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Secretion of biologically active pancreatitis-associated protein I (PAP) by genetically modified dairy Lactococcus lactis NZ9000 in the prevention of intestinal mucositis

BACKGROUND: Mucositis is one of the most relevant gastrointestinal inflammatory conditions in humans, generated by the use of chemotherapy drugs, such as 5-fluoracil (5-FU). 5-FU-induced mucositis affects 80% of patients undergoing oncological treatment causing mucosal gut dysfunctions and great dis...

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Autores principales: Carvalho, Rodrigo D., Breyner, Natalia, Menezes-Garcia, Zelia, Rodrigues, Nubia M., Lemos, Luisa, Maioli, Tatiane U., da Gloria Souza, Danielle, Carmona, Denise, de Faria, Ana M. C., Langella, Philippe, Chatel, Jean-Marc, Bermúdez-Humarán, Luis G., Figueiredo, Henrique C. P., Azevedo, Vasco, de Azevedo, Marcela S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5307810/
https://www.ncbi.nlm.nih.gov/pubmed/28193209
http://dx.doi.org/10.1186/s12934-017-0624-x
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author Carvalho, Rodrigo D.
Breyner, Natalia
Menezes-Garcia, Zelia
Rodrigues, Nubia M.
Lemos, Luisa
Maioli, Tatiane U.
da Gloria Souza, Danielle
Carmona, Denise
de Faria, Ana M. C.
Langella, Philippe
Chatel, Jean-Marc
Bermúdez-Humarán, Luis G.
Figueiredo, Henrique C. P.
Azevedo, Vasco
de Azevedo, Marcela S.
author_facet Carvalho, Rodrigo D.
Breyner, Natalia
Menezes-Garcia, Zelia
Rodrigues, Nubia M.
Lemos, Luisa
Maioli, Tatiane U.
da Gloria Souza, Danielle
Carmona, Denise
de Faria, Ana M. C.
Langella, Philippe
Chatel, Jean-Marc
Bermúdez-Humarán, Luis G.
Figueiredo, Henrique C. P.
Azevedo, Vasco
de Azevedo, Marcela S.
author_sort Carvalho, Rodrigo D.
collection PubMed
description BACKGROUND: Mucositis is one of the most relevant gastrointestinal inflammatory conditions in humans, generated by the use of chemotherapy drugs, such as 5-fluoracil (5-FU). 5-FU-induced mucositis affects 80% of patients undergoing oncological treatment causing mucosal gut dysfunctions and great discomfort. As current therapy drugs presents limitations in alleviating mucositis symptoms, alternative strategies are being pursued. Recent studies have shown that the antimicrobial pancreatitis-associated protein (PAP) has a protective role in intestinal inflammatory processes. Indeed, it was demonstrated that a recombinant strain of Lactococcus lactis expressing human PAP (LL-PAP) could prevent and improve murine DNBS-induced colitis, an inflammatory bowel disease (IBD) that causes severe inflammation of the colon. Hence, in this study we sought to evaluate the protective effects of LL-PAP on 5-FU-induced experimental mucositis in BALB/c mice as a novel approach to treat the disease. RESULTS: Our results show that non-recombinant L. lactis NZ9000 have antagonistic activity, in vitro, against the enteroinvasive gastrointestinal pathogen L. monocytogenes and confirmed PAP inhibitory effect against Opportunistic E. faecalis. Moreover, L. lactis was able to prevent histological damage, reduce neutrophil and eosinophil infiltration and secretory Immunoglobulin-A in mice injected with 5-FU. Recombinant lactococci carrying antimicrobial PAP did not improve those markers of inflammation, although its expression was associated with villous architecture preservation and increased secretory granules density inside Paneth cells in response to 5-FU inflammation. CONCLUSIONS: We have demonstrated for the first time that L. lactis NZ9000 by itself, is able to prevent 5-FU-induced intestinal inflammation in BALB/c mice. Moreover, PAP delivered by recombinant L. lactis strain showed additional protective effects in mice epithelium, revealing to be a promising strategy to treat intestinal mucositis.
