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Celiac disease microbiota and its applications

Celiac disease microbiota and its applications Ann Microbiol (2014) 64:899–903 DOI 10.1007/s13213-013-0780-0 REVIEW ARTICLE Iulia Lupan & Genel Sur & Diana Deleanu & Victor Cristea & Gabriel Samasca & Peter Makovicky Received: 14 May 2013 /Accepted: 2 December 2013 /Published online: 14 December 2013 Springer-Verlag Berlin Heidelberg and the University of Milan 2013 Abstract Intestinal microbiota plays an important role in role in assuring intestinal health. In recent years, special maintaining the overall health of an individual. It can be attention has been paid to studying the intestinal microbiota affected by diet but also inflammation of the intestine due to in intestinal disease, as well as changes in the microbiata with various causes. In the last decade, particular attention has been dietary variations and with age. paid to the study of the interaction between mucosal cells and An important therapeutic strategy for many mucosal and intestinal microbiota, and to the host immune response to non-mucosal immune-related conditions is to harness the skill change in community structure. Here, we review the most of microbiota to disturb host immunity (Ivanov and Honda significant studies on human microbiota in patients with celiac 2012). Alterations in microbial flora accompany various med- disease, and also the potential biotechnological use of micro- ical conditions (Serban 2011), such as inflammatory bowel organisms for the production of gluten-free products. diseases and celiac disease (CD). The intestinal microbiota also changes substantially during aging (Cheng et al. 2011). . . . Keywords Adolescence Gluten-free Microbiology This review discusses important recent discoveries regarding Sorghum microbiota in relation to gluten-free diet (GFD) in patients with CD. Introduction Celiac disease Most microorganisms in the human microbiota are in the intestine. The intestinal microbiota plays an important role in Immunopathological state of CD metabolic and nutritional processes, but also has a defensive Under immunopathological conditions, e.g., during infection, inflammatory bowel disease and CD, both epithelial cells and I. Lupan intraepithelial lymphocytes participate substantially in inflam- Molecular Biology Center, Institute for Interdisciplinary Research on Bio-Nano-Sciences, Babes-Bolyai University, matory reactions (Tlaskalová-Hogenová et al. 1995). Cluj-Napoca, Romania Intestinal microbiota influence the Th1 pro-inflammatory mi- lieu characteristic of CD (Medina et al. 2008). Serological G. Sur responses to different microbial antigens have been demon- Department of Pediatrics II, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania strated (Ashorn et al. 2009). Persons with selective IgA defi- ciency carry an increased risk of CD. The microbiota of IgA- : : D. Deleanu V. Cristea G. Samasca (*) deficient people is characterized by an increased frequency of Department of Immunology, “Iuliu Haţieganu” University of Escherichia coli with inflammatogenic potential, and can thus Medicine and Pharmacy, Croitorilor Street, 19-21 No, Cluj-Napoca, Romania contribute to the development of inflammatory bowel diseases e-mail: Gabriel.Samasca@umfcluj.ro (Friman et al. 2002). A reduction in IgA-coated bacteria is associated with intestinal dysbiosis, providing new insights P. Makovicky into the possible relationships between gut microbiota and Department of Veterinary Science, Czech University of Life Science, host defences in CD patients (De Palma et al. 2010). Prague, Czech Republic 900 Ann Microbiol (2014) 64:899–903 Celiac disease studies Clinical implications CD patients with intestinal enzymopathy have, in general, Cesarean delivery can affect the early biodiversity of intestinal diminished protective flora and increased hemolytic and bacteria (Biasucci et al. 2008). An association was described lactose-negative enterobacteria (Kamilova et al. 2001). The between cesarean delivery and CD. Alterations of the mucosal levels of Bacteroides, Clostridium and Staphylococcus were host-microbial interaction during the neonatal period might much higher (P <0.05) in fecal samples from CD patients than contribute to the pathogenesis of inflammatory diseases such in those of healthy subjects when analyzed by culture methods as CD (Decker et al. 2011). (Collado et al. 2007). The species Lactobacillus curvatus, Breast milk is the gold-standard feeding method during Leuconostoc mesenteroides and Leuconostoc carnosum infancy for optimal nutrition (Salvatore et al. 2008). But were characteristic of CD patients, while