Wheat ATIs: Characteristics and Role in Human Disease

Sabrina Geißlitz1, Peter R. Shewry2, Fred Brouns3, Antoine H. P. America4, Giacomo Caio5, Matthew Daly6, Stefano D’Amico7, Roberto De Giorgio8, L.J.W.J. Gilissen4, H. Grausgruber9, Xin Huang10, Daisy Jonkers11, Dániel Keszthelyi11, Colette Larré12, Stefania Masci13, E. N. Clare Mills14, Marie Sofie Møller15, Mark E. Sorrells16, Birte Svensson15, Detlef Schuppan17, P.L. Weegels4
1Karlsruher Institut für Technologie
2Rothamsted Research;
3Fac Hlth Med & Life Sci, Dept Human Biol, Nutr & Toxicol Res Inst Maastricht NUTRIM
4Wageningen University and Research [Wageningen]
5Università degli Studi di Ferrara = University of Ferrara
6IHU-LIRYC
7Austrian Agency for Health and Food Safety (AGES)
8Department of Internal Medicine and Gastroenterology
9University of Vienna, Vienna
10Helsingin yliopisto = Helsingfors universitet = University of Helsinki
11Maastricht University [Maastricht]
12Unité de recherche sur les Biopolymères, Interactions Assemblages
13Università degli studi della Tuscia [Viterbo]
14University of Manchester, Manchester
15Danmarks Tekniske Universitet = Technical University of Denmark
16Cornell University, New York
17University of Northumbria at Newcastle, United Kingdom

Tóm tắt

Amylase/trypsin-inhibitors (ATIs) comprise about 2–4% of the total wheat grain proteins and may contribute to natural defense against pests and pathogens. However, they are currently among the most widely studied wheat components because of their proposed role in adverse reactions to wheat consumption in humans. ATIs have long been known to contribute to IgE-mediated allergy (notably Bakers' asthma), but interest has increased since 2012 when they were shown to be able to trigger the innate immune system, with attention focused on their role in coeliac disease which affects about 1% of the population and, more recently, in non-coeliac wheat sensitivity which may affect up to 10% of the population. This has led to studies of their structure, inhibitory properties, genetics, control of expression, behavior during processing, effects on human adverse reactions to wheat and, most recently, strategies to modify their expression in the plant using gene editing. We therefore present an integrated account of this range of research, identifying inconsistencies, and gaps in our knowledge and identifying future research needs.Note This paper is the outcome of an invited international ATI expert meeting held in Amsterdam, February 3-5 2020

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Tài liệu tham khảo

Weegels, 2019, The future of bread in view of its contribution to nutrient intake as a starchy staple food, Plant Foods Hum Nutr., 74, 1, 10.1007/s11130-019-0713-6

Shewry, 2009, Wheat grain proteins., Wheat: Chemistry and Technology, 223, 10.1094/9781891127557.008

Dupont, 2011, Deciphering the complexities of the wheat flour proteome using quantitative two-dimensional electrophoresis, three proteases and tandem mass spectrometry, Proteome Sci., 9, 10, 10.1186/1477-5956-9-10

Kneen, 1946, Distribution and general properties of an amylase inhibitor in cereals, Arch Biochem., 9, 235

Buonocore, 1977, Wheat protein inhibitors of α-amylase, Phytochemistry., 16, 811, 10.1016/S0031-9422(00)86672-8

Caminero, 2019, Lactobacilli degrade wheat amylase trypsin inhibitors to reduce intestinal dysfunction induced by immunogenic wheat proteins, Gastroenterology., 156, 2266, 10.1053/j.gastro.2019.02.028

Biesiekierski, 2013, No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates, Gastroenterology., 145, 320, 10.1053/j.gastro.2013.04.051

Huebener, 2015, Specific nongluten proteins of wheat are novel target antigens in celiac disease humoral response, J Proteome Res., 14, 503, 10.1021/pr500809b

Shewry, 1999, The prolamins of the Triticeae, Seed Proteins, 35, 10.1007/978-94-011-4431-5_3

Mills, 2004, Structural, biological, and evolutionary relationships of plant food allergens sensitizing via the gastrointestinal tract, Crit Rev Food Sci Nutr., 44, 379, 10.1080/10408690490489224

Oda, 1997, Tertiary and quaternary structures of 0.19 α-amylase inhibitor from wheat kernel determined by x-ray analysis at 2.06 Å resolution., Biochemistry., 36, 13503, 10.1021/bi971307m