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spelling pubmed-53078102017-02-22 Secretion of biologically active pancreatitis-associated protein I (PAP) by genetically modified dairy Lactococcus lactis NZ9000 in the prevention of intestinal mucositis Carvalho, Rodrigo D. Breyner, Natalia Menezes-Garcia, Zelia Rodrigues, Nubia M. Lemos, Luisa Maioli, Tatiane U. da Gloria Souza, Danielle Carmona, Denise de Faria, Ana M. C. Langella, Philippe Chatel, Jean-Marc Bermúdez-Humarán, Luis G. Figueiredo, Henrique C. P. Azevedo, Vasco de Azevedo, Marcela S. Microb Cell Fact Research BACKGROUND: Mucositis is one of the most relevant gastrointestinal inflammatory conditions in humans, generated by the use of chemotherapy drugs, such as 5-fluoracil (5-FU). 5-FU-induced mucositis affects 80% of patients undergoing oncological treatment causing mucosal gut dysfunctions and great discomfort. As current therapy drugs presents limitations in alleviating mucositis symptoms, alternative strategies are being pursued. Recent studies have shown that the antimicrobial pancreatitis-associated protein (PAP) has a protective role in intestinal inflammatory processes. Indeed, it was demonstrated that a recombinant strain of Lactococcus lactis expressing human PAP (LL-PAP) could prevent and improve murine DNBS-induced colitis, an inflammatory bowel disease (IBD) that causes severe inflammation of the colon. Hence, in this study we sought to evaluate the protective effects of LL-PAP on 5-FU-induced experimental mucositis in BALB/c mice as a novel approach to treat the disease. RESULTS: Our results show that non-recombinant L. lactis NZ9000 have antagonistic activity, in vitro, against the enteroinvasive gastrointestinal pathogen L. monocytogenes and confirmed PAP inhibitory effect against Opportunistic E. faecalis. Moreover, L. lactis was able to prevent histological damage, reduce neutrophil and eosinophil infiltration and secretory Immunoglobulin-A in mice injected with 5-FU. Recombinant lactococci carrying antimicrobial PAP did not improve those markers of inflammation, although its expression was associated with villous architecture preservation and increased secretory granules density inside Paneth cells in response to 5-FU inflammation. CONCLUSIONS: We have demonstrated for the first time that L. lactis NZ9000 by itself, is able to prevent 5-FU-induced intestinal inflammation in BALB/c mice. Moreover, PAP delivered by recombinant L. lactis strain showed additional protective effects in mice epithelium, revealing to be a promising strategy to treat intestinal mucositis. BioMed Central 2017-02-13 /pmc/articles/PMC5307810/ /pubmed/28193209 http://dx.doi.org/10.1186/s12934-017-0624-x Text en © The Author(s) 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Carvalho, Rodrigo D.
Breyner, Natalia
Menezes-Garcia, Zelia
Rodrigues, Nubia M.
Lemos, Luisa
Maioli, Tatiane U.
da Gloria Souza, Danielle
Carmona, Denise
de Faria, Ana M. C.
Langella, Philippe
Chatel, Jean-Marc
Bermúdez-Humarán, Luis G.
Figueiredo, Henrique C. P.
Azevedo, Vasco
de Azevedo, Marcela S.
Secretion of biologically active pancreatitis-associated protein I (PAP) by genetically modified dairy Lactococcus lactis NZ9000 in the prevention of intestinal mucositis
title Secretion of biologically active pancreatitis-associated protein I (PAP) by genetically modified dairy Lactococcus lactis NZ9000 in the prevention of intestinal mucositis
title_full Secretion of biologically active pancreatitis-associated protein I (PAP) by genetically modified dairy Lactococcus lactis NZ9000 in the prevention of intestinal mucositis
title_fullStr Secretion of biologically active pancreatitis-associated protein I (PAP) by genetically modified dairy Lactococcus lactis NZ9000 in the prevention of intestinal mucositis
title_full_unstemmed Secretion of biologically active pancreatitis-associated protein I (PAP) by genetically modified dairy Lactococcus lactis NZ9000 in the prevention of intestinal mucositis
title_short Secretion of biologically active pancreatitis-associated protein I (PAP) by genetically modified dairy Lactococcus lactis NZ9000 in the prevention of intestinal mucositis
title_sort secretion of biologically active pancreatitis-associated protein i (pap) by genetically modified dairy lactococcus lactis nz9000 in the prevention of intestinal mucositis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5307810/
https://www.ncbi.nlm.nih.gov/pubmed/28193209
http://dx.doi.org/10.1186/s12934-017-0624-x
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