those of the milk-feeding type can also play a role in CD (Sanz et al. Lactobacillus casei group were characteristic of healthy 2011). The effects of milk-feeding practices on intestinal controls (Sanz et al. 2007). colonization of Bacteroides species in infants at risk of CD Analysis of fecal samples and duodenal biopsies using development was investigated. Breast-fed infants showed a denaturing gradient gel electrophoresis specific for total bac- higher prevalence of Bacteroides uniformis at 1 and4months teria, lactobacilli and bifidobacteria the microbial population of age, while formula-fed infants had a higher prevalence of showed that bacteria adhering to duodenal biopsies were not Bacteroides intestinalis at all sampling times, of Bacteroides dominating in stool samples (Kopecný et al. 2008). A peculiar caccae at 7 days and 4 months, and of Bacteroides plebeius at microbial temporal temperature gradient gel electrophoresis 4 months. The conclusion was that both the type of milk profile and a significant higher biodiversity were identified in feeding influences the colonization process of Bacteroides the duodenal mucosa of CD pediatric patients. Bacteroides species, and possibly disease risk (Sánchez et al. 2011). vulgatus and E. coli were detected more often in CD patients Another study came to a similar conclusion, i.e., that milk- than in controls (P <0.0001) (Schippa et al. 2010). Thus, feeding type plays a role in establishing infants’ gut microbi- virulence features of the enteric microbiota are linked to CD ota (De Palma et al. 2012). (Sánchez et al. 2008). Examination of differences in Bacteroides spp. and their pathogenic features between CD patients and controls re- Gluten-free diet vealed an increased abundance of Bacteroides fragilis strains with metalloprotease activities, which could play a role in CD Gluten-free diet and CD pathogenesis (Sánchez et al. 2012a). Two novel, obligately anaerobic, Gram-stain-positive, saccharolytic and non- The accepted treatment for CD is a gluten-free diet (GFD) proteolytic spore-forming bacilli [strains CD3:22(T) and N1 (Samaşca et al. 2013). However, GFD influences the struc- (T)] were described. One of them, strain CD3:22(T) was ture of the gut bacterial population and its metabolism mark- isolated from a biopsy of the small intestine of a child with edly (Kopecný et al. 2006). GFD has been shown to lead to CD (Hedberg et al. 2012). reductions in beneficial gut bacteria populations and stimu- late the host’s immunity (De Palma et al. 2009). The analysis Active and non-active celiac disease of fecal microbiota and dietary intake after GFD indicated that the numbers of healthy gut bacteria decreased, while The proportions of total bacteria and Gram-negative bacteria numbers of unhealthy bacteria increased parallel to reduc- were much higher in CD patients with active disease than in tions in the intake of polysaccharides in CD adults (Sanz symptom-free CD patients and controls (Nadal et al. 2007). 2010). In conclusion, there are bacterial differences in the Reductions in total Bifidobacterium and Bacteroides longum upper small bacteria microbiota between treated and untreat- populations were associated with both active and non-active ed CD adults due to treatment with a GFD (Nistal et al. CD when compared to controls (Collado et al. 2008). 2012). Duodenal and fecal microbiotas are unbalanced in Bacteroides, Bifidobacterium and lactic acid bacteria (LAB) children with untreated CD and only partially restored after populations in the duodenum of children with typical CD long-term treatment with GFD (Collado et al. 2009). A lower (active and treated) and controls differ in diversity and species ratio of cultivable LAB and Bifidobacterium to Bacteroides composition; this could help illustrate features of the disease and enterobacteria in CD children after GFD compared to (Sánchez et al. 2010). Increased abundance of Staphylococcus healthy children was observed—even lower in CD children epidermidis carrying the mecA gene in active and non-active before GFD(Di Cagno et al. 2009). Therefore, GFD lasting at CD patients most likely reflects increased exposure of these least 2 years did not completely restore the microbiota and, subjects to opportunistic pathogens and antimicrobials thus, the metabolome of CD children (Di Cagno et al. 2011). So what are the solutions? (Sánchez et al. 2012b). Ann Microbiol (2014) 64:899–903 901 Plant extract solutions spectrum of yeast species and LAB. The selection of dominant yeast and Lactobacillus species as starters for the production The crude water-soluble extract from amaranth seeds has an of sourdough destined for GF bread production was suggested inhibitory effect towards many fungal species isolated from (Moroni et al. 2011). Another promising approach to improve bakeries and is used as an ingredient in the manufacture of bread-making for GFD can be to manipulate microbial gluten-free (GF) and wheat bread (Rizzello et al. 2009), ex- exopolysaccharide amounts to reach effectual levels through tending the shelf-life of gluten-free and wheat flour breads. optimization, as corroborated by the application of microbial The alcohol-soluble fraction from some cereals (tef, millet, exopolysaccharide-forming starter cultures (Rühmkorf et al. amaranth, and quinoa) has been shown to be safe for diets of 2012; Galle et al. 2012). The use of two lactic bacteria CD patients, with the absence of any immune cross-reactivity (Lactobacillus plantarum CRL 775 and Pediococcus of them toward wheat gliadin being of note (Bergamo et al. pentosaceus CRL 792) as cell free extract and pooled cells 2011). The aqueous extract of kiwifruit puree, which has good showed a higher efficiency of cell extracts in the reduction of stability and contains polyphenols and antioxidants, was also gliadin concentration, thus use of cell-free extract may be considered as a functional ingredient for GF bread (Sun- considered a practical alternative technology for the manufac- Waterhouse et al. 2009). But the replacement of gluten still ture of GF products (Gerez et al. 2012). Microbial fermenta- presents a significant technological challenge, as it is an tion by LAB and yeast is considered one of the most essential structure-building protein necessary for formulating ecological/economical methods of producing and preserving high-quality baked goods (Zannini et al. 2012a). food (Zannini et al. 2012b). Sourdough biotechnologies Conclusions Sourdough has been used since ancient times for the produc- tion of rye and wheat bread; its universal usage has been The role of intestinal microbial flora in certain pathologies attributed to the improved quality, nutritional properties and such as CD currently remains unknown. Most studies in this shelf life of sourdough-based breads (Arendt et al. 2011). area have revealed changes in gut microbiota but not their role Producing sourdough bread that is tolerated by CD patients in the evolution of CD pathology. Bacterial species other than has been an important focus for many researchers (Di Cagno those present in healthy subjects prevail in the intestinal et al. 2004)with biotechnologies that use selected sourdough microbiota of patients with CD. The most effective treatment LAB and probiotics and their potential to decrease the risk of in CD, i.e., GFD, does not contribute to restoring of the gluten contamination in gluten-free products being investigat- intestinal microbiota, with the observed imbalance being ed (Gobbetti et al. 2007). maintained even after treatment. Meanwhile, microbial bio- Lactobacillus plantarum CRL 759 and CRL 778 have an technology can provide solutions for making gluten-free active proteolytic system that is responsible for high amino products. acid release during sourdough fermentation and the hydrolysis of 31–43 alpha-gliadin-like fragments (Rollán et al. 2005). Conflict of interest The authors report no conflicts of interest. The kinetics of the hydrolysis of this 33-mer by lactobacilli were highly efficient (Rizzello et al. 2007). The ability of LAB strains to degrade alpha-gliadin fragments is not correlated to individual peptidase activities. Results have shown that sev- References eral strains separately degraded 31–43 and 62–75 alpha- gliadin fragments, while a mixture of peptidase profiles from Arendt EK, Moroni A, Zannini E (2011) Medical nutrition therapy: use of pooled LAB strains was associated with 57–89 peptide deg- sourdough lactic acid bacteria as a cell factory for delivering func- radation (Gerez et al. 2008). Other studies supported the same tional biomolecules and food ingredients in gluten free bread. conclusion. The use of sourdough in GF baking was sug- Microb Cell Fact 10:S15 gested as a new frontier for increasing the quality, safety and Ashorn S, Välineva T, Kaukinen K, Ashorn M, Braun J, Raukola H, Rantala I, Collin P, Mäki M, Luukkaala T, Iltanen S (2009) acceptability of GF bread (Moroni et al. 2009). Serological responses to microbial antigens in celiac disease patients The use of a pool of selected enterococci and fungal pro- during a gluten-free diet. J Clin Immunol 29:190–195 teases (Rhizopus oryzae) to hydrolyze wheat gluten during Bergamo P, Maurano F, Mazzarella G, Iaquinto G, Vocca I, Rivelli AR, long-duration fermentation was investigated. This microbial De Falco E, Gianfrani C, Rossi M (2011) Immunological evaluation of the alcohol-soluble protein fraction from gluten-free grains in and protein cocktail showed a decrease in the gluten concen- relation to celiac disease. Mol Nutr Food Res 55:1266–1270 tration of more than 98 % during longer fermentation (M’hir Biasucci G, Benenati B, Morelli L, Bessi E, Boehm G (2008) Cesarean et al. 2009). The biodiversity of spontaneous environmental delivery may affect the early biodiversity of intestinal bacteria. 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Celiac disease microbiota and its applications

