R , Kraiczy J , Stelzl T , Gedrich K , Scherling C , Zietek T , Daniel H . Mice lacking the intestinal peptide transporter display reduced energy intake and a subtle maldigestion/‐absorption that protects them from diet‐induced obesity. Am J Physiol Gastrointest Liver Physiol 304(10): G897‐G907, 2013.
 103. Koshikawa N , Hasegawa S , Nagashima Y , Mitsuhashi K , Tsubota Y , Miyata S , Miyagi Y , Yasumitsu H , Miyazaki K . Expression of trypsin by epithelial cells of various tissues, leukocytes, and neurons in human and mouse. Am J Pathol 153: 937‐944, 1998.
 104. Kottra G , Spanier B , Verri T , Daniel H . Peptide transporter isoforms are discriminated by the fluorophore‐conjugated dipeptides beta‐Ala‐ and d‐Ala‐Lys‐N‐7‐amino‐4‐methylcoumarin‐3‐acetic acid. Physiol Rep 1: e00165, 2013.
 105. Kovacs‐Nolan J , Zhang H , Ibuki M , Nakamori T , Yoshiura K , Turner PV , Matsui T , Mine Y . The PepT1‐transportable soy tripeptide VPY reduces intestinal inflammation. Biochim Biophys Acta 1820: 1753‐1763, 2012.
 106. Koven W , Schulte P . The effect of fasting and refeeding on mRNA expression of PepT1 and gastrointestinal hormones regulating digestion and food intake in zebrafish (Danio rerio). Fish Physiol Biochem 38: 1565‐1575, 2012.
 107. Laforenza U , Miceli E , Gastaldi G , Scaffino MF , Ventura U , Fontana JM , Orsenigo MN , Corazza GR . Solute transporters and aquaporins are impaired in celiac disease. Biol Cell 102: 457‐467, 2010.
 108. Lavery DJ , Lopez‐Molina L , Margueron R , Fleury‐Olela F , Conquet F , Schibler U , Bonfils C . Circadian expression of the steroid 15 alpha‐hydroxylase (Cyp2a4) and coumarin 7‐hydroxylase (Cyp2a5) genes in mouse liver is regulated by the PAR leucine zipper transcription factor DBP. Mol Cell Biol 19: 6488‐6499, 1999.
 109. Lebwohl B , Ludvigsson JF , Green PH . Celiac disease and non‐celiac gluten sensitivity. BMJ 351: h4347, 2015.
 110. Liang R , Fei YJ , Prasad PD , Ramamoorthy S , Han H , Yang‐Feng TL , Hediger MA , Ganapathy V , Leibach FH . Human intestinal H+/peptide cotransporter. Cloning, functional expression, and chromosomal localization. J Biol Chem 270: 6456‐6463, 1995.
 111. Lo Cascio P , Calabro C , Bertuccio C , Paterniti I , Palombieri D , Calo M , Albergamo A , Salvo A , Gabriella Denaro M . Effects of fasting and refeeding on the digestive tract of zebrafish (Danio rerio) fed with Spirulina (Arthrospira platensis), a high protein feed source. Nat Prod Res 31(13): 1478‐1485, 2017.
 112. Long X , Spycher C , Han ZS , Rose AM , Muller F , Avruch J . TOR deficiency in C. elegans causes developmental arrest and intestinal atrophy by inhibition of mRNA translation. Curr Biol 12: 1448‐1461, 2002.
 113. Ma K , Hu Y , Smith DE . Influence of fed‐fasted state on intestinal PEPT1 expression and in vivo pharmacokinetics of glycylsarcosine in wild‐type and Pept1 knockout mice. Pharm Res 29(2): 535‐545, 2012.
 114. Mace OJ , Lister N , Morgan E , Shepherd E , Affleck J , Helliwell P , Bronk JR , Kellett GL , Meredith D , Boyd R , Pieri M , Bailey PD , Pettcrew R , Foley D . An energy supply network of nutrient absorption coordinated by calcium and T1R taste receptors in rat small intestine. J Physiol 587: 195‐210, 2009.
 115. Mackenzie B , Fei YJ , Ganapathy V , Leibach FH . The human intestinal H+/oligopeptide cotransporter hPEPT1 transports differently‐charged dipeptides with identical electrogenic properties. Biochim Biophys Acta 1284: 125‐128, 1996.
