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Recombinant CRAMP-producing Lactococcus lactis attenuates dextran sulfate sodium-induced colitis by colonic colonization and inhibiting p38/NF-κB signaling

BACKGROUND: Inflammatory bowel diseases (IBDs) are generally characterized by persistent abdominal pain and diarrhea caused by chronic inflammation in the intestine. Cathelicidins are antimicrobial peptides with pleiotropic roles in anti-infection, wound healing, and immune modulation. However, the...

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Autores principales: Li, Jiahong, Yu, Shiwen, Pan, Xiaohua, Zhang, Ming, Lv, Zhuwu, Pan, Li-Long, Sun, Jia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Open Academia 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494263/
https://www.ncbi.nlm.nih.gov/pubmed/34650393
http://dx.doi.org/10.29219/fnr.v65.5570
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author Li, Jiahong
Yu, Shiwen
Pan, Xiaohua
Zhang, Ming
Lv, Zhuwu
Pan, Li-Long
Sun, Jia
author_facet Li, Jiahong
Yu, Shiwen
Pan, Xiaohua
Zhang, Ming
Lv, Zhuwu
Pan, Li-Long
Sun, Jia
author_sort Li, Jiahong
collection PubMed
description BACKGROUND: Inflammatory bowel diseases (IBDs) are generally characterized by persistent abdominal pain and diarrhea caused by chronic inflammation in the intestine. Cathelicidins are antimicrobial peptides with pleiotropic roles in anti-infection, wound healing, and immune modulation. However, the sensitivity to the acidic environment and short half-life of cathelicidins limit their application in IBD treatment. Recombinant cathelicidin-related antimicrobial peptide (CRAMP)-producing Lactococcus lactis may represent a potential approach for IBD therapy. OBJECTIVE: The aim of this study was to develop recombinant CRAMP-producing L. lactis NZ9000 and explore the role and mechanism of recombinant L. lactis NZ9000 expressing CRAMP in colitis. DESIGN: We constructed two strains of CRAMP-producing L. lactis NZ9000 with different plasmids pMG36e (L.L-pMU45CR) or pNZ8148 (L.L-pNU45CR), which use a Usp45 secretion signal to drive the secretion of CRAMP. Bacterial suspensions were orally supplemented to mice with a syringe for 4 days after dextran sodium sulfate (DSS) treatment. Body weight change, disease active score, colon length, and colonic histology were determined. The expression of tight junction (ZO-1, ZO-2, and Occludin) and cytokines (IL-6, IL-1β, TNF-α, and IL-10) in colon was performed by qPCR. The expression of p-ERK, p-p38, and p-p65 was determined by Western blot analysis. RESULTS: Both CRAMP-producing L. lactis NZ9000 strains protected against colitis, as shown by reduced weight loss and disease activity score, improved colon shortening, and histopathological injury. In addition, CRAMP-producing L. lactis NZ9000 restored gut barrier by upregulating ZO-1, ZO-2, and occludin. Moreover, CRAMP-producing L. lactis NZ9000 regulated the colonic cytokines profile with reduced IL-6, IL-1β, and TNF-α production, and increased IL-10 production. By further analysis, we found that CRAMP-producing L. lactis NZ9000 reduced the expression of p-p38 and p-p65. CONCLUSIONS: Together, our data suggested that CRAMP-secreting L. lactis NZ9000 attenuated dextran sulfate sodium-induced colitis by colonic colonization and inhibiting p38/NF-κB signaling. Orally administered recombinant CRAMP-secreting L. lactis NZ9000 represents a potential strategy for colitis therapy.
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spelling pubmed-84942632021-10-13 Recombinant CRAMP-producing Lactococcus lactis attenuates dextran sulfate sodium-induced colitis by colonic colonization and inhibiting p38/NF-κB signaling Li, Jiahong Yu, Shiwen Pan, Xiaohua Zhang, Ming Lv, Zhuwu Pan, Li-Long Sun, Jia Food Nutr Res Original Article BACKGROUND: Inflammatory bowel diseases (IBDs) are generally characterized by persistent abdominal pain and diarrhea caused by chronic inflammation in the intestine. Cathelicidins are antimicrobial peptides with pleiotropic roles in anti-infection, wound healing, and immune modulation. However, the sensitivity to the acidic environment and short half-life of cathelicidins limit their application in IBD treatment. Recombinant cathelicidin-related antimicrobial peptide (CRAMP)-producing Lactococcus lactis may represent a potential approach for IBD therapy. OBJECTIVE: The aim of this study was to develop recombinant CRAMP-producing L. lactis NZ9000 and explore the role and mechanism of recombinant L. lactis NZ9000 expressing CRAMP in colitis. DESIGN: We constructed two strains of CRAMP-producing L. lactis NZ9000 with different plasmids pMG36e (L.L-pMU45CR) or pNZ8148 (L.L-pNU45CR), which use a Usp45 secretion signal to drive the secretion of CRAMP. Bacterial suspensions were orally supplemented to mice with a syringe for 4 days after dextran sodium sulfate (DSS) treatment. Body weight change, disease active score, colon length, and colonic histology were determined. The expression of tight junction (ZO-1, ZO-2, and Occludin) and cytokines (IL-6, IL-1β, TNF-α, and IL-10) in colon was performed by qPCR. The expression of p-ERK, p-p38, and p-p65 was determined by Western blot analysis. RESULTS: Both CRAMP-producing L. lactis NZ9000 strains protected against colitis, as shown by reduced weight loss and disease activity score, improved colon shortening, and histopathological injury. In addition, CRAMP-producing L. lactis NZ9000 restored gut barrier by upregulating ZO-1, ZO-2, and occludin. Moreover, CRAMP-producing L. lactis NZ9000 regulated the colonic cytokines profile with reduced IL-6, IL-1β, and TNF-α production, and increased IL-10 production. By further analysis, we found that CRAMP-producing L. lactis NZ9000 reduced the expression of p-p38 and p-p65. CONCLUSIONS: Together, our data suggested that CRAMP-secreting L. lactis NZ9000 attenuated dextran sulfate sodium-induced colitis by colonic colonization and inhibiting p38/NF-κB signaling. Orally administered recombinant CRAMP-secreting L. lactis NZ9000 represents a potential strategy for colitis therapy. Open Academia 2021-09-28 /pmc/articles/PMC8494263/ /pubmed/34650393 http://dx.doi.org/10.29219/fnr.v65.5570 Text en © 2021 Jiahong Li et al. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material for any purpose, even commercially, provided the original work is properly cited and states its license.
spellingShingle Original Article
Li, Jiahong
Yu, Shiwen
Pan, Xiaohua
Zhang, Ming
Lv, Zhuwu
Pan, Li-Long
Sun, Jia
Recombinant CRAMP-producing Lactococcus lactis attenuates dextran sulfate sodium-induced colitis by colonic colonization and inhibiting p38/NF-κB signaling
title Recombinant CRAMP-producing Lactococcus lactis attenuates dextran sulfate sodium-induced colitis by colonic colonization and inhibiting p38/NF-κB signaling
title_full Recombinant CRAMP-producing Lactococcus lactis attenuates dextran sulfate sodium-induced colitis by colonic colonization and inhibiting p38/NF-κB signaling
title_fullStr Recombinant CRAMP-producing Lactococcus lactis attenuates dextran sulfate sodium-induced colitis by colonic colonization and inhibiting p38/NF-κB signaling
title_full_unstemmed Recombinant CRAMP-producing Lactococcus lactis attenuates dextran sulfate sodium-induced colitis by colonic colonization and inhibiting p38/NF-κB signaling
title_short Recