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Are intact peptides absorbed from the healthy gut in the adult human?

  • Warren M. Miner-Williams (a1), Bruce R. Stevens (a2) and Paul J. Moughan (a1)


For over 100 years it was believed that dietary protein must be completely hydrolysed before its constituent amino acids could be absorbed via specific amino acid transport systems. It is now known that the uptake of di- and tripeptides into the enterocyte is considerable, being transported across the intestinal endothelium by the PepT1 H+/peptide co-transporter. There is also evidence that some di- and tripeptides may survive cytosolic hydrolysis and be transported intact across the basolateral membrane. However, other than antigen sampling, the transport of larger intact macromolecules across the intestinal endothelium of the healthy adult human remains a controversial issue as there is little unequivocal in vivo evidence to support this postulation. The aim of the present review was to critically evaluate the scientific evidence that peptides/proteins are absorbed by healthy intestinal epithelia and pass intact into the hepatic portal system. The question of the absorption of oliogopeptides is paramount to the emerging science of food-derived bioactive peptides, their mode of action and physiological effects. Overall, we conclude that there is little unequivocal evidence that dietary bioactive peptides, other than di- and tripeptides, can cross the gut wall intact and enter the hepatic portal system in physiologically relevant concentrations.

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Corresponding author

* Corresponding author: Professor P. J. Moughan, email


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1 Bajaj-Elliott, M & Sanderson, IR (2004) Structure and function of the gastrointestinal mucosa. In Oral Tolerance: The Responce of the Intestinal Mucosa to Dietary Antigens, pp. 113 [Morteau, O, editor]. New York: Kluwer Academic/Plenum Publishers.
2 Sanderson, IR & Walker, WA (1999) Part 1, section A(4). In Handbook of Mucosal Immunology, 2nd ed., pp. 4148 [Ogra, R and Mestecky, J, editors]. San Diego: Academic Press.
3 Bevins, CL, Martin-Porter, E & Ganz, T (1999) Defensins and innate host defence of the gastrointestinal tract. Gut 271, 1403814045.
4 Wehkamp, J, Schmid, M & Stange, EF (2007) Defensins and other antimicrobial peptides in inflammatory bowel disease. Curr Opin Gastroenterol 23, 370378.
5 Sanderson, IR & Walker, WA (1993) Uptake and transport of macromolecules by the intestine: possible role in clinical disorders. Gastroenterology 104, 622639.
6 Matthews, DM (1975) Intestinal absorption of peptides. Physiol Rev 55, 537608.
7 Cohnheim, O (1901) Die Umwandlung des Eiweiss durch die Darmwand (The conversion of protein through the intestinal wall). Z Physiol Chem 33, 451465.
8 Abderhalden, E, Körösy, KV & London, ES (1907) Weitere Studien uber die normale Verdauung der Eiweißkörper im Magendarmkanal des Hundes (Further studies about the normal digestion of protein bodies in the gastrointestinal tract of the dog). Hoppe-Seylers Z Physiol Chem 53, 148163.
9 Kutscher, F & Seemann, J (1901–1902) Zur Kenntniss der Verdauungsvorgange im Dunndarm. I (To the knowledge of the digestive system in the small intestine. I). Hoppe-Seylers Z Physiol Chem 34, 528543.
10 Stevens, BR (2010) Amino acid transport by epithelial membranes. In Epithelial Transport Physiology, pp. 353378 [Gerencser, GA, editor]. New York: Humana Press.
11 Newey, H & Smyth, DH (1959) The intestinal absorption of some dipeptides. J Physiol 145, 4856.
12 Adibi, SA (1971) Intestinal transport of dipeptides in man: relative importance of hydrolysis and intact absorption. J Clin Invest 50, 22662275.
13 Adibi, SA, Morse, EL, Masilamani, SS, et al. (1975) Evidence for 2 different modes of tripeptide disappearance in human intestine – uptake by peptide carrier systems and hydrolysis by peptide hydrolases. J Clin Invest 56, 13551363.
14 Ganapathy, V & Leibach, FH (1983) Role of pH gradient and membrane potential in dipeptide transport in intestinal and renal brush-border membrane-vesicles from the rabbit – studies with l-carnosine and glycyl-l-proline. J Biol Chem 258, 41894192.
15 Fei, YJ, Kanai, Y, Nussberger, S, et al. (1994) Expression cloning of a mammalian proton-coupled oligopeptide transporter. Nature 368, 563566.
16 Brandsch, M & Brandsch, C (2003) Intestinal transport of amino acids, peptides and proteins. In Progress in Research on Energy and Protein Metabolism, pp. 667680 [Souffrant, WB and Metges, CC, editors]. Wageningen: Wageningen Academic Publishers.
17 Matthews, DM, Craft, IL, Geddes, DM, et al. (1968) Absorption of glycine and glycine peptides from the small intestine of the rat. Clin Sci 35, 415424.
18 Matthews, DM & Adibi, SA (1976) Peptide absorption. Gastroenterology 71, 151161.
19 Craft, IL, Geddes, D, Hyde, CW, et al. (1968) Absorption and malabsorption of glycine and glycine peptides in man. Gut 9, 425437.
20 Vermeirssen, V, Van Camp, J & Verstraete, W (2004) Bioavailability of angiotensin I converting enzyme inhibitory peptides. Br J Nutr 92, 357366.
21 Daniel, H (2004) Molecular and integrative physiology of intestinal peptide transport. Annu Rev Physiol 66, 361384.
22 Yang, CY, Dantzig, AH & Pidgeon, C (1999) Intestinal peptide transport systems and oral drug availability. Pharm Res 16, 13311343.
23 Adibi, SA (2003) Regulation of expression of the intestinal oligopeptide transporter (Pept-1) in health and disease. Am J Physiol Gastrointest Liver Physiol 285, G779G788.
24 Rubio-Aliaga, I & Daniel, H (2008) Peptide transporters and their roles in physiological processes and drug disposition. Xenobiotica 38, 10221042.
25 Daniel, H, Morse, EL & Adibi, SA (1992) Determinants of substrate affinity for the oligopeptide/H+ symporter in the renal brush-border membrane. J Biol Chem 267, 95659573.
26 Adibi, SA (1997) The oligopeptide transporter (Pept-1) in human intestine: biology and function. Gastroenterology 113, 332340.
27 Terada, T, Shimada, Y, Pan, XY, et al. (2005) Expression profiles of various transporters for oligopeptides, amino acids and organic ions along the human digestive tract. Biochem Pharmacol 70, 17561763.
28 Hara, H, Funabiki, R, Iwata, M, et al. (1984) Portal absorption of small peptides in rats under unrestrained conditions. J Nutr 114, 11221129.
29 Nussberger, S, Steel, A, Trotti, D, et al. (1997) Symmetry of H+ binding to the intra- and extracellular side of the H+-coupled oligopeptide cotransporter PepT1. J Biol Chem 272, 77777785.
30 Foltz, M, van der Pijl, PC & Duchateau, G (2010) Current in vitro testing of bioactive peptides is not valuable. J Nutr 140, 117118.
31 Ganapathy, V, Ganapathy, ME & Leibach, FH (2001) Intestinal transport of peptides and amino acids. In Gastrointestinal Transport: Molecular Physiology, Current Topics in Membranes, vol. 50, pp. 379412 [Barrett, KE and Donowitz, M, editors]. San Diego: Academic Press.
32 Meredith, D & Boyd, CAR (2000) Structure and function of eukaryotic peptide transporters. Cell Mol Life Sci 57, 754778.