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Springer Journals
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Copyright © 2013 by Springer-Verlag Berlin Heidelberg and the University of Milan
Subject
Life Sciences; Microbiology; Microbial Genetics and Genomics; Microbial Ecology; Fungus Genetics; Medical Microbiology; Applied Microbiology
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1869-2044
DOI
10.1007/s13213-013-0780-0
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Abstract

Ann Microbiol (2014) 64:899–903 DOI 10.1007/s13213-013-0780-0 REVIEW ARTICLE Iulia Lupan & Genel Sur & Diana Deleanu & Victor Cristea & Gabriel Samasca & Peter Makovicky Received: 14 May 2013 /Accepted: 2 December 2013 /Published online: 14 December 2013 Springer-Verlag Berlin Heidelberg and the University of Milan 2013 Abstract Intestinal microbiota plays an important role in role in assuring intestinal health. In recent years, special maintaining the overall health of an individual. It can be attention has been paid to studying the intestinal microbiota affected by diet but also inflammation of the intestine due to in intestinal disease, as well as changes in the microbiata with various causes. In the last decade, particular attention has been dietary variations and with age. paid to the study of the interaction between mucosal cells and An important therapeutic strategy for many mucosal and intestinal microbiota, and to the host immune response to non-mucosal immune-related conditions is to harness the skill change in community structure. Here, we review the most of microbiota to disturb host immunity (Ivanov and Honda significant studies on human microbiota in patients with celiac 2012). Alterations in microbial flora accompany various med- disease, and also the potential biotechnological use of micro- ical conditions (Serban 2011), such as inflammatory bowel organisms for the production of gluten-free products. diseases and celiac disease (CD). The intestinal microbiota also changes substantially during aging (Cheng et al. 2011). . . . Keywords Adolescence Gluten-free Microbiology This review discusses important recent discoveries regarding Sorghum microbiota in relation to gluten-free diet (GFD) in patients with CD. Introduction Celiac disease Most microorganisms in the human microbiota are in the intestine. The intestinal microbiota plays an important role in Immunopathological state of CD metabolic and nutritional processes, but also has a defensive Under immunopathological conditions, e.g., during infection, inflammatory bowel disease and CD, both epithelial cells and I. Lupan intraepithelial lymphocytes participate substantially in inflam- Molecular Biology Center, Institute for Interdisciplinary Research on Bio-Nano-Sciences, Babes-Bolyai University, matory reactions (Tlaskalová-Hogenová et al. 1995). Cluj-Napoca, Romania Intestinal microbiota influence the Th1 pro-inflammatory mi- lieu characteristic of CD (Medina et al. 2008). Serological G. Sur responses to different microbial antigens have been demon- Department of Pediatrics II, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania strated (Ashorn et al. 2009). Persons with selective IgA defi- ciency carry an increased risk of CD. The microbiota of IgA- : : D. Deleanu V. Cristea G. Samasca (*) deficient people is characterized by an increased frequency of Department of Immunology, “Iuliu Haţieganu” University of Escherichia coli with inflammatogenic potential, and can thus Medicine and Pharmacy, Croitorilor Street, 19-21 No, Cluj-Napoca, Romania contribute to the development of inflammatory bowel diseases e-mail: Gabriel.Samasca@umfcluj.ro (Friman et al. 2002). A reduction in IgA-coated bacteria is associated with intestinal dysbiosis, providing new insights P. Makovicky into the possible relationships between gut microbiota and Department of Veterinary Science, Czech University of Life Science, host defences in CD patients (De Palma et al. 2010). Prague, Czech Republic 900 Ann Microbiol (2014) 64:899–903 Celiac disease