 116. Madhavan S , Scow JS , Chaudhry RM , Nagao M , Zheng Y , Duenes JA , Sarr MG . Intestinal adaptation for oligopeptide absorption via PepT1 after massive (70%) mid‐small bowel resection. J Gastrointest Surg 15: 240‐247; discussion 247‐249, 2011.
 117. Madsen SL , Wong EA . Expression of the chicken peptide transporter 1 and the peroxisome proliferator‐activated receptor alpha following feed restriction and subsequent refeeding. Poult Sci 90: 2295‐2300, 2011.
 118. Makky K , Tekiela J , Mayer AN . Target of rapamycin (TOR) signaling controls epithelial morphogenesis in the vertebrate intestine. Dev Biol 303: 501‐513, 2007.
 119. Mandrika I , Muceniece R , Wikberg JE . Effects of melanocortin peptides on lipopolysaccharide/interferon‐gamma‐induced NF‐kappaB DNA binding and nitric oxide production in macrophage‐like RAW 264.7 cells: Evidence for dual mechanisms of action. Biochem Pharmacol 61: 613‐621, 2001.
 120. Matijasic M , Mestrovic T , Peric M , Cipcic Paljetak H , Panek M , Vranesic Bender D , Ljubas Kelecic D , Krznaric Z , Verbanac D . Modulating composition and metabolic activity of the gut microbiota in IBD patients. Int J Mol Sci 17: pii: E578, 2016.
 121. McKenna LB , Schug J , Vourekas A , McKenna JB , Bramswig NC , Friedman JR , Kaestner KH . MicroRNAs control intestinal epithelial differentiation, architecture, and barrier function. Gastroenterology 139: 1654‐1664, 2010.
 122. McWalter GK , Higgins LG , McLellan LI , Henderson CJ , Song L , Thornalley PJ , Itoh K , Yamamoto M , Hayes JD . Transcription factor Nrf2 is essential for induction of NAD(P)H:quinone oxidoreductase 1, glutathione S‐transferases, and glutamate cysteine ligase by broccoli seeds and isothiocyanates. J Nutr 134: 3499S‐3506S, 2004.
 123. Meissner B , Boll M , Daniel H , Baumeister R . Deletion of the intestinal peptide transporter affects insulin and TOR signaling in Caenorhabditis elegans . J Biol Chem 279: 36739‐36745, 2004.
 124. 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.
 125. Miyamoto Y , Ganapathy V , Leibach FH . Proton gradient‐coupled uphill transport of glycylsarcosine in rabbit renal brush‐border membrane vesicles. Biochem Biophys Res Commun 132: 946‐953, 1985.
 126. Miyauchi E , Tachikawa M , Decleves X , Uchida Y , Bouillot JL , Poitou C , Oppert JM , Mouly S , Bergmann JF , Terasaki T , Scherrmann JM , Lloret‐Linares C . Quantitative atlas of cytochrome P450, UDP‐glucuronosyltransferase, and transporter proteins in jejunum of morbidly obese subjects. Mol Pharm 13: 2631‐2640, 2016.
 127. Moore VA , Irwin WJ , Timmins P , Chong S , Dando SA , Morrison RA . A rapid screening system to determine drug affinities for the intestinal dipeptide transporter 1: System characterisation. Int J Pharm 210: 15‐27, 2000.
 128. Myers MG , Cowley MA , Munzberg H . Mechanisms of leptin action and leptin resistance. Annu Rev Physiol 70: 537‐556, 2008.
 129. Nakamura N , Lill JR , Phung Q , Jiang Z , Bakalarski C , de Maziere A , Klumperman J , Schlatter M , Delamarre L , Mellman I . Endosomes are specialized platforms for bacterial sensing and NOD2 signalling. Nature 509: 240‐244, 2014.
 130. Nassl AM , Rubio‐Aliaga I , Fenselau H , Marth MK , Kottra G , Daniel H . Amino acid absorption and homeostasis in mice lacking the intestinal peptide transporter PEPT1. Am J Physiol Gastrointest Liver Physiol 301: G128‐G137, 2011.
 131. Nassl AM , Rubio‐Aliaga I , Sailer M , Daniel H . The intestinal peptide transporter PEPT1 is involved in food intake regulation in mice fed a high‐protein diet. PLoS One 6: e26407, 2011.
 132. Nduati V , Yan Y , Dalmasso G , Driss A , Sitaraman S , Merlin D . Leptin transcriptionally enhances peptide transporter (hPepT1) expression and activity via the cAMP‐response element‐binding protein and Cdx2 transcription factors. J Biol Chem 282: 1359‐1373, 2007.