33 Silva, SV & Malcata, FX (2005) Caseins as source of bioactive peptides. Int Dairy J 15, 115.
34 Meisel, H (1997) Biochemical properties of bioactive peptides derived from milk proteins: potential nutraceuticals for food and pharmaceutical applications. Livest Prod Sci 50, 125138.
35 Haque, E, Chand, R & Kapila, S (2009) Biofunctional properties of bioactive peptides of milk origin. Food Rev Int 25, 2843.
36 Deacon, CF, Nauck, MA, Toftnielsen, M, et al. (1995) Both subcutaneously and intravenously administered glucagon-like peptide-1 are rapidly degraded from the NH2-terminus in type-II diabetic-patients and in healthy-subjects. Diabetes 44, 11261131.
37 Gardner, MLG (1998) Transmucosal passage of intact peptides. In Peptides in Mammalian Protein Metabolism: Tissue Utilization and Clinical Targeting, vol. 11, pp. 1129 [Grimble, GK and Backwell, FRC, editors]. London: Portland Press.
38 Weaver, LT & Walker, WA (1989) Uptake of macromolecules in the neonate. In Human Gastrointestinal Development, pp. 731748 [Lebenthal, E, editor]. New York: Raven Press.
39 Walker, WA & Isselbacher, KJ (1974) Uptake and transport of macromolecules by intestine – possible role in clinical disorders. Gastroenterology 67, 531550.
40 Ménard, S, Cerf-Bensussan, N & Heyman, M (2010) Multiple facets of intestinal permeability and epithelial handling of dietary antigens. Mucosal Immunol 3, 247259.
41 Izcue, A, Coombes, JL & Powrie, F (2006) Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol Rev 212, 256271.
42 Strobel, S & Mowat, AM (1998) Immune responses to dietary antigens: oral tolerance. Immunol Today 19, 173181.
43 Travis, S & Menzies, I (1992) Intestinal permeability: functional assessment and significance. Clin Sci 82, 471488.
44 Bjarnason, I, Macpherson, A & Hollander, D (1995) Intestinal permeability: an overview. Gastroenterology 108, 15661581.
45 Gersemann, M, Wehkamp, J & Stange, EF (2012) Innate immune dysfunction in inflammatory bowel disease. J Intern Med 271, 421428.
46 Ingersoll, SA, Ayyadurai, S, Charania, MA, et al. (2012) The role and pathophysiological relevance of membrane transporter PepT1 in intestinal inflammation and inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 302, G484G492.
47 Shan, L, Molberg, O, Parrot, I, et al. (2002) Structural basis for gluten intolerance in celiac sprue. Science 297, 22752279.
48 Shan, L, Qiao, SW, Arentz-Hansen, H, et al. (2005) Identification and analysis of multivalent proteolytically resistant peptides from gluten: implications for celiac sprue. J Proteome Res 4, 17321741.
49 Heyman, M, Grasset, E, Ducroc, R, et al. (1988) Antigen absorption by the jejunal epithelium of children with cow's milk allergy. Pediatr Res 24, 197202.
50 Kitts, DD & Weiler, K (2003) Bioactive proteins and peptides from food sources. Applications of bioprocesses used in isolation and recovery. Curr Pharm Des 9, 13091323.
51 Moughan, PJ, Fuller, MF, Han, KS, et al. (2007) Food-derived bioactive peptides influence gut function. Int J Sport Nutr Exerc Metab 17, S5S22.
52 Meisel, H (2004) Multifunctional peptides encrypted in milk proteins. Biofactors 21, 5561.
53 Rowan, AM, Haggarty, NW & Ram, S (2005) Milk biloactives: discovery and proof of concept. Aust J Dairy Technol 60, 114120.
54 Wilkinson, PC (1974) Surface and cell-membrane activities of leukocyte chemotactic factors. Nature 251, 5860.
55 Miner-Williams, W (2012) The protein composition of endogenous losses in the human gut. PhD thesis, Massey University, Palmerston North, New Zealand.
56 Rutherfurd-Markwick, KJ & Moughan, PJ (2005) Bioactive peptides derived from food. J AOAC Int 88, 955966.
57 Korhonen, H & Pihlanto, A (2006) Bioactive peptides: production and functionality. Int Dairy J 16, 945960.
58 Heyman, M (2001) How dietary antigens access the mucosal immune system. Proc Nutr Soc 60, 419426.
59 Mahe, S, Messing, B, Thuillier, F, et al. (1991) Digestion of bovine-milk proteins in patients with a high jejunostomy. Am J Clin Nutr 54, 534538.
60 Astwood, JD, Leach, JN & Fuchs, RL (1996) Stability of food allergens to digestion in vitro . Nat Biotechnol 14, 12691273.
61 Furuse, M, Fujita, K, Hiiragi, T, et al. (1998) Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol 141, 15391550.
62 Furuse, M, Hirase, T, Itoh, M, et al. (1993) Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol 123, 17771788.
63 Mandell, KJ, McCall, IC & Parkos, CA (2004) Involvement of the junctional adhesion molecule-1 (JAM1) homodimer interface in regulation of epithelial barrier function. J Biol Chem 279, 1625416262.
64 Ikenouchi, J, Furuse, M, Furuse, K, et al. (2005) Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells. J Cell Biol 171, 939945.
65 Gebbers, JO & Laissue, JA (1989) Immunologic structures and functions of the gut. Schweizer Archiv Fur Tierheilkunde 131, 221238.
66 Lennernäs, H (2007) Intestinal permeability and its relevance for absorption and elimination. Xenobiotica 37, 10151051.
67 Madara, JL (1990) Maintenance of the macromolecular barrier at cell extrusion sites in intestinal epithelium: physiological rearrangement of tight junctions. J Membr Biol 116, 177184.
68 Shimizu, M, Tsunogai, M & Arai, S (1997) Transepithelial transport of oligopeptides in the human intestinal cell. Caco-2. Peptides 18, 681687.
69 Shen, WC, Wan, JS & Ekrami, H (1992) (3) Enhancement of polypeptide and protein-absorption by macromolecular carriers via endocytosis and transcytosis. Adv Drug Deliver Rev 8, 93113.
70 Van Niel, G, Mallegol, J, Bevilacqua, C, et al. (2003) Intestinal epithelial exosomes carry MHC class II/peptides able to inform the immune system in mice. Gut 52, 16901697.
71 Bockman, DE & Winborn, WB (1966) Light and electron microscopy of intestinal ferritin absorption. Observations in sensitized and nonsensitized hamsters (Mesocricetus auratus). Anat Rec 155, 603621.
72 Volkheimer, G (1964) Permeability of the intestinal mucous membrane to large corpuscular elements (Herbst effect). Z Gastroenterol 2, 5767.
73 Weiner, ML (1988) Intestinal transport of some macromolecules in food. Food Chem Toxicol 26, 867880.
74 Agar, WT, Hird, FJR & Sidhu, GS (1953) The active absorption of amino acids by the intestine. J Physiol 121, 255263.
75 Wiggans, DS & Johnston, JM (1959) The absorption of peptides. Biochim Biophys Acta 32, 6973.
76 Hueckel, HJ & Rogers, QR (1970) Urinary excretion of hydroxyproline-containing peptides in man, rat, hamster, dog and monkey after feeding gelatin. Comp Biochem Physiol 32, 716.
77 Hellier, MD, Holdsworth, CD, McColl, I, et al. (1972) Dipeptide absorption in man. Gut 13, 965969.
78 Boullin, DJ, Crampton, RF, Heading, CE, et al. (1973) Intestinal absorption of dipeptides containing glycine, phenylalanine, proline, β-alanine or histidine in rat. Clin Sci Mol Med 45, 849858.