studies Clinical implications CD patients with intestinal enzymopathy have, in general, Cesarean delivery can affect the early biodiversity of intestinal diminished protective flora and increased hemolytic and bacteria (Biasucci et al. 2008). An association was described lactose-negative enterobacteria (Kamilova et al. 2001). The between cesarean delivery and CD. Alterations of the mucosal levels of Bacteroides, Clostridium and Staphylococcus were host-microbial interaction during the neonatal period might much higher (P <0.05) in fecal samples from CD patients than contribute to the pathogenesis of inflammatory diseases such in those of healthy subjects when analyzed by culture methods as CD (Decker et al. 2011). (Collado et al. 2007). The species Lactobacillus curvatus, Breast milk is the gold-standard feeding method during Leuconostoc mesenteroides and Leuconostoc carnosum infancy for optimal nutrition (Salvatore et al. 2008). But were characteristic of CD patients, while those of the milk-feeding type can also play a role in CD (Sanz et al. Lactobacillus casei group were characteristic of healthy 2011). The effects of milk-feeding practices on intestinal controls (Sanz et al. 2007). colonization of Bacteroides species in infants at risk of CD Analysis of fecal samples and duodenal biopsies using development was investigated. Breast-fed infants showed a denaturing gradient gel electrophoresis specific for total bac- higher prevalence of Bacteroides uniformis at 1 and4months teria, lactobacilli and bifidobacteria the microbial population of age, while formula-fed infants had a higher prevalence of showed that bacteria adhering to duodenal biopsies were not Bacteroides intestinalis at all sampling times, of Bacteroides dominating in stool samples (Kopecný et al. 2008). A peculiar caccae at 7 days and 4 months, and of Bacteroides plebeius at microbial temporal temperature gradient gel electrophoresis 4 months. The conclusion was that both the type of milk profile and a significant higher biodiversity were identified in feeding influences the colonization process of Bacteroides the duodenal mucosa of CD pediatric patients. Bacteroides species, and possibly disease risk (Sánchez et al. 2011). vulgatus and E. coli were detected more often in CD patients Another study came to a similar conclusion, i.e., that milk- than in controls (P <0.0001) (Schippa et al. 2010). Thus, feeding type plays a role in establishing infants’ gut microbi- virulence features of the enteric microbiota are linked to CD ota (De Palma et al. 2012). (Sánchez et al. 2008). Examination of differences in Bacteroides spp. and their pathogenic features between CD patients and controls re- Gluten-free diet vealed an increased abundance of Bacteroides fragilis strains with metalloprotease activities, which could play a role in CD Gluten-free diet and CD pathogenesis (Sánchez et al. 2012a). Two novel, obligately anaerobic, Gram-stain-positive, saccharolytic and non- The accepted treatment for CD is a gluten-free diet (GFD) proteolytic spore-forming bacilli [strains CD3:22(T) and N1 (Samaşca et al. 2013). However, GFD influences the struc- (T)] were described. One of them, strain CD3:22(T) was ture of the gut bacterial population and its metabolism mark- isolated from a biopsy of the small intestine of a child with edly (Kopecný et al. 2006). GFD has been shown to lead to CD (Hedberg et al. 2012). reductions in beneficial gut bacteria populations and stimu- late the host’s immunity (De Palma et al. 2009). The analysis Active and non-active celiac disease of fecal microbiota and dietary intake after GFD indicated that the numbers of healthy gut bacteria decreased, while The proportions of total bacteria and Gram-negative bacteria numbers of unhealthy bacteria increased parallel to reduc- were much higher in CD patients with active disease than in tions in the intake of polysaccharides in CD adults (Sanz symptom-free CD patients and controls (Nadal et al. 2007). 2010). In conclusion, there are bacterial differences in the Reductions in total Bifidobacterium and Bacteroides longum upper small bacteria microbiota between treated and untreat- populations were associated with both active and non-active ed CD adults due to treatment with a GFD (Nistal et al. CD when compared to controls (Collado et al. 2008). 