 133. Nehrke K. A reduction in intestinal cell pHi due to loss of the Caenorhabditis elegans Na+/H+ exchanger NHX‐2 increases life span. J Biol Chem 278: 44657‐44666, 2003.
 134. Neudeck BL , Loeb JM , Faith NG . Lactobacillus casei alters hPEPT1‐mediated glycylsarcosine uptake in Caco‐2 cells. J Nutr 134: 1120‐1123, 2004.
 135. Newstead S. Recent advances in understanding proton coupled peptide transport via the POT family. Curr Opin Struct Biol 45: 17‐24, 2016.
 136. Newstead S , Drew D , Cameron AD , Postis VL , Xia X , Fowler PW , Ingram JC , Carpenter EP , Sansom MS , McPherson MJ , Baldwin SA , Iwata S . Crystal structure of a prokaryotic homologue of the mammalian oligopeptide‐proton symporters, PepT1 and PepT2. EMBO J 30: 417‐426, 2011.
 137. Nguyen HT , Charrier‐Hisamuddin L , Dalmasso G , Hiol A , Sitaraman S , Merlin D . Association of PepT1 with lipid rafts differently modulates its transport activity in polarized and nonpolarized cells. Am J Physiol Gastrointest Liver Physiol 293: G1155‐G1165, 2007.
 138. Nguyen HT , Dalmasso G , Powell KR , Yan Y , Bhatt S , Kalman D , Sitaraman SV , Merlin D . Pathogenic bacteria induce colonic PepT1 expression: An implication in host defense response. Gastroenterology 137: 1435‐1447, 2009.
 139. Nielsen CU , Amstrup J , Nielsen R , Steffansen B , Frokjaer S , Brodin B . Epidermal growth factor and insulin short‐term increase hPepT1‐mediated glycylsarcosine uptake in Caco‐2 cells. Acta Physiol Scand 178: 139‐148, 2003.
 140. Ogihara H , Saito H , Shin BC , Terado T , Takenoshita S , Nagamachi Y , Inui K , Takata K . Immuno‐localization of H+/peptide cotransporter in rat digestive tract. Biochem Biophys Res Commun 220: 848‐852, 1996.
 141. Ogihara H , Suzuki T , Nagamachi Y , Inui K , Takata K . Peptide transporter in the rat small intestine: Ultrastructural localization and the effect of starvation and administration of amino acids. Histochem J 31: 169‐174, 1999.
 142. Okamura A , Koyanagi S , Dilxiat A , Kusunose N , Chen JJ , Matsunaga N , Shibata S , Ohdo S . Bile acid‐regulated peroxisome proliferator‐activated receptor‐alpha (PPARalpha) activity underlies circadian expression of intestinal peptide absorption transporter PepT1/Slc15a1. J Biol Chem 289: 25296‐25305, 2014.
 143. Parker JL , Mindell JA , Newstead S . Thermodynamic evidence for a dual transport mechanism in a POT peptide transporter. Elife 3: e04273, 2014. DOI: 10.7554/eLife.04273.
 144. Pieri M , Christian HC , Wilkins RJ , Boyd CA , Meredith D . The apical (hPepT1) and basolateral peptide transport systems of Caco‐2 cells are regulated by AMP‐activated protein kinase. Am J Physiol Gastrointest Liver Physiol 299: G136‐G143, 2010.
 145. Roder PV , Geillinger KE , Zietek TS , Thorens B , Koepsell H , Daniel H . The role of SGLT1 and GLUT2 in intestinal glucose transport and sensing. PLoS One 9: e89977, 2014.
 146. Ronnestad I , Murashita K , Kottra G , Jordal AE , Narawane S , Jolly C , Daniel H , Verri T . Molecular cloning and functional expression of Atlantic salmon peptide transporter 1 in Xenopus oocytes reveals efficient intestinal uptake of lysine‐containing and other bioactive di‐ and tripeptides in teleost fish. J Nutr 140: 893‐900, 2010.
 147. Rubio‐Aliaga I , Boll M , Daniel H . Cloning and characterization of the gene encoding the mouse peptide transporter PEPT2. Biochem Biophys Res Commun 276: 734‐741, 2000.
 148. Rubio‐Aliaga I , Daniel H . Peptide transporters and their roles in physiological processes and drug disposition. Xenobiotica 38: 1022‐1042, 2008.
 149. Runtsch MC , Round JL , O'Connell RM . MicroRNAs and the regulation of intestinal homeostasis. Frontiers in genetics 5: 347, 2014.
 150. Saito H , Inui K . Dipeptide transporters in apical and basolateral membranes of the human intestinal cell line Caco‐2. Am J Physiol 265: G289‐G294, 1993.
 151. Saito H , Okuda M , Terada T , Sasaki S , Inui K . Cloning and characterization of a rat H+/peptide cotransporter mediating absorption of beta‐lactam antibiotics in the intestine and kidney. J Pharmacol Exp Ther 275: 1631‐1637, 1995.
 152. Saito H , Terada T , Shimakura J , Katsura T , Inui K . Regulatory mechanism governing the diurnal rhythm of intestinal H+/peptide cotransporter 1 (PEPT1). Am J Physiol Gastrointest Liver Physiol 295: G395‐G402, 2008.
 153. Sampson LL , Davis AK , Grogg MW , Zheng Y . mTOR disruption causes intestinal epithelial cell defects and intestinal atrophy postinjury in mice. FASEB J 30: 1263‐1275, 2016.
 154. Shi B , Song D , Xue H , Li N , Li J . PepT1 mediates colon damage by transporting fMLP in rats with bowel resection. J Surg Res 136: 38‐44, 2006.
 155. Shimakura J , Terada T , Katsura T , Inui K . Characterization of the human peptide transporter PEPT1 promoter: Sp1 functions as a basal transcriptional regulator of human PEPT1. Am J Physiol Gastrointest Liver Physiol 289: G471‐G477, 2005.
 156. Shimakura J , Terada T , Saito H , Katsura T , Inui K . Induction of intestinal peptide transporter 1 expression during fasting is mediated via peroxisome proliferator‐activated receptor alpha. Am J Physiol Gastrointest Liver Physiol 291: G851‐G856, 2006.
 157. Shimakura J , Terada T , Shimada Y , Katsura T , Inui K . The transcription factor Cdx2 regulates the intestine‐specific expression of human peptide transporter 1 through functional interaction with Sp1. Biochem Pharmacol 71: 1581‐1588, 2006.
 158. Shiraga T , Miyamoto K , Tanaka H , Yamamoto H , Taketani Y , Morita K , Tamai I , Tsuji A , Takeda E . Cellular and molecular mechanisms of dietary regulation on rat intestinal H+/Peptide transporter PepT1. Gastroenterology 116: 354‐362, 1999.
 159. Shu HJ , Takeda H , Shinzawa H , Takahashi T , Kawata S . Effect of lipopolysaccharide on peptide transporter 1 expression in rat small intestine and its attenuation by dexamethasone. Digestion 65: 21‐29, 2002.
 160. Smith DE , Clemencon B , Hediger MA . Proton‐coupled oligopeptide transporter family SLC15: Physiological, pharmacological and pathological implications. Mol Aspects Med 34: 323‐336, 2013.
 161. Smith DE , Pavlova A , Berger UV , Hediger MA , Yang T , Huang YG , Schnermann JB . Tubular localization and tissue distribution of peptide transporters in rat kidney. Pharm Res 15: 1244‐1249, 1998.
 162. Solcan N , Kwok J , Fowler PW , Cameron AD , Drew D , Iwata S , Newstead S . Alternating access mechanism in the POT family of oligopeptide transporters. EMBO J 31: 3411‐3421, 2012.
 163. Sopjani M , Dermaku‐Sopjani M . Klotho‐dependent cellular transport regulation. Vitam Horm 101: 59‐84, 2016.
 164. Spanier B. Transcriptional and functional regulation of the intestinal peptide transporter PEPT1. J Physiol 592: 871‐879, 2014.
 165. Spanier B , Lasch K , Marsch S , Benner J , Liao W , Hu H , Kienberger H , Eisenreich W , Daniel H . How the intestinal peptide transporter PEPT‐1 contributes to an obesity phenotype in Caenorhabditits elegans . PLoS One 4: e6279, 2009.
 166. Steiner HY , Naider F , Becker JM . The PTR family: A new group of peptide transporters. Mol Microbiol 16: 825‐834, 1995.
 167. Stelzl T , Baranov T , Geillinger KE , Kottra G , Daniel H . Effect of N‐glycosylation on the transport activity of the peptide transporter PEPT1. Am J Physiol Gastrointest Liver Physiol 310: G128‐G141, 2016.