79 Adibi, SA (1976) Intestinal phase of protein assimilation in man. Am J Clin Nutr 29, 205215.
80 Silk, DBA, Perrett, D, Webb, JPW, et al. (1974) Absorption of 2 tripeptides by human small intestine: a study using a perfusion technique. Clin Sci Mol Med 46, 393402.
81 Hellier, MD, Holdsworth, CD, Perrett, D, et al. (1972) Intestinal dipeptide transport in normal and cystinuric subjects. Clin Sci 43, 659668.
82 Silk, DBA, Perrett, D & Clark, ML (1975) Jejunal and ileal absorption of dibasic amino acids and an arginine-containing dipeptide in cystinuria. Gastroenterology 68, 14261432.
83 Asatoor, AM, Cheng, B, Edwards, KDG, et al. (1970) Intestinal absorption of two dipeptides in Hartnup disease. Gut 11, 380387.
84 Tarlow, MJ, Thomas, AJ, Seakins, JWT, et al. (1972) Absorption of amino acids and peptides in a child with a variant of Hartnup disease and coexistent celiac disease. Arch Dis Child 47, 798803.
85 Adibi, SA & Morse, EL (1977) Number of glycine residues which limits intact absorption of glycine oligopeptides in human jejunum. J Clin Invest 60, 10081016.
86 Chung, YC, Silk, DBA & Kim, YS (1979) Intestinal transport of a tetrapeptide, L-leucylglycylglycylglycine, in rat small intestine in vivo . Clin Sci 57, 111.
87 Burston, D, Taylor, E & Matthews, DM (1979) Intestinal handling of two tetrapeptides by rodent small intestine in vitro . Biochim Biophys Acta 353, 175178.
88 Addison, JM, Burston, D, Payne, JW, et al. (1975) Evidence for active transport of tripeptides by hamster jejunum in vitro . Clin Sci Mol Med 49, 305312.
89 Kerchner, GA & Geary, LE (1983) Studies on the transport of enkephalin-like oligopeptides in rat intestinal mucosa. J Pharmacol Exp Ther 226, 3338.
90 Matthews, DM & Payne, JW (1980) Current Topics in Membrane and Transport, vol. 14. New York: Academic Press.
91 Rogers, CS, Heading, CE & Wilkinson, S (1980) Absorption of 2 tyrosine containing tetrapeptides from the ileum of the rat. IRCS Med Sci Biochem 8, 648649.
92 Langguth, P, Bohner, V, Biber, J, et al. (1994) Metabolism and transport of the pentapeptide metkephamid by brush-border membrane-vesicles of rat intestine. J Pharm Pharmacol 46, 3440.
93 Fricker, G, Bruns, C, Munzer, J, et al. (1991) Intestinal-absorption of the octapeptide SMS-201-995 visualized by fluorescence derivatization. Gastroenterology 100, 15441552.
94 Takaori, K, Burton, J & Donowitz, M (1986) The transport of an intact oligopeptide across adult mammalian jejunum. Biochem Biophys Res Commun 137, 682687.
95 Lundin, S & Vilhardt, H (1986) Absorption of 1-deamino-8-d-arginine vasopressin from different regions of the gastrointestinal tract in rabbits. Acta Endocrinol 112, 457460.
96 Amoss, M, Rivier, J & Guillemin, R (1972) Release of gonadotropins by oral administration of synthetic LRF or a tripeptide fragment of LRF. J Clin Endocrinol Metab 35, 175177.
97 Ptachcinski, RJ, Burckart, GJ & Venkataramanan, R (1985) Cyclosporine. Drug Intell Clin Pharm 19, 90100.
98 Drewe, J, Meier, R, Vonderscher, J, et al. (1992) Enhancement of the oral absorption of cyclosporine in man. Br J Clin Pharmacol 34, 6064.
99 Walker, WA, Cornell, R, Davenport, LM, et al. (1972) Macromolecular absorption. Mechanism of horseradish peroxidase uptake and transport in adult and neonatal rat intestine. J Cell Biol 54, 195205.
100 Heyman, M, Ducroc, R, Desjeux, JF, et al. (1982) Horseradish peroxidase transport across adult rabbit jejunum in vitro . Am J Physiol 242, G558G564.
101 Neutra, MR, Phillips, TL, Mayer, EL, et al. (1987) Transport of membrane-bound macromolecules by M-cells in follicle-associated epithelium of rabbit Peyer patch. Cell Tissue Res 247, 537546.
102 Weltzin, R, Luciajandris, P, Michetti, P, et al. (1989) Binding and transepithelial transport of immunoglobulins by intestinal M-cells: demonstration using monoclonal IgA antibodies against enteric viral proteins. J Cell Biol 108, 16731685.
103 Keljo, D & Hamilton, JR (1983) Quantitative determination of macromolecular transport rate across intestinal Peyer's patches. Am J Physiol 244, G637G644.
104 Hemmings, C, Hemmings, WA, Patey, AL, et al. (1977) Ingestion of dietary protein as large molecular mass degradation products in adult rats. Proc Royal Soc Lond B Biol Sci 198, 439453.
105 Hemmings, WA & Williams, EW (1978) Transport of large breakdown products of dietary protein through the gut wall. Gut 19, 715723.
106 Hemmings, WA & Williams, EW (1976) The use of direct deposition electron microscope autoradiography in studies of protein transport. J Microsc 106, 131143.
107 Jones, EA & Waldmann, TA (1971) Mechanism of intestinal uptake and transcellular transport of IgG in neonatal rat. Gut 12, 855856.
108 Mostov, KE (1994) Transepithelial transport of immunoglobulins. Annu Rev Immunol 12, 6384.
109 Bloch, KJ, Wright, JA, Bishara, SM, et al. (1988) Uptake of polypeptide fragments of proteins by rat intestine in vitro and in vivo . Gastroenterology 95, 12721278.
110 Phelan, M & Kerins, D (2011) The potential role of milk-derived peptides in cardiovascular disease. Food Funct 2, 153167.
111 Jahan-Mihan, A, Luhovyy, BL, El Khoury, D, et al. (2011) Dietary proteins as determinants of metabolic and physiologic functions of the gastrointestinal tract. Nutrients 3, 574603.
112 Meisel, H (2001) Bioactive peptides from milk proteins: a perspective for consumers and producers. Aust J Dairy Technol 56, 8392.
113 Agyei, D & Danquah, MK (2012) Rethinking food-derived bioactive peptides for antimicrobial and immunomodulatory activities. Trends Food Sci Technol 23, 6269.
114 Agyei, D & Danquah, MK (2011) Industrial-scale manufacturing of pharmaceutical-grade bioactive peptides. Biotechnol Adv 29, 272277.
115 Roberts, PR, Burney, JD, Black, KW, et al. (1999) Effect of chain length on absorption of biologically active peptides from the gastrointestinal tract. Digestion 60, 332337.
116 Erdmann, K, Cheung, BWY & Schroder, H (2008) The possible roles of food-derived bioactive peptides in reducing the risk of cardiovascular disease. J Nutr Biochem 19, 643654.
117 Foltz, M, Cerstiaens, A, van Meensel, A, et al. (2008) The angiotensin converting enzyme inhibitory tripeptides Ile-Pro-Pro and Val-Pro-Pro show increasing permeabilities with increasing physiological relevance of absorption models. Peptides 29, 13121320.
118 Séverin, S & Xia, WS (2005) Milk biologically active components as nutraceuticals: review. Crit Rev Food Sci Nutr 45, 645656.
119 Nakamura, Y, Yamamoto, N, Sakai, K, et al. (1995) Antihypertensive effect of sour milk and peptides isolated from it that are inhibitors to angiotensin I-converting enzyme. J Dairy Sci 78, 12531257.
120 Robert, MC, Razaname, A, Mutter, M, et al. (2004) Peptides derived from sodium caseinate hydrolysates produced by Lactobacillus helveticus NCC 2765. J Agric Food Chem 52, 69236931.
121 Zaloga, GP & Siddiqui, RA (2004) Biologically active dietary peptides. Mini Rev Med Chem 4, 815821.
122 Miguel, M, Muguerza, B, Sanchez, E, et al. (2005) Changes in arterial blood pressure in hypertensive rats caused by long-term intake of milk fermented by Enterococcus faecalis CECT 5728. Br J Nutr 94, 3643.
123 Mizuno, S, Matsuura, K, Gotou, T, et al. (2005) Antihypertensive effect of casein hydrolysate in a placebo-controlled study in subjects with high-normal blood pressure and mild hypertension. Br J Nutr 94, 8491.
124 Fitzgerald, RJ & Murray, BA (2006) Bioactive peptides and lactic fermentations. Int J Dairy Technol 59, 118125.
125 Foltz, M, Meynen, EE, Bianco, V, et al. (2007) Angiotensin converting enzyme inhibitory peptides from a lactotripeptide-enriched milk beverage are absorbed intact into the circulation. J Nutr 137, 953958.
126 Escudero, E, Sentandreu, MA, Arihara, K, et al. (2010) Angiotensin I-converting enzyme inhibitory peptides generated from in vitro gastrointestinal digestion of pork meat. J Agric Food Chem 58, 28952901.
127 Muguerza, B, Ramos, M, Sanchez, E, et al. (2006) Antihypertensive activity of milk fermented by Enterococcus faecalis strains isolated from raw milk. Int Dairy J 16, 6169.
128 Nakamura, T, Mizutani, J, Sasaki, K, et al. (2009) Beneficial potential of casein hydrolysate containing Val-Pro-Pro and Ile-Pro-Pro on central blood pressure and hemodynamic index: a preliminary study. J Med Food 12, 12211226.
129 Hata, Y, Yamamoto, M, Ohni, M, et al. (1996) Placebo-controlled study of the effect of sour milk on blood pressure in hypertensive subjects. Am J Clin Nutr 64, 767771.
130 Sano, J, Ohki, K, Higuchi, T, et al. (2005) Effect of casein hydrolysate, prepared with protease derived from Aspergillus oryzae, on subjects with high-normal blood pressure or mild hypertension. J Med Food 8, 423430.
131 Seppo, L, Jauhiainen, T, Poussa, T, et al. (2003) A fermented milk high in bioactive peptides has a blood pressure-lowering effect in hypertensive subjects. Am J Clin Nutr 77, 326330.
132 Jauhiainen, T, Vapaatalo, H, Poussa, T, et al. (2005) Lactobacillus helveticus fermented milk lowers blood pressure in hypertensive subjects in 24-h ambulatory blood pressure measurement. Am J Hypertens 18, 16001605.
133 Xu, J-Y, Qin, L-Q, Wang, P-Y, et al. (2008) Effect of milk tripeptides on blood pressure: a meta-analysis of randomized controlled trials. Nutrition 24, 933940.
134 Boelsma, E & Kloek, J (2009) Lactotripeptides and antihypertensive effects: a critical review. Br J Nutr 101, 776786.
135 Masuda, O, Nakamura, Y & Takano, T (1996) Antihypertensive peptides are present in aorta after oral administration of sour milk containing these peptides to spontaneously hypertensive rats. J Nutr 126, 30633068.
136 Nilsson, D, Fagerholm, U & Lennernas, H (1994) The influence of net water absorption on the permeability of antipyrine and levodopa in the human jejunum. Pharm Res 11, 15401544.
137 Lennernäs, H, Ahrenstedt, O & Ungell, AL (1994) Intestinal drug absorption during induced net water absorption in man: a mechanistic study using antipyrine, atenolol and enalaprilat. Br J Clin Pharmacol 37, 589596.
138 Fagerholm, U, Nilsson, D, Knutson, L, et al. (1999) Jejunal permeability in humans in vivo and rats insitu: investigation of molecular size selectivity and solvent drag. Acta Physiol Scand 165, 315324.
139 Satake, M, Enjoh, M, Nakamura, Y, et al. (2002) Transepithelial transport of the bioactive tripeptide, Val-Pro-Pro, in human intestinal Caco-2 cell monolayers. Biosci Biotechnol Biochem 66, 378384.
140 Camenisch, G, Alsenz, J, van de Waterbeemd, H, et al. (1998) Estimation of permeability by passive diffusion through Caco-2 cell monolayers using the drugs' lipophilicity and molecular weight. Eur J Pharm Sci 6, 317324.
141 Daniel, H & Herget, M (1997) Cellular and molecular mechanisms of renal peptide transport. Am J Physiol 273, F1F8.
142 Brandsch, M, Knutter, I & Bosse-Doenecke, E (2008) Pharmaceutical and pharmacological importance of peptide transporters. J Pharm Pharmacol 60, 543585.
143 Picariello, G, Ferranti, P, Fierro, O, et al. (2010) Peptides surviving the simulated gastrointestinal digestion of milk proteins: biological and toxicological implications. J Chromatogr B Analyt Technol Biomed Life Sci 878, 295308.
144 van der Pijl, PC, Kies, AK, Ten Have, GAM, et al. (2008) Pharmacokinetics of proline-rich tripeptides in the pig. Peptides 29, 21962202.
145 van Platerink, CJ, Janssen, HGM & Haverkamp, J (2007) Development of an at-line method for the identification of angiotensin-I inhibiting peptides in protein hydrolysates. J Chromatogr B Analyt Technol Biomed Life Sci 846, 147154.
146 Korhonen, H (2009) Milk-derived bioactive peptides: from science to applications. J Funct Food 1, 177187.
147 Ricci, I, Artacho, R & Olalla, M (2010) Milk protein peptides with angiotensin I-converting enzyme inhibitory (ACEI) activity. Crit Rev Food Sci Nutr 50, 390402.
148 Fitzgerald, RJ, Murray, BA & Walsh, DJ (2004) Hypotensive peptides from milk proteins. J Nutr 134, 980S988S.
149 Matsufuji, H, Matsui, T, Seki, E, et al. (1994) Angiotensin I-converting enzyme-inhibitory peptides in an alkaline protease hydrolyzate derived from sardine muscle. Biosci Biotechnol Biochem 58, 22442245.
150 Yamamoto, N, Ejiri, M & Mizuno, S (2003) Biogenic peptides and their potential use. Curr Pharm Des 9, 13451355.
151 Li, GH, Le, GW, Shi, YH, et al. (2004) Angiotensin I-converting enzyme inhibitory peptides derived from food proteins and their physiological and pharmacological effects. Nutr Res 24, 469486.
152 Gobbetti, M, Minervini, F & Rizzello, CG (2004) Angiotensin I-converting-enzyme-inhibitory and antimicrobial bioactive peptides. Int J Dairy Technol 57, 173188.
153 Matsui, T, Tamaya, K, Seki, E, et al. (2002) Val-Tyr as a natural antihypertensive dipeptide can be absorbed into the human circulatory blood system. Clin Exp Pharmacol Physiol 29, 204208.