2012). Duodenal and fecal microbiotas are unbalanced in Bacteroides, Bifidobacterium and lactic acid bacteria (LAB) children with untreated CD and only partially restored after populations in the duodenum of children with typical CD long-term treatment with GFD (Collado et al. 2009). A lower (active and treated) and controls differ in diversity and species ratio of cultivable LAB and Bifidobacterium to Bacteroides composition; this could help illustrate features of the disease and enterobacteria in CD children after GFD compared to (Sánchez et al. 2010). Increased abundance of Staphylococcus healthy children was observed—even lower in CD children epidermidis carrying the mecA gene in active and non-active before GFD(Di Cagno et al. 2009). Therefore, GFD lasting at CD patients most likely reflects increased exposure of these least 2 years did not completely restore the microbiota and, subjects to opportunistic pathogens and antimicrobials thus, the metabolome of CD children (Di Cagno et al. 2011). So what are the solutions? (Sánchez et al. 2012b). Ann Microbiol (2014) 64:899–903 901 Plant extract solutions spectrum of yeast species and LAB. The selection of dominant yeast and Lactobacillus species as starters for the production The crude water-soluble extract from amaranth seeds has an of sourdough destined for GF bread production was suggested inhibitory effect towards many fungal species isolated from (Moroni et al. 2011). Another promising approach to improve bakeries and is used as an ingredient in the manufacture of bread-making for GFD can be to manipulate microbial gluten-free (GF) and wheat bread (Rizzello et al. 2009), ex- exopolysaccharide amounts to reach effectual levels through tending the shelf-life of gluten-free and wheat flour breads. optimization, as corroborated by the application of microbial The alcohol-soluble fraction from some cereals (tef, millet, exopolysaccharide-forming starter cultures (Rühmkorf et al. amaranth, and quinoa) has been shown to be safe for diets of 2012; Galle et al. 2012). The use of two lactic bacteria CD patients, with the absence of any immune cross-reactivity (Lactobacillus plantarum CRL 775 and Pediococcus of them toward wheat gliadin being of note (Bergamo et al. pentosaceus CRL 792) as cell free extract and pooled cells 2011). The aqueous extract of kiwifruit puree, which has good showed a higher efficiency of cell extracts in the reduction of stability and contains polyphenols and antioxidants, was also gliadin concentration, thus use of cell-free extract may be considered as a functional ingredient for GF bread (Sun- considered a practical alternative technology for the manufac- Waterhouse et al. 2009). But the replacement of gluten still ture of GF products (Gerez et al. 2012). Microbial fermenta- presents a significant technological challenge, as it is an tion by LAB and yeast is considered one of the most essential structure-building protein necessary for formulating ecological/economical methods of producing and preserving high-quality baked goods (Zannini et al. 2012a). food (Zannini et al. 2012b). Sourdough biotechnologies Conclusions Sourdough has been used since ancient times for the produc- tion of rye and wheat bread; its universal usage has been The role of intestinal microbial flora in certain pathologies attributed to the improved quality, nutritional properties and such as CD currently remains unknown. Most studies in this shelf life of sourdough-based breads (Arendt et al. 2011). area have revealed changes in gut microbiota but not their role Producing sourdough bread that is tolerated by CD patients in the evolution of CD pathology. Bacterial species other than has been an important focus for many researchers (Di Cagno those present in healthy subjects prevail in the intestinal et al. 2004)with biotechnologies that use selected sourdough microbiota of patients with CD. The most effective treatment LAB and probiotics and their potential to decrease the risk of in CD, i.e., GFD, does not contribute to restoring of the gluten contamination in gluten-free products being investigat- intestinal microbiota, with the observed imbalance being ed (Gobbetti et al. 2007). maintained even after treatment. Meanwhile, microbial bio- Lactobacillus plantarum CRL 759 and CRL 778 have an technology can provide solutions for making gluten-free active proteolytic system that is responsible for high amino products. acid release during sourdough fermentation and the hydrolysis of 31–43 alpha-gliadin-like fragments (Rollán et al. 2005). Conflict of interest The authors report no conflicts of interest. The kinetics of the hydrolysis of this 33-mer by lactobacilli were highly efficient (Rizzello et al. 2007). The ability of LAB strains to degrade alpha-gliadin fragments is not correlated to individual peptidase activities. 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Annals of MicrobiologySpringer Journals

Published: Dec 14, 2013

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