 168. Stelzl T , Geillinger‐Kastle KE , Stolz J , Daniel H . Glycans in the intestinal peptide transporter PEPT1 contribute to function and protect from proteolysis. Am J Physiol Gastrointest Liver Physiol 312(6): G580‐G591, 2017.
 169. Sugiura T , Kato Y , Wakayama T , Silver DL , Kubo Y , Iseki S , Tsuji A . PDZK1 regulates two intestinal solute carriers (Slc15a1 and Slc22a5) in mice. Drug Metab Dispos 36: 1181‐1188, 2008.
 170. Sun Y , Sun J , Shi S , Jing Y , Yin S , Chen Y , Li G , Xu Y , He Z . Synthesis, transport and pharmacokinetics of 5′‐amino acid ester prodrugs of 1‐beta‐D‐arabinofuranosylcytosine. Mol Pharm 6: 315‐325, 2009.
 171. Tavernier A , Cavin JB , Le Gall M, Ducroc R , Denis RG , Cluzeaud F , Guilmeau S , Sakar Y , Barbot L , Kapel N , Le Beyec J, Joly F , Chua S , Luquet S , Bado A . Intestinal deletion of leptin signaling alters activity of nutrient transporters and delayed the onset of obesity in mice. FASEB J 28: 4100‐4110, 2014.
 172. Terova G , Robaina L , Izquierdo M , Cattaneo A , Molinari S , Bernardini G , Saroglia M . PepT1 mRNA expression levels in sea bream (Sparus aurata) fed different plant protein sources. SpringerPlus 2: 17, 2013.
 173. Thamotharan M , Bawani SZ , Zhou X , Adibi SA . Functional and molecular expression of intestinal oligopeptide transporter (Pept‐1) after a brief fast. Metabolism 48: 681‐684, 1999.
 174. Ullman TA , Itzkowitz SH . Intestinal inflammation and cancer. Gastroenterology 140: 1807‐1816, 2011.
 175. Vavricka SR , Musch MW , Fujiya M , Kles K , Chang L , Eloranta JJ , Kullak‐Ublick GA , Drabik K , Merlin D , Chang EB . Tumor necrosis factor‐alpha and interferon‐gamma increase PepT1 expression and activity in the human colon carcinoma cell line Caco‐2/bbe and in mouse intestine. Pflugers Arch 452: 71‐80, 2006.
 176. Verri T , Barca A , Pisani P , Piccinni B , Storelli C , Romano A . Di‐ and tripeptide transport in vertebrates: The contribution of teleost fish models. J Comp Physiol B 187: 395‐462, 2017.
 177. Viennois E , Ingersoll SA , Ayyadurai S , Zhao Y , Wang L , Zhang M , Han MK , Garg P , Xiao B , Merlin D . Critical role of PepT1 in promoting colitis‐associated cancer and therapeutic benefits of the anti‐inflammatory PepT1‐mediated tripeptide KPV in a murine model. Cell Mol Gastroenterol Hepatol 2: 340‐357, 2016.
 178. Wang CL , Fan YB , Lu HH , Tsai TH , Tsai MC , Wang HP . Evidence of D‐phenylglycine as delivering tool for improving L‐dopa absorption. J Biomed Sci 17: 71, 2010.
 179. Wang P , Lu YQ , Wen Y , Yu DY , Ge L , Dong WR , Xiang LX , Shao JZ . IL‐16 induces intestinal inflammation via PepT1 upregulation in a pufferfish model: New insights into the molecular mechanism of inflammatory bowel disease. J Immunol 191: 1413‐1427, 2013.
 180. Warsi J , Dong L , Elvira B , Salker MS , Shumilina E , Hosseinzadeh Z , Lang F . SPAK dependent regulation of peptide transporters PEPT1 and PEPT2. Kidney Blood Press Res 39: 388‐398, 2014.
 181. Warsi J , Elvira B , Bissinger R , Shumilina E , Hosseinzadeh Z , Lang F . Downregulation of peptide transporters PEPT1 and PEPT2 by oxidative stress responsive kinase OSR1. Kidney Blood Press Res 39: 591‐599, 2014.
 182. Warsi J , Hosseinzadeh Z , Dong L , Pakladok T , Umbach AT , Bhavsar SK , Shumilina E , Lang F . Effect of Janus kinase 3 on the peptide transporters PEPT1 and PEPT2. J Membr Biol 246: 885‐892, 2013.