154 Clare, DA & Swaisgood, HE (2000) Bioactive milk peptides: a prospectus. J Dairy Sci 83, 11871195.
155 Shah, NP (2000) Effects of milk-derived bioactives: an overview. Br J Nutr 84, S3S10.
156 Lonnerdal, B (2003) Nutritional and physiologic significance of human milk proteins. Am J Clin Nutr 77, 1537S1543S.
157 Meisel, H (2005) Biochemical properties of peptides encrypted in bovine milk proteins. Curr Med Chem 12, 19051919.
158 Martínez-Maqueda, D, Miralles, B, Recio, I, et al. (2012) Antihypertensive peptides from food proteins: a review. Food Funct 3, 350361.
159 Fitzgerald, RJ & Meisel, H (2000) Milk protein-derived peptide inhibitors of angiotensin-I-converting enzyme. Br J Nutr 84, S33S37.
160 van Platerink, CJ, Janssen, HGM, Horsten, R, et al. (2006) Quantification of ACE inhibiting peptides in human plasma using high performance liquid chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 830, 151157.
161 Klee, WA, Zioudrou, C & Streaty, RA (1978) Endorphins in Mental Health Research. New York: Macmillan.
162 Fukudome, S & Yoshikawa, M (1992) Opioid peptides derived from wheat gluten: their isolation and characterization. FEBS Lett 296, 107111.
163 Fanciulli, G, Dettori, A, Demontis, MP, et al. (2005) Gluten exorphin B5 stimulates prolactin secretion through opioid receptors located outside the blood-brain barrier. Life Sci 76, 17131719.
164 Ivanov, VT, Karelin, AA, Philippova, MM, et al. (1997) Hemoglobin as a source of endogenous bioactive peptides: the concept of tissue-specific peptide pool. Biopolymers 43, 171188.
165 Zhao, Q, Garreau, I, Sannier, F, et al. (1997) Opioid peptides derived from hemoglobin: hemorphins. Biopolymers 43, 7598.
166 Brantl, V, Teschemacher, H, Henschen, A, et al. (1979) Novel opioid peptides derived from casein (β-casomorphins). 1. Isolation from bovine casein peptone. Hoppe Seylers Z Physiol Chem 360, 12111216.
167 Zioudrou, C, Streaty, RA & Klee, WA (1979) Opioid peptides derived from food proteins – exorphins. J Biol Chem 254, 24462449.
168 Teschemacher, H (2003) Opioid receptor ligands derived from food proteins. Curr Pharm Des 9, 13311344.
169 Teschemacher, H, Koch, G & Brantl, V (1997) Milk protein-derived opioid receptor ligands. Biopolymers 43, 99117.
170 Meisel, H & Fitzgerald, RJ (2000) Opioid peptides encrypted in intact milk protein sequences. Br J Nutr 84, S27S31.
171 Simon, EJ, Hiller, JM & Edelman, I (1973) Stereospecific binding of potent narcotic analgesic [3H]etorphine to rat-brain homogenate. Proc Natl Acad Sci U S A 70, 19471949.
172 Pert, CB & Snyder, SH (1973) Opiate receptor: demonstration in nervous tissue. Science 179, 10111014.
173 Terenius, L (1973) Characteristics of the receptor for narcotic analgesics in synaptic plasma membrane fraction from rat brain. Acta Pharmacol Toxicol 33, 377384.
174 Mansour, A & Watson, SJ (1993) Handbook of Experimental Pharmacology, vol. 104/I. Berlin: Springer.
175 Satoh, M & Minami, M (1995) Molecular pharmacology of the opioid receptors. Pharmacol Ther 68, 343364.
176 Nishimura, E, Buchan, AMJ & McIntosh, CHS (1986) Autoradiographic localization of μ- and δ-type opioid receptors in the gastrointestinal tract of the rat and guinea-pig. Gastroenterology 91, 10841094.
177 Karras, PJ & North, RA (1981) Acute and chronic effects of opiates on single neurons of the myenteric-plexus. J Pharmacol Exp Ther 217, 7080.
178 Teschemacher, H, Koch, G & Brantl, V (1994) Milk protein derived atypical peptides and related compounds with opioid antagonist activity (review). In β-Casomorphins and Related Peptides: Recent Developments, pp. 317 [Brantl, V and Teschemacher, H, editors]. Weinheim: VCH.
179 Höllt, V (1986) Opioid peptide processing and receptor selectivity. Annu Rev Pharmacol Toxicol 26, 5977.
180 Paterson, SJ, Robson, LE & Kosterlitz, HW (1983) Classification of opioid receptors. Br Med Bull 39, 3136.
181 Chang, KJ, Killian, A, Hazum, E, et al. (1981) Morphiceptin (NH4-Tyr-Pro-Phe-Pro-ConH2): a potent and specific agonist for morphine (Mu) receptors. Science 212, 7577.
182 Mierke, DF, Nossner, G, Schiller, PW, et al. (1990) Morphiceptin analogs containing 2-aminocyclopentane carboxylic-acid as a peptidomimetic for proline. Int J Pept Protein Res 35, 3545.
183 Schulte-Frohlinde, E, Schimd, R, Brantl, V, et al (1994) Effect of bovine β-casomorphins-4-amide on gastrointestinal transit and pancreatic endocrine function in man. In β-Casomorphins and Related Peptides: Recent Developments, pp. 155160 [Brantl, V and Teschemacher, H, editors]. Weinheim: VCH.
184 Froetschel, MA (1996) Bioactive peptides in digesta that regulate gastrointestinal function and intake. J Anim Sci 74, 25002508.
185 Allescher, HD, Storr, M, Brechmann, C, et al. (2000) Modulatory effect of endogenous and exogenous opioids on the excitatory reflex pathway of the rat ileum. Neuropeptides 34, 6268.
186 Brandsch, M, Brust, P, Neubert, K, et al (1994) Evidence for a functional significance of natural β-casomorphins. β-Casomorphins: chemical signals of intestinal transport systems. In β-Casomorphins and Related Peptides: Recent Developments, pp. 207219 [Brantl, V and Teschemacher, H, editors]. Weinheim: VCH.
187 Daniel, H, Vohwinkel, M & Rehner, G (1990) Effect of casein and β-casomorphins on gastrointestinal motility in rats. J Nutr 120, 252257.
188 Matthies, H, Stark, H, Hartrodt, B, et al. (1984) Derivatives of β-casomorphins with high analgesic potency. Peptides 5, 463470.
189 Taira, T, Hilakivi, LA, Aalto, J, et al. (1990) Effect of β-casomorphin on neonatal sleep in rats. Peptides 11, 14.
190 Yamada, Y, Matoba, N, Usui, H, et al. (2002) Design of a highly potent anti-hypertensive peptide based on ovokinin(2-7). Biosci Biotechnol Biochem 66, 12131217.
191 Jiang, Z, Tian, B, Brodkorb, A, et al. (2010) Production, analysis and in vivo evaluation of novel angiotensin-I-converting enzyme inhibitory peptides from bovine casein. Food Chem 123, 779786.
192 Yoshikawa, M, Tani, F, Shiota, H, et al (1994) Casoxin D, an opioid antagonist ileum-contracting/vasorelaxing peptide derived from human αs1-casein. In β-Casomorphins and Related Peptides: Recent Developments, pp. 4348 [Brantl, V and Teschemacher, H, editors]. Weinheim: VCH.
193 Hernández-Ledesma, B, del Mar Contreras, M & Recio, I (2011) Antihypertensive peptides: production, bioavailability and incorporation into foods. Adv Colloid Interface Sci 165, 2335.
194 Nurminen, ML, Sipola, M, Kaarto, H, et al. (2000) α-Lactorphin lowers blood pressure measured by radiotelemetry in normotensive and spontaneously hypertensive rats. Life Sci 66, 15351543.