Kumar, 2018, MEGA X: molecular evolutionary genetics analysis across computing platforms, Mol Biol Evol., 35, 1547, 10.1093/molbev/msy096

Huson, 2012, Dendroscope 3: an interactive tool for rooted phylogenetic trees and networks, Syst Biol., 61, 1061, 10.1093/sysbio/sys062

Waterhouse, 2009, Jalview Version 2 - a multiple sequence alignment editor and analysis workbench, Bioinformatics., 25, 1189, 10.1093/bioinformatics/btp033

Breiteneder, 2004, A classification of plant food allergens, J Allergy Clin Immunol., 113, 821, 10.1016/j.jaci.2004.01.779

Altenbach, 2011, The spectrum of low molecular weight α-amylase/protease inhibitor genes expressed in the US bread wheat cultivar Butte 86, BMC Res Notes., 4, 242, 10.1186/1756-0500-4-242

Carbonero, 1999, A multigene family of trypsin/α-amylase inhibitors from cereals, Seed Proteins, 617, 10.1007/978-94-011-4431-5_26

Rodriguez-Loperena, 1975, Heterogeneity of wheat endosperm proteolipids (CM proteins), Phytochemistry., 14, 1219, 10.1016/S0031-9422(00)98598-4

Jashni, 2015, The battle in the apoplast: further insights into the roles of proteases and their inhibitors in plant-pathogen interactions, Front Plant Sci., 6, 584, 10.3389/fpls.2015.00584

Franco, 2002, Plant α-amylase inhibitors and their interaction with insect α-amylases, Europ J Biochem., 269, 397, 10.1046/j.0014-2956.2001.02656.x

Franco, 2000, Activity of wheat α-amylase inhibitors towards bruchid α-amylases and structural explanation of observed specificities, Europ J Biochem., 267, 2166, 10.1046/j.1432-1327.2000.01199.x

Prieto, 1993, Functional properties of low Mr wheat proteins. I. isolation, characterization and comparison with other reported low Mr wheat proteins, J Cereal Sci., 17, 203, 10.1006/jcrs.1993.1020

Cuccioloni, 2016, Interaction between wheat alpha-amylase/trypsin bi-functional inhibitor and mammalian digestive enzymes: kinetic, equilibrium and structural characterization of binding, Food Chem., 213, 571, 10.1016/j.foodchem.2016.07.020

Tundo, 2018, Wheat ATI CM3, CM16 and 0.28 allergens produced in Pichia pastoris display a different eliciting potential in food allergy to wheat., Plants., 7, 101, 10.3390/plants7040101

Bose, 2020, Identification and quantitation of amylase trypsin inhibitors across cultivars representing the diversity of bread wheat, J Proteome Res., 19, 2136, 10.1021/acs.jproteome.0c00059

Carbonero, 1999, Cereal α-amylase/trypsin inhibitors and transgenic insect resistance, Genetics and Breeding for Crop Quality and Resistance. Developments in Plant Breeding, 147, 10.1007/978-94-011-4475-9_17

Call, 2020, Synthesis and accumulation of amylase-trypsin inhibitors and FODMAPs in bread wheat (Triticum aestivum L, BMC Plant Biol., 21, 113, 10.21203/rs.3.rs-72372/v1

Sandstedt, 1946, Photomiciographic studies of wheat starch. 2. amylolytic enzymes and the amylase inhibitor of the developing wheat kernel, Cereal Chem., 23, 548

Saunders, 1975, Alpha-amylase inhibitors in wheat and other cereals, Cereal Foods World., 20, 282

Kobrehel, 1991, A comparative analysis of the sulfur-rich proteins of durum and bread wheats–their possible functional properties, Cereal Chem., 68, 1

van Loon, 2006, Significance of inducible defense-related proteins in infected plants, Annu Rev Phytopathol., 44, 135, 10.1146/annurev.phyto.44.070505.143425

Green, 2014, Genetic resistance to and effect of leaf rust and powdery mildew on yield and its components in 50 soft red winter wheat cultivars, Crop Prot., 64, 177, 10.1016/j.cropro.2014.06.023

Vensel, 2005, Developmental changes in the metabolic protein profiles of wheat endosperm, Proteomics., 5, 1594, 10.1002/pmic.200401034

Yang, 2011, Implications of high-temperature events and water deficits on protein profiles in wheat (Triticum aestivum L cv. Vinjett) grain, Proteomics., 11, 1684, 10.1002/pmic.201000654