 183. Warsi J , Hosseinzadeh Z , Elvira B , Pelzl L , Shumilina E , Zhang DE , Lang KS , Lang PA , Lang F . USP18 sensitivity of peptide transporters PEPT1 and PEPT2. PLoS One 10: e0129365, 2015.
 184. Watanabe C , Kato Y , Ito S , Kubo Y , Sai Y , Tsuji A . Na+/H+ exchanger 3 affects transport property of H+/oligopeptide transporter 1. Drug Metab Pharmacokinet 20: 443‐451, 2005.
 185. Watanabe K , Terada K , Jinriki T , Sato J . Effect of insulin on cephalexin uptake and transepithelial transport in the human intestinal cell line Caco‐2. Eur J Pharm Sci 21: 87‐95, 2004.
 186. Watanabe K , Terada K , Sato J . Intestinal absorption of cephalexin in diabetes mellitus model rats. Eur J Pharm Sci 19: 91‐98, 2003.
 187. Waterston RH , Lindblad‐Toh K , Birney E , Rogers J , Abril JF , Agarwal P , Agarwala R , Ainscough R , Alexandersson M , An P , Antonarakis SE , Attwood J , Baertsch R , Bailey J , Barlow K , Beck S , Berry E , Birren B , Bloom T , Bork P , Botcherby M , Bray N , Brent MR , Brown DG , Brown SD , Bult C , Burton J , Butler J , Campbell RD , Carninci P , Cawley S , Chiaromonte F , Chinwalla AT , Church DM , Clamp M , Clee C , Collins FS , Cook LL , Copley RR , Coulson A , Couronne O , Cuff J , Curwen V , Cutts T , Daly M , David R , Davies J , Delehaunty KD , Deri J , Dermitzakis ET , Dewey C , Dickens NJ , Diekhans M , Dodge S , Dubchak I , Dunn DM , Eddy SR , Elnitski L , Emes RD , Eswara P , Eyras E , Felsenfeld A , Fewell GA , Flicek P , Foley K , Frankel WN , Fulton LA , Fulton RS , Furey TS , Gage D , Gibbs RA , Glusman G , Gnerre S , Goldman N , Goodstadt L , Grafham D , Graves TA , Green ED , Gregory S , Guigo R , Guyer M , Hardison RC , Haussler D , Hayashizaki Y , Hillier LW , Hinrichs A , Hlavina W , Holzer T , Hsu F , Hua A , Hubbard T , Hunt A , Jackson I , Jaffe DB , Johnson LS , Jones M , Jones TA , Joy A , Kamal M , Karlsson EK , Karolchik D , Kasprzyk A , Kawai J , Keibler E , Kells C , Kent WJ , Kirby A , Kolbe DL , Korf I , Kucherlapati RS , Kulbokas EJ , Kulp D , Landers T , Leger JP , Leonard S , Letunic I , Levine R , Li J , Li M , Lloyd C , Lucas S , Ma B , Maglott DR , Mardis ER , Matthews L , Mauceli E , Mayer JH , McCarthy M , McCombie WR , McLaren S , McLay K , McPherson JD , Meldrim J , Meredith B , Mesirov JP , Miller W , Miner TL , Mongin E , Montgomery KT , Morgan M , Mott R , Mullikin JC , Muzny DM , Nash WE , Nelson JO , Nhan MN , Nicol R , Ning Z , Nusbaum C , O'Connor MJ , Okazaki Y , Oliver K , Overton‐Larty E , Pachter L , Parra G , Pepin KH , Peterson J , Pevzner P , Plumb R , Pohl CS , Poliakov A , Ponce TC , Ponting CP , Potter S , Quail M , Reymond A , Roe BA , Roskin KM , Rubin EM , Rust AG , Santos R , Sapojnikov V , Schultz B , Schultz J , Schwartz MS , Schwartz S , Scott C , Seaman S , Searle S , Sharpe T , Sheridan A , Shownkeen R , Sims S , Singer JB , Slater G , Smit A , Smith DR , Spencer B , Stabenau A , Stange‐Thomann N , Sugnet C , Suyama M , Tesler G , Thompson J , Torrents D , Trevaskis E , Tromp J , Ucla C , Ureta‐Vidal A , Vinson JP , Von Niederhausern AC , Wade CM , Wall M , Weber RJ , Weiss RB , Wendl MC , West AP , Wetterstrand K , Wheeler R , Whelan S , Wierzbowski J , Willey D , Williams S , Wilson RK , Winter E , Worley KC , Wyman D , Yang S , Yang SP , Zdobnov EM , Zody MC , Lander ES . Initial sequencing and comparative analysis of the mouse genome. Nature 420: 520‐562, 2002.