195 Sipola, M, Finckenberg, P, Vapaatalo, H, et al. (2002) α-Lactorphin and β-lactorphin improve arterial function in spontaneously hypertensive rats. Life Sci 71, 12451253.
196 Miguel, M, Gómez-Ruiz, , Recio, I, et al. (2010) Changes in arterial blood pressure after single oral administration of milk-casein-derived peptides in spontaneously hypertensive rats. Mol Nutr Food Res 54, 14221427.
197 Miguel, M, Manso, MA, López-Fandiño, R, et al. (2007) Vascular effects and antihypertensive properties of κ-casein macropeptide. Int Dairy J 17, 14731477.
198 Miguel, M, Manso, M, Aleixandre, A, et al. (2007) Vascular effects, angiotensin I-converting enzyme (ACE)-inhibitory activity, and anti hypertensive properties of peptides derived from egg white. J Agric Food Chem 55, 1061510621.
199 Miguel, M, Alvarez, Y, López-Fandiño, R, et al. (2007) Vasodilator effects of peptides derived from egg white proteins. Regul Pept 140, 131135.
200 Dávalos, A, Miguel, M, Bartolome, B, et al. (2004) Antioxidant activity of peptides derived from egg white proteins by enzymatic hydrolysis. J Food Prot 67, 19391944.
201 del Mar Contreras, M, Carron, R, Jose Montero, M, et al. (2009) Novel casein-derived peptides with antihypertensive activity. Int Dairy J 19, 566573.
202 Hirota, T, Ohki, K, Kawagishi, R, et al. (2007) Casein hydrolysate containing the antihypertensive tripeptides Val-Pro-Pro and Ile-Pro-Pro improves vascular endothelial function independent of blood pressure-lowering effects: contribution of the inhibitory action of angiotensin-converting enzyme. Hypertens Res 30, 489496.
203 Wong, TP, Debnam, ES & Leung, PS (2007) Involvement of an enterocyte renin-angiotensin system in the local control of SGLT1-dependent glucose uptake across the rat small intestinal brush border membrane. J Physiol 584, 613623.
204 Leung, PS (2010) Local RAS. In Renin–Angiotensin System: Current Research Progress in the Pancreas: The RAS in the Pancreas, vol. 690, pp. 6987 [Leung, PS, editor]. Dordrecht: Springer.
205 Stevens, BR, Fernandez, A, Kneer, C, et al. (1988) Human intestinal brush-border angiotensin-converting enzyme-activity and its inhibition by antihypertensive Ramipril. Gastroenterology 94, 942947.
206 Bruneval, P, Hinglais, N, Alhenc-Gelas, F, et al. (1986) Angiotensin I converting enzyme in human intestine and kidney. Ultrastructural immunohistochemical localization. Histochemistry 85, 7380.
207 Cox, HM, Munday, KA & Poat, JA (1986) Identification of selective, high-affinity I-125 angiotensin and I-125 bradykinin binding-sites in rat intestinal epithelia. Br J Pharmacol 87, 201209.
208 Jin, XH, Wang, ZQ, Siragy, HM, et al. (1998) Regulation of jejunal sodium and water absorption by angiotensin subtype receptors. Am J Physiol 275, R515R523.
209 Yoshioka, M, Erickson, RH, Woodley, JF, et al. (1987) Role of rat intestinal brush-border membrane angiotensin-converting enzyme in dietary-protein digestion. Am J Physiol 253, G781G786.
210 Dorey, PG, King, J, Munday, KA, et al. (1983) Intestinal fluid absorption in spontaneously hypertensive rats. J Physiol 344, 19.
211 Catalanotto, F, Schechter, PJ & Henkin, RI (1972) Preference for NaCl in spontaneously hypertensive rat. Life Sci 1 11, 557564.
212 Dahl, LK (1961) Possible role of chronic excess salt consumption in pathogenesis of essential hypertension. Am J Cardiol 8, 571575.
213 Ehlers, MRW & Riordan, JF (1989) Angiotensin-converting enzyme: new concepts concerning its biological role. Biochemistry 28, 53115318.
214 Amidon, GL & Sadée, WE (1999) Membrane Transporters as Drug Targets. Pharmaceutical Biotechnology , vol. 12. New York: Kluwer Academic/Plenum Publishers.
215 Bai, JPF & Amidon, GL (1992) Structural specificity of mucosal-cell transport and metabolism of peptide drugs – implication for oral peptide drug delivery. Pharm Res 9, 969978.
216 Chabance, B, Marteau, P, Rambaud, JC, et al. (1998) Casein peptide release and passage to the blood in humans during digestion of milk or yogurt. Biochimie 80, 155165.
217 Meisel, H & Schlimme, E (1990) Milk proteins: precursors of bioactive peptides. Trends Food Sci Technol 1, 4143.
218 Meisel, H (1997) Biochemical properties of regulatory peptides derived from milk proteins. Biopolymers 43, 119128.
219 Clare, DA, Catignani, GL & Swaisgood, HE (2003) Biodefense properties of milk – the role of antimicrobial proteins and peptides. Curr Pharm Des 9, 12391255.
220 Korhonen, H & Pihlanto, A (2003) Food-derived bioactive peptides – opportunities for designing future foods. Curr Pharm Des 9, 12971308.
221 Petrilli, P, Picone, D, Caporale, C, et al. (1984) Does casomorphin have a functional role? FEBS Lett 169, 5356.
222 Kreil, G, Umbach, M, Brantl, V, et al. (1983) Studies on the enzymatic degradation of β-casomorphins. Life Sci 33, 137140.
223 Daniel, H & Hahn, A (1990) β-Casomorphins opioid-peptides derived from milk proteins. Ernährungs-Umschau 37, 95101.
224 Schmelzer, CEH, Schöps, R, Reynell, L, et al. (2007) Peptic digestion of β-casein. Time course and fate of possible bioactive peptides. J Chromatogr A 1166, 108115.
225 Tome, D & Debabbi, H (1998) Physiological effects of milk protein components. Int Dairy J 8, 383392.
226 Pihlanto-Leppala, A (2000) Bioactive peptides derived from bovine whey proteins: opioid and ACE-inhibitory peptides. Trends Food Sci Technol 11, 347356.
227 Gardner, MLG (1988) Gastrointestinal absorption of intact proteins. Annu Rev Nutr 8, 329350.
228 Paganelli, R & Levinsky, RJ (1980) Solid-phase radioimmunoassay for detection of circulating food protein antigens in human serum. J Immunol Methods 37, 333341.
229 Kenrick, KG (1970) Immunoglobulins and dietary protein antibodies in childhood coeliac disease. Gut 11, 635640.
230 Roberton, DM, Paganelli, R, Dinwiddie, R, et al. (1982) Milk antigen absorption in the preterm and term neonate. Arch Dis Child 57, 369372.
231 Bazin, H, Andre, C & Heremans, JF (1973) Immunological responses to orally ingested antigens. Ann D Immunol C124, 253272.
232 Cunningham-Rundles, C (1987) Failure of antigen exclusion. In Food Allergy and Intolerance, pp. 223236 [Brostoff, J and Challocombe, CJ, editors]. London: Bailliere Tindall.
233 Husby, S, Foged, N, Høst, A, et al. (1987) Passage of dietary antigens into the blood of children with celiac disease. Quantification and size distribution of absorbed antigens. Gut 28, 10621072.
234 Jakobsson, I, Lindberg, T, Lothe, L, et al. (1986) Human alpha-lactalbumin as a marker of macromolecular absorption. Gut 27, 10291034.