Li, 2017, Proteomic analysis of developing wheat grains infected by powdery mildew (Blumeria graminis f.sp. tritici), J Plant Physiol., 215, 140, 10.1016/j.jplph.2017.06.003

Zhou, 2005, Identification of proteins induced or upregulated by Fusarium head blight infection in the spikes of hexaploid wheat (Triticum aestivum), Genome., 48, 770, 10.1139/g05-041

Perlikowski, 2014, Identification of kernel proteins associated with the resistance to fusarium head blight in winter wheat (Triticum aestivum L, PLoS ONE., 9, e110822, 10.1371/journal.pone.0110822

Terras, 1993, Synergistic enhancement of the antifungal activity of wheat and barley thionins by radish and oilseed rape 2S albumins and by barley trypsin inhibitors, Plant Physiol., 103, 1311, 10.1104/pp.103.4.1311

Juhász, 2018, Genome mapping of seed-borne allergens and immunoresponsive proteins in wheat, Sci Adv., 4, eaar8602, 10.1126/sciadv.aar8602

Sanchez-Monge, 1989, New dimeric inhibitor of heterologous alpha-amylases encoded by a duplicated gene in the short arm of chromosome 3B of wheat (Triticum aestivum L, Eur J Biochem., 183, 37, 10.1111/j.1432-1033.1989.tb14893.x

Priya, 2013, Specificity of α-amylase and trypsin inhibitor proteins in wheat against insect pests, New Zeal J Crop Hort Sci., 41, 49, 10.1080/01140671.2012.722112

The biological activity of wheat, rye and triticale varieties harvested in four consecutive years556 Piasecka-KwiatkowskaD MadajD WarchalewskiJR Acta Sci Pol Technol Aliment.62007

Piasecka-Kwiatkowska, 2012, Digestive enzyme inhibitors from grains as potential components of nutraceuticals, J Nutrional Sci Vitaminol., 58, 217, 10.3177/jnsv.58.217

Call, 2020, Effects of species and breeding on wheat protein composition, J Cereal Sci., 93, 102974, 10.1016/j.jcs.2020.102974

Prandi, 2013, LC/MS analysis of proteolytic peptides in wheat extracts for determining the content of the allergen amylase/trypsin inhibitor CM3: influence of growing area and variety, Food Chem., 140, 141, 10.1016/j.foodchem.2013.02.039

Salcedo, 1982, The isolation and characterization of low molecular weight hydrophobic salt-soluble proteins from barley, J Exp Bot., 33, 1325, 10.1093/jxb/33.6.1325

Sandiford, 1997, Identification of the major water/salt insoluble wheat proteins involved in cereal hypersensitivity, Clin Exp Allergy., 27, 1120, 10.1046/j.1365-2222.1997.1310936.x

Petrucci, 1974, Comparison of wheat albumin inhibitors of α-amylase and trypsin, Phytochemistry., 13, 2487, 10.1016/S0031-9422(00)86925-3

Hurkman, 2007, Extraction of wheat endosperm proteins for proteome analysis, J Chromatogr B., 849, 344, 10.1016/j.jchromb.2006.11.047

Zevallos, 2017, Nutritional wheat amylase-trypsin inhibitors promote intestinal inflammation via activation of myeloid cells, Gastroenterology., 152, 1100, 10.1053/j.gastro.2016.12.006

Wong, 2004, Thioredoxin reduction alters the solubility of proteins of wheat starchy endosperm: an early event in cereal germination, Plant Cell Physiol., 45, 407, 10.1093/pcp/pch044

De Zorzi, 2007, Effect of pasta drying temperature on gastrointestinal digestibility and allergenicity of durum wheat proteins, Food Chem., 104, 353, 10.1016/j.foodchem.2006.11.057

Petitot, 2009, Modification of pasta structure induced by high drying temperatures. effects on the in vitro digestibility of protein and starch fractions and the potential allergenicity of protein hydrolysates, Food Chem., 116, 401, 10.1016/j.foodchem.2009.01.001

Gomez, 1989, Wheat tetrameric inhibitors of insect α-amylases: alloploid heterosis at the molecular level, Proc Natl Acad Sci USA., 86, 3242, 10.1073/pnas.86.9.3242

Fraberger, 2020, Insights into the potential of sourdough-related lactic acid bacteria to degrade proteins in wheat, Microorganisms., 8, 1689, 10.3390/microorganisms8111689

Howe, 2019, Ensembl Genomes 2020 - enabling non-vertebrate genomic research, Nucleic Acids Res., 48, D689, 10.1093/nar/gkz890

Call, 2019, Development of an enzymatic assay for the quantitative determination of trypsin inhibitory activity in wheat, Food Chem., 299, 125038, 10.1016/j.foodchem.2019.125038

Capocchi, 2013, A heterotetrameric alpha-amylase inhibitor from emmer (Triticum dicoccon Schrank) seeds, Phytochemistry., 88, 6, 10.1016/j.phytochem.2012.12.010

Rogniaux, 2015, Allergen relative abundance in several wheat varieties as revealed via a targeted quantitative approach using MS, Proteomics., 15, 1736, 10.1002/pmic.201400416

Geisslitz, 2020, Comparative quantitative LC–MS/MS analysis of 13 amylase/trypsin inhibitors in ancient and modern Triticum species, Sci Rep., 10, 14570, 10.1038/s41598-020-71413-z

Ludwig, 2014, CHAPTER 4 getting absolute: determining absolute protein quantities via selected reaction monitoring mass spectrometry, Quantitative Proteomics, 80, 10.1039/9781782626985-00080

Sander, 2015, Component-resolved diagnosis of baker's allergy based on specific IgE to recombinant wheat flour proteins, J Allergy Clin Immunol., 135, 1529, 10.1016/j.jaci.2014.11.021

Pastorello, 2007, Wheat IgE-mediated food allergy in European patients: α-amylase inhibitors, lipid transfer proteins and low-molecular-weight glutenins, Int Arch Allergy Immunol., 144, 10, 10.1159/000102609

Sotkovský, 2011, A new approach to the isolation and characterization of wheat flour allergens, Clin Exp Allergy., 41, 1031, 10.1111/j.1365-2222.2011.03766.x

Sotkovský, 2008, Proteomic analysis of wheat proteins recognized by IgE antibodies of allergic patients, Proteomics., 8, 1677, 10.1002/pmic.200700347

Sander, 2016, A further wheat allergen for baker's asthma: Tri a 40, J Allergy Clin Immunol., 137, 1286, 10.1016/j.jaci.2015.11.026

Junker, 2012, Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4, J Exp Med., 209, 2395, 10.1084/jem.20102660

Sigrist, 2013, New and continuing developments at PROSITE, Nucleic Acids Res., 41, D344, 10.1093/nar/gks1067

Mitchell, 2019, InterPro in 2019: improving coverage, classification and access to protein sequence annotations, Nucleic Acids Res., 47, D351, 10.1093/nar/gky1100

Bedetti, 1974, Amylase protein inhibitors and the role of Aegilops species in polyploid wheat speciation, Biochim Biophys Acta., 362, 299, 10.1016/0304-4165(74)90222-0

Konarev, 1999, Polymorphism of inhibitors of hydrolytic enzymes present in cereal and sunflower seeds, Genetics and Breeding for Crop Quality and Resistance, 135, 10.1007/978-94-011-4475-9_16

Sanchez-Monge, 1996, Inhibitory activities against heterologous α-amylases and in vitro allergenic reactivity of einkorn wheats, Theor Appl Genet., 93, 745, 10.1007/BF00224071

Vittozzi, 1976, The phylogenesis of protein α-amylase inhibitors from wheat seed and the speciation of polyploid wheats, Theor Appl Genet., 48, 279, 10.1007/BF00264959

Zoccatelli, 2012, Expression of α-amylase inhibitors in diploid Triticum species, Food Chem., 135, 2643, 10.1016/j.foodchem.2012.06.123

Garcia-Olmedo, 1987, Plant proteinaceous inhibitors of proteinases and α-amylases, Oxford Surv Plant Mol Cell Biol., 4, 275

Sánchez-Monge, 1988, Genetics of the α-amylase/trypsin inhibitor family in wheat and related species, An Aula Dei., 19, 195

Lázaro, 1988, A dimeric inhibitor or insect α-amylase from barley, Eur J Biochem., 172, 129, 10.1111/j.1432-1033.1988.tb13864.x

Sanchez-Monge, 1986, Genes encoding α-amylase inhibitors are located in the short arms of chromosomes 3B, 3D and 6D of wheat (Triticum aestivum L, Theor Appl Genet., 72, 108, 10.1007/BF00261464