 188. Wisniewski JR , Friedrich A , Keller T , Mann M , Koepsell H . The impact of high‐fat diet on metabolism and immune defense in small intestine mucosa. J Proteome Res 14: 353‐365, 2015.
 189. Wojtal KA , Eloranta JJ , Hruz P , Gutmann H , Drewe J , Staumann A , Beglinger C , Fried M , Kullak‐Ublick GA , Vavricka SR . Changes in mRNA expression levels of solute carrier transporters in inflammatory bowel disease patients. Drug Metab Dispos 37: 1871‐1877, 2009.
 190. Wu SP , Smith DE . Impact of intestinal PepT1 on the kinetics and dynamics of N‐formyl‐methionyl‐leucyl‐phenylalanine, a bacterially‐produced chemotactic peptide. Mol Pharm 10: 677‐684, 2013.
 191. Wuensch T , Schulz S , Ullrich S , Lill N , Stelzl T , Rubio‐Aliaga I , Loh G , Chamaillard M , Haller D , Daniel H . The peptide transporter PEPT1 is expressed in distal colon in rodents and humans and contributes to water absorption. Am J Physiol Gastrointest Liver Physiol 305: G66‐G73, 2013.
 192. Wuensch T , Ullrich S , Schulz S , Chamaillard M , Schaltenberg N , Rath E , Goebel U , Sartor RB , Prager M , Buning C , Bugert P , Witt H , Haller D , Daniel H . Colonic expression of the peptide transporter PEPT1 is downregulated during intestinal inflammation and is not required for NOD2‐dependent immune activation. Inflamm Bowel Dis 20: 671‐684, 2014.
 193. Yang B , Smith DE . Significance of peptide transporter 1 in the intestinal permeability of valacyclovir in wild‐type and PepT1 knockout mice. Drug Metab Dispos 41: 608‐614, 2013.
 194. Zachos NC , Tse M , Donowitz M . Molecular physiology of intestinal Na+/H+ exchange. Annu Rev Physiol 67: 411‐443, 2005.
 195. Zhang EY , Fu DJ , Pak YA , Stewart T , Mukhopadhyay N , Wrighton SA , Hillgren KM . Genetic polymorphisms in human proton‐dependent dipeptide transporter PEPT1: Implications for the functional role of Pro586. J Pharmacol Exp Ther 310: 437‐445, 2004.
 196. Zhang Y , Viennois E , Zhang M , Xiao B , Han MK , Walter L , Garg P , Merlin D . PepT1 expression helps maintain intestinal homeostasis by mediating the differential expression of miRNAs along the crypt‐villus axis. Sci Rep 6: 27119, 2016.
 197. Zhao Y , Mao G , Liu M , Zhang L , Wang X , Zhang XC . Crystal structure of the E. coli peptide transporter YbgH. Structure 22: 1152‐1160, 2014.
 198. Zheng L , Zhang W , Zhou Y , Li F , Wei H , Peng J . Recent advances in understanding amino acid sensing mechanisms that regulate mTORC1. Int J Mol Sci 17: pii: E1636, 2016.
 199. Ziegler TR , Fernandez‐Estivariz C , Gu LH , Bazargan N , Umeakunne K , Wallace TM , Diaz EE , Rosado KE , Pascal RR , Galloway JR , Wilcox JN , Leader LM . Distribution of the H+/peptide transporter PepT1 in human intestine: Up‐regulated expression in the colonic mucosa of patients with short‐bowel syndrome. Am J Clin Nutr 75: 922‐930, 2002.
 200. Zietek T , Rath E , Haller D , Daniel H . Intestinal organoids for assessing nutrient transport, sensing and incretin secretion. Sci Rep 5: 16831, 2015.
 201. Zimmermann C , Rudloff S , Lochnit G , Arampatzi S , Maison W , Zimmer KP . Epithelial transport of immunogenic and toxic gliadin peptides in vitro. PLoS One 9: e113932, 2014.