235 McLean, E & Ash, R (1987) The time-course of appearance and net accumulation of horseradish peroxidase (HRP) presented orally to rainbow trout Salmo gairdneri (Richardson). Comp Biochem Physiol A Comp Physiol 88, 507510.
236 McLean, E & Ash, R (1986) The time-course of appearance and net accumulation of horseradish peroxidase (HRP) presented orally to juvenile carp Cyprinus carpio (L.). Comp Biochem Physiol A Comp Physiol 84, 687690.
237 Walker, WA, Abel, SN, Wu, M, et al. (1976) Intestinal uptake of macromolecules 5. Comparison of in vitro uptake by rat small intestine of antigen-antibody complexes prepared in antibody or antigen excess. J Immunol 117, 10281032.
238 Walker, WA, Wu, M, Isselbacher, KJ, et al. (1975) Intestinal uptake of macromolecules 4. Effect of pancreatic duct ligation on breakdown of antigen and antigen-antibody complexes on intestinal surface. Gastroenterology 69, 12231229.
239 Fiat, AM, Miglioresamour, D, Jolles, P, et al. (1993) Biologically-active peptides from milk proteins with emphasis on 2 examples concerning antithrombotic and immunomodulating activities. J Dairy Sci 76, 301310.
240 Wolf, JL, Rubin, DH, Finberg, R, et al. (1981) Intestinal M-cells: a pathway for entry of reovirus into the host. Science 212, 471472.
241 Gardner, MLG (1984) Intestinal assimilation of intact peptides and proteins from the diet – a neglected field. Biol Rev Camb Philos Soc 59, 289331.
242 Teschemacher, H, Umbach, M, Hamel, U, et al. (1986) No evidence for the presence of β-casomorphins in human-plasma after ingestion of cows milk or milk products. J Dairy Res 53, 135138.
243 Mahe, S, Tome, D, Dumontier, AM, et al. (1989) Absorption of intact morphiceptin by diisopropylfluorophosphate-treated rabbit ileum. Peptides 10, 4552.
244 Read, LC, Lord, APD, Brantl, V, et al. (1990) Absorption of β-casomorphins from autoperfused lamb and piglet small intestine. Am J Physiol 259, G443G452.
245 Tiruppathi, C, Miyamoto, Y, Ganapathy, V, et al. (1993) Genetic evidence for role of DPP-IV in intestinal hydrolysis and assimilation of prolyl peptides. Am J Physiol 265, G81G89.
246 Gill, HS, Doull, F, Rutherfurd, KJ, et al. (2000) Immunoregulatory peptides in bovine milk. Br J Nutr 84, S111S117.
247 Bray, GA (2000) Afferent signals regulating food intake. Proc Nutr Soc 59, 373384.
248 Bakalkin, GY, Demuth, HU & Nyberg, F (1992) Relationship between primary structure and activity in exorphins and endogenous opioid peptides. FEBS Lett 310, 1316.
249 Nyberg, F, Sanderson, K & Glamsta, EL (1997) The hemorphins: a new class of opioid peptides derived from the blood protein hemoglobin. Biopolymers 43, 147156.
250 Yoshikawa, M, Tani, F, Ashikaga, T, et al. (1986) Purification and characterization of an opioid antagonist from a peptic digest of bovine κ-casein. Agric Biol Chem 50, 29512954.
251 Lin, L, Umahara, M, York, DA, et al. (1998) β-Casomorphins stimulate and enterostatin inhibits the intake of dietary fat in rats. Peptides 19, 325331.
252 Hedner, J & Hedner, T (1987) β-Casomorphins induce apnea and irregular breathing in adult rats and newborn rabbits. Life Sci 41, 23032312.
253 Cheng, FY, Liu, YT, Wan, TC, et al. (2008) The development of angiotensin I-converting enzyme inhibitor derived from chicken bone protein. Anim Sci J 79, 122128.
254 Medhus, AW, Sandstad, O, Bredesen, J, et al. (1999) Delay of gastric emptying by duodenal intubation: sensitive measurement of gastric emptying by the paracetamol absorption test. Aliment Pharmacol Ther 13, 609620.
255 Fone, DR, Horowitz, M, Heddle, R, et al. (1991) Comparative effects of duodenal and ileal intubation on gastric emptying and postprandial antral, pyloric, and duodenal motility. Scand J Gastroenterol 26, 1622.
256 Read, NW, Aljanabi, MN, Bates, TE, et al. (1983) Effect of gastrointestinal intubation on the passage of a solid meal through the stomach and small intestine in humans. Gastroenterology 84, 15681572.
257 Hendrix, TR & Bayless, TM (1970) Digestion: intestinal secretion. Annu Rev Physiol 32, 139164.
258 Rao, RK, Koldovsky, O & Davis, TP (1990) Inhibition of intestinal degradation of somatostatin by rat milk. Am J Physiol 258, G426G431.
259 Sarfati, P & Morisset, J (1988) Inhibition of pancreatic exocrine secretion of intraintestinal somatostatin possible mechanism of action involving the proximal duodenum. Pancreas 3, 616.
260 Konturek, SJ, Tasler, J, Cieszkowski, M, et al. (1981) Studies on the inhibition of pancreatic secretion by luminal somatostatin. Am J Physiol 241, G109G115.
261 Konturek, SJ, Bilski, J, Jaworek, J, et al. (1988) Comparison of somatostatin and its highly potent hexapeptide and octapeptide analogs on exocrine and endocrine pancreatic secretion. Proc Soc Exp Biol Med 187, 241249.
262 Jones, RE (1977) De-iodination of labeled protein during intestinal transmission in suckling rat. Proc R Soc Lond B Biol Sci 199, 279290.
263 Moriya, H, Moriwaki, C, Akimoto, S, et al. (1967) Studies on passage of α-chymotrypsin across intestine. Chem Pharm Bull (Tokyo) 15, 16621668.
264 Miller, JM, Williard, RF & Polachek, AA (1960) An investigation of trypsin I-131 in patients. Exp Med Surg 18, 352370.
265 Kabacoff, BL, Avakian, S, Wohlman, A, et al. (1963) Absorption of chymotrypsin from intestinal tract. Nature 199, 815.
266 Ambrus, JL, Lassman, HB & Demarchi, JJ (1967) Absorption of exogenous and endogenous proteolytic enzymes. Clin Pharm Ther 8, 362368.
267 Avakian, S (1964) Further studies on absorption of chymotrypsin. Clin Pharm Ther 5, 712715.
268 Goldberg, DM, Campbell, R & Roy, AD (1968) Binding of trypsin and chymotrypsin by human intestinal mucosa. Biochim Biophys Acta 167, 613615.
269 Katayama, K & Fujita, T (1972) Studies on biotransformation of elastase 2. Intestinal-absorption of I-131-labeled elastase in-vivo . Biochim Biophys Acta 288, 181189.
270 Megel, H, Beiler, M, Ho, R, et al. (1964) Detection of trypsin-like activity in plasma of rats after oral administration of trypsin. Arch Biochem Biophys 108, 193199.
271 Urban, E, Zingery, AA, Bundrant, T, et al. (1982) Permeability of adolescent rat intestine to pancreatic ribonuclease. J Pediatr Gastroenterol Nutr 1, 267272.
272 Walker, WA, Isselbacher, KJ & Bloch, KJ (1972) Intestinal uptake of macromolecules: effect of oral immunization. Science 177, 608610.
273 Warshaw, AL, Walker, WA & Isselbacher, KJ (1974) Protein uptake by intestine: evidence for absorption of intact macromolecules. Gastroenterology 66, 987992.