García-Casado, 1994, Rye chromosome arm 3RS encodes a homodimeric inhibitor of insect α-amylase, Theor Appl Genet., 89, 60, 10.1007/BF00226983

García-Casado, 1994, Rye inhibitors of animal α-amylases show different specifities, aggregative properties and IgE-binding capacities than their homologues from wheat and barley, Eur J Biochem., 224, 525, 10.1111/j.1432-1033.1994.00525.x

Lyons, 1987, Characterization of homologous inhibitors of trypsin and α-amylase from seeds of rye (Secale cereale L, Biochim Biophys Acta Protein Struct Mol Enzymol., 915, 305, 10.1016/0167-4838(87)90314-1

Gazza, 2016, The starch-bound alpha-amylase/trypsin-inhibitors in Avena, Mol Genet Genomics, 291, 2043, 10.1007/s00438-016-1238-4

Walsh, 1989, A method for the detection of IgE binding sequences of allergens based on a modification of epitope mapping, J Immunol Methods., 121, 275, 10.1016/0022-1759(89)90171-3

Gass, 2007, Enhancement of dietary protein digestion by conjugated bile acids, Gastroenterology., 133, 16, 10.1053/j.gastro.2007.04.008

Schuppan, 2015, Non-celiac wheat sensitivity: Differential diagnosis, triggers and implications, Best Pract Res Clin Gastroenterol., 29, 469, 10.1016/j.bpg.2015.04.002

Cuccioloni, 2017, Interfering with the high-affinity interaction between wheat amylase trypsin inhibitor CM3 and toll-like receptor 4: In silico and biosensor-based studies, Sci Rep., 7, 13169, 10.1038/s41598-017-13709-1

Pickert, 2020, Wheat consumption aggravates colitis in mice via amylase trypsin inhibitor-mediated dysbiosis, Gastroenterology., 159, 257, 10.1053/j.gastro.2020.03.064

Carroccio, 2020, Wheat consumption leads to immune activation and symptom worsening in patients with familial mediterranean fever: a pilot randomized trial, Nutrients., 12, 1127, 10.3390/nu12041127

Caminero, 2016, Duodenal bacteria from patients with celiac disease and healthy subjects distinctly affect gluten breakdown and immunogenicity, Gastroenterology., 151, 670, 10.1053/j.gastro.2016.06.041

Ashfaq-Khan, 2019, Dietary wheat amylase trypsin inhibitors promote features of murine non-alcoholic fatty liver disease, Sci Rep., 9, 17463, 10.1038/s41598-019-53323-x

Dos Santos Guilherme, 2020, Dietary wheat amylase trypsin inhibitors impact Alzheimer's disease pathology in 5xFAD model mice, Int J Mol Sci., 21, 6288, 10.3390/ijms21176288

Leonard, 2017, Celiac disease and nonceliac gluten sensitivity: a review, JAMA., 318, 647, 10.1001/jama.2017.9730

Vazquez–Roque, 2013, A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function, Gastroenterology., 144, 903, 10.1053/j.gastro.2013.01.049

Biesiekierski, 2011, Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial, Am J Gastroenterol., 106, 508, 10.1038/ajg.2010.487

Sapone, 2011, Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: Celiac disease and gluten sensitivity, BMC Med., 9, 23, 10.1186/1741-7015-9-23

Laatikainen, 2017, Pilot tudy: comparison of sourdough wheat bread and yeast-fermented wheat bread in individuals with wheat sensitivity and irritable bowel syndrome, Nutrients., 9, 1215, 10.3390/nu9111215

Casella, 2018, Non celiac gluten sensitivity and diagnostic challenges, Gastroenterol Hepatol Bed Bench., 11, 197

Brouns, 2019, Adverse reactions to wheat or wheat components, Compr Rev Food Sci F., 18, 1437, 10.1111/1541-4337.12475

Cianferoni, 2016, Wheat allergy: diagnosis and management, J Asthma Allergy., 9, 13, 10.2147/JAA.S81550

Scherf, 2015, Gluten and wheat sensitivities - an overview, J Cereal Sci., 67, 2, 10.1016/j.jcs.2015.07.008

Gilissen, 2014, Reducing the incidence of allergy and intolerance to cereals, J Cereal Sci., 59, 337, 10.1016/j.jcs.2014.01.005

Zevallos, 2019, Dietary wheat amylase trypsin inhibitors exacerbate murine allergic airway inflammation, Eur J Nutr., 58, 1507, 10.1007/s00394-018-1681-6