 202. Zucchelli M , Torkvist L , Bresso F , Halfvarson J , Hellquist A , Anedda F , Assadi G , Lindgren GB , Svanfeldt M , Janson M , Noble CL , Pettersson S , Lappalainen M , Paavola‐Sakki P , Halme L , Farkkila M , Turunen U , Satsangi J , Kontula K , Lofberg R , Kere J , D'Amato M . PepT1 oligopeptide transporter (SLC15A1) gene polymorphism in inflammatory bowel disease. Inflamm Bowel Dis 15: 1562‐1569, 2009.

Teaching Material

B. Spanier, F. Rohm. Proton Coupled Oligopeptide Transporter 1 (PepT1) Function, Regulation, and Influence on the Intestinal Homeostasis. Compr Physiol. 8: 2018, 843-869.

Didactic Synopsis

Major Teaching Points:

  1. Peptide transporter PepT1 is responsible for absorption of di- and tripeptides and of numerous structurally related peptidomimetic drugs into intestinal epithelia cells and regulate their bioavailability.
  2. The di- and tripeptide uptake is driven by the membrane potential in form of an inward directed proton gradient which is maintained by sodium-proton exchanger NHE3.
  3. PepT1 expression and function is controlled at the transcriptional, translational, and post-translational level.
  4. Systemic changes and compensatory processes after the loss of PepT1 are studied in various models including Caenorhabditis elegans, Mus musculus, and the human colon carcinoma cell line Caco-2.
  5. PepT1 is involved in intestinal homeostasis regarding metabolite profiles and tissue physiology, both in health and disease (inflammatory bowel disease, obesity, diabetes, and celiac disease).

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: The uptake and exchange of amino acids into gut epithelia cells and their release into the blood stream is facilitated by a set of amino acid and oligopeptide transporters. The physiological transporter functions like substrate preferences and coupling to ion gradients are described in the formal figure legend. Peptide transporter PepT1 function is strictly dependent on the pH gradient between gut lumen and cytoplasm. Most of its substrates, comprising more than 8000 di- and tripeptides, are hydrolyzed by numerous cytosolic peptidases. The released free amino acids enter cell metabolism, protein de novo synthesis or leave the cell via basolateral amino acid transporters. The transporter for the export of small peptides and structurally related drugs has not been characterized yet.

Figure 2. Teaching points: The two oligopeptide transporters PepT1 and PepT2 exhibit distinct expression patterns in humans. The PepT1 protein is mainly expressed in the small intestine, following an increasing expression gradient from proximal to distal. It can also be found in low levels in the distal colon, in the proximal tubules of the kidney and in bile duct, pancreas, and placenta. PepT2 is the renal isoform, predominantly expressed in the distal tubules of the kidney, but also present in brain, glia cells, lung, and mammary gland.

Figure 3. Teaching points: The expression of PepT1 protein along the colon in health and disease is a topic that is controversially discussed. While in some studies PepT1 protein is only present in inflamed colon tissue, a basal PepT1 expression in healthy mouse colon tissue, next to the stable expression in samples from small intestine, was shown by our group. PepT1 expression increases from proximal to distal colon.

Figure 4. Teaching points: The role of PepT1 in intestinal homeostasis. Besides dietary oligopeptides and structurally related drugs, the range of PepT1 transport substrates also contains certain bacterial products. The uptake of these oligopeptides from intestinal bacteria into intestinal epithelial cells and intestinal immune cells can cause or contribute to intestinal inflammation. There are however also other bacterial oligopeptides as well as certain dietary oligopeptides that prevent or reduce intestinal inflammation when taken up via PepT1. Besides this anti-inflammatory effects associated with its transport activity, PepT1 may also be involved in the defense against pathogenic intestinal bacteria by preventing their attachment to specific regions of the enterocyte membrane called lipid rafts.

Figure 5. Teaching points: Functions of peptide transporter PepT1. Next to its main function as transporter for di- and tripeptides, in the last years it became clear that PepT1 is a mediator between nutrient supply, protein breakdown and de novo synthesis, microbiota, and the epithelia cells. PepT1 stabilizes the intestinal homeostasis between health and disease by sensing environmental factors via its transceptor function, allows direct and indirect interaction with bacteria (e.g., by uptake of bacteria-derived peptides), and enables the treatment of selected diseases by transport of selected peptidomimetic drugs.


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How to Cite

Britta Spanier, Florian Rohm. Proton Coupled Oligopeptide Transporter 1 (PepT1) Function, Regulation, and Influence on the Intestinal Homeostasis. Compr Physiol 2018, 8: 843-869. doi: 10.1002/cphy.c170038