274 Rothman, S, Liebow, C & Isenman, L (2002) Conservation of digestive enzymes. Physiol Rev 82, 118.
275 Goetze, H & Rothman, SS (1978) Amylase transport across ileal epithelium in-vitro . Biochim Biophys Acta 512, 214220.
276 Liebow, C & Rothman, SS (1974) Enteropancreatic circulation of an intact digestive enzyme. Fed Proc 33, 409.
277 Levitt, MD, Ellis, CJ, Murphy, SM, et al. (1981) Study of the possible enteropancreatic circulation of pancreatic amylase in the dog. Am J Physiol 241, G54G58.
278 Rosenblum, JL, Raab, BK & Alpers, DH (1982) Hepatobiliary and pancreatic clearance of circulating pancreatic amylase. Am J Physiol 243, G21G27.
279 Levitt, MD (1983) Is there an enteropancreatic circulation of digestive enzyme? Am J Physiol 244, G103G104.
280 Rohr, G, Kern, H & Scheele, G (1981) Enteropancreatic circulation of digestive enzymes does not exist in the rat. Nature 292, 470472.
281 Rothman, SS & Grendell, JH (1983) Is there an enteropancreatic circulation of digestive enzyme? Am J Physiol 244, G101G102.
282 Rohr, G, Kern, H & Scheele, G (1983) Is there an enteropancreatic circulation of digestive enzyme? Am J Physiol 244, G104G106.
283 Rosenblum, JL, Raab, BK & Alpers, DH (1983) Is there an enteropancreatic circulation of digestive enzyme? – reply. Am J Physiol 244, G103.
284 Joo, K & Kato, Y (2006) Assessment of allergenic activity of a heat-coagulated ovalbumin after in vivo digestion. Biosci Biotechnol Biochem 70, 591597.
285 Matsubara, T, Aoki, N, Honjoh, T, et al. (2008) Absorption, migration and kinetics in peripheral blood of orally administered ovalbumin in a mouse model. Biosci Biotechnol Biochem 72, 25552565.
286 Furrie, E, Turner, MW & Strobel, S (1995) Partial characterization of a circulating tolerogenic moiety which, after a feed of ovalbumin, suppresses delayed-type hypersensitivity in recipient mice. Immunology 86, 480486.
287 Tsume, Y, Taki, Y, Sakane, T, et al. (1996) Quantitative evaluation of the gastrointestinal absorption of protein into the blood and lymph circulation. Biol Pharm Bull 19, 13321337.
288 Moreno, FJ (2007) Gastrointestinal digestion of food allergens: effect on their allergenicity. Biomed Pharmacother 61, 5060.
289 Wharton, CW (1974) Structure and mechanism of stem bromelain. Evaluation of homogeneity of purified stem bromelain, determination of molecular-weight and kinetic analysis of bromelain-catalyzed hydrolysis of N-benzyloxycarbonyl-l-phenylalanyl-l-serine methyl-ester. Biochem J 143, 575586.
290 Soderholm, JD, Peterson, KH, Olaison, G, et al. (1999) Epithelial permeability to proteins in the noninflamed ileum of Crohn's disease? Gastroenterology 117, 6572.
291 Chehade, M & Mayer, L (2005) Oral tolerance and its relation to food hypersensitivities. J Allergy Clin Immunol 115, 312.
292 Frossard, CP, Hauser, C & Eigenmann, PA (2004) Antigen-specific secretory IgA antibodies in the gut are decreased in a mouse model of food allergy. J Allergy Clin Immunol 114, 377382.
293 Dannaeus, A, Inganas, M, Johansson, SGO, et al. (1979) Intestinal uptake of ovalbumin in malabsorption and food allergy in relation to serum IgG antibody and orally-administered sodium cromoglycate. Clin Allergy 9, 263270.
294 Diesner, SC, Knittelfelder, R, Krishnamurthy, D, et al. (2008) Dose-dependent food allergy induction against ovalbumin under acid suppression: a murine food allergy model. Immunol Lett 121, 4551.
295 James, JM (2004) Food allergy: opportunities and challenges in the clinical practice of allergy and immunology. Clin Rev Allergy Immunol 27, 105114.
296 Castell, JV, Friedrich, G, Kuhn, CS, et al. (1997) Intestinal absorption of undegraded proteins in men: presence of bromelain in plasma after oral intake. Am J Physiol Gastrointest Liver Physiol 273, G139G146.
297 Walker, WA (1987) Pathophysiology of intestinal uptake and absorption of antigens in food allergy. Ann Allergy 59, 716.
298 Heyman, M (2005) Gut barrier dysfunction in food allergy. Eur J Gastroenterol Hepatol 17, 12791285.
299 Gupta, S, Jain, A, Chakraborty, M, et al. (2013) Oral delivery of therapeutic proteins and peptides: a review on recent developments. Drug Deliv 20, 237246.
300 Rabanel, JM, Aoun, V, Elkin, I, et al. (2012) Drug-loaded nanocarriers: passive targeting and crossing of biological barriers. Curr Med Chem 19, 30703102.
301 Kamei, N, Nielsen, EJB, Khafagy, el-S, et al. (2013) Noninvasive insulin delivery: the great potential of cell-penetrating peptides. Ther Del 4, 315326.
302 Renukuntla, J, Vadlapudi, AD, Patel, A, et al. (2013) Approaches for enhancing oral bioavailability of peptides and proteins. Int J Pharm 447, 7593.
303 Swaminathan, J & Ehrhardt, C (2012) Liposomal delivery of proteins and peptides. Expert Opin Drug Deliv 9, 14891503.
304 Zhang, YL, Wei, W, Lv, PP, et al. (2011) Preparation and evaluation of alginate-chitosan microspheres for oral delivery of insulin. Eur J Pharm Biopharm 77, 1119.
305 Mukhopadhyay, P, Mishra, R, Rana, D, et al. (2012) Strategies for effective oral insulin delivery with modified chitosan nanoparticles: a review. Prog Polymer Sci 37, 14571475.
306 Olaison, G, Sjodahl, R & Tagesson, C (1990) Abnormal intestinal permeability in Crohn's-disease – a possible pathogenic factor. Scand J Gastroenterol 25, 321328.
307 Hollander, D (1992) The intestinal permeability barrier. A hypothesis as to its regulation and involvement in Crohn's disease. Scand J Gastroenterol 27, 721726.
308 Charrier, L & Merlin, D (2006) The oligopeptide transporter hPepT1: gateway to the innate immune response. Lab Invest 86, 538546.
309 Dalmasso, G, Nguyen, HTT, Charrier-Hisamuddin, L, et al. (2010) PepT1 mediates transport of the proinflammatory bacterial tripeptide l-Ala-γ-d-Glu-meso-DAP in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 299, G687G696.
310 Terada, T, Sawada, K, Saito, H, et al. (1999) Functional characteristics of basolateral peptide transporter in the human intestinal cell line Caco-2. Am J Physiol 276, G1435G1441.
311 Terada, T, Irie, M, Okuda, M, et al. (2004) Genetic variant Arg57His in human H+/peptide cotransporter 2 causes a complete loss of transport function. Biochem Biophys Res Commun 316, 416420.
312 Shepherd, EJ, Lister, N, Affleck, JA, et al. (2002) Identification of a candidate membrane protein for the basolateral peptide transporter of rat small intestine. Biochem Biophys Res Commun 296, 918922.
313 Irie, M, Terada, T, Okuda, M, et al. (2004) Efflux properties of basolateral peptide transporter in human intestinal cell line Caco-2. Pflugers Arch 449, 186194.