Bellinghausen, 2019, Wheat amylase-trypsin inhibitors exacerbate intestinal and airway allergic immune responses in humanized mice, J Allergy Clin Immunol., 143, 201, 10.1016/j.jaci.2018.02.041

Puls, 1973, Influence of an α -amylase inhibitor (BAY d 7791) on blood glucose, serum insulin and nefa in starch loading tests in rats, dogs and man, Diabetologia., 9, 97, 10.1007/BF01230687

Kataoka, 1999, Effect of prolonged intraluminal alpha-amylase inhibition on eating, weight, and the small intestine of rats, Nutrition., 15, 123, 10.1016/S0899-9007(98)00170-1

Lankisch, 1998, Acute postprandial gastrointestinal and metabolic effects of wheat amylase inhibitor (WAI) in normal, obese, and diabetic humans, Pancreas., 17, 176, 10.1097/00006676-199808000-00011

Spaenij-Dekking, 2005, Natural variation in toxicity of wheat: potential for selection of nontoxic varieties for celiac disease patients, Gastroenterology., 129, 797, 10.1053/j.gastro.2005.06.017

Kalunke, 2020, Reduction of allergenic potential in bread wheat RNAi transgenic lines silenced for CM3, CM16 and 0.28 ATI genes, Int J Mol Sci., 21, 5817, 10.3390/ijms21165817

Camerlengo, 2020, CRISPR-Cas9 multiplex editing of the α-amylase/trypsin inhibitor genes to reduce allergen proteins in durum wheat, Front Sustain Food Syst., 4, 104, 10.3389/fsufs.2020.00104

Jouanin, 2018, Development of wheat with hypoimmunogenic gluten obstructed by the gene editing policy in Europe, Front Plant Sci., 9, 1523, 10.3389/fpls.2018.01523

Krasileva, 2017, Uncovering hidden variation in polyploid wheat, PNAS., 114, E913, 10.1073/pnas.1619268114

Naji, 2011, A study of the bread preparation stages on salivary alpha-amylase inhibitors extracted from wheat variety IPA 99, Tikrit J Agric Sci., 11, 1

Gélinas, 2018, Inhibitory activity towards human α-amylase in cereal foods, LWT-Food Sci Technol., 93, 268, 10.1016/j.lwt.2018.03.049

Granum, 1979, Studies on α-amylase inhibitors in foods, Food Chem., 4, 173, 10.1016/0308-8146(79)90001-3

Kostekli, 2017, Protease inhibitors in various flours and breads: Effect of fermentation, baking and in vitro digestion on trypsin and chymotrypsin inhibitory activities, Food Chem., 224, 62, 10.1016/j.foodchem.2016.12.048

Simonato, 2004, Potential allergens in durum wheat semolina and pasta: fate during cooking and digestion, Ital J Food Sci., 16, 151

Mamone, 2015, Tracking the fate of pasta (T. durum semolina) immunogenic proteins by in vitro simulated digestion, J Agric Food Chem., 63, 2660, 10.1021/jf505461x

Simonato, 2001, Food allergy to wheat products: the effect of bread baking and in vitro digestion on wheat allergenic proteins. a study with bread dough, crumb, and crust, J Agric Food Chem., 49, 5668, 10.1021/jf0104984

Pasini, 2001, Modifications of wheat flour proteins during in vitro digestion of bread dough, crumb, and crust: an electrophoretic and immunological study, J Agri Food Chem., 49, 2254, 10.1021/jf0014260

de Gregorio, 2009, Salt-soluble proteins from wheat-derived foodstuffs show lower allergenic potency than those from raw flour, J Agric Food Chem., 57, 3325, 10.1021/jf803475v

Di Cagno, 2002, Proteolysis by sourdough lactic acid bacteria: effects on wheat flour protein fractions and gliadin peptides involved in human cereal intolerance, Appl Environ Microbiol., 68, 623, 10.1128/AEM.68.2.623-633.2002

Huang, 2020, Sourdough fermentation degrades wheat alpha-amylase/trypsin inhibitor (ATI) and reduces pro-inflammatory activity, Foods., 9, 943, 10.3390/foods9070943

Yin, 2015, Protein degradation in wheat sourdough fermentation with Lactobacillus plantarum M616, Interdiscip Sci., 7, 205, 10.1007/s12539-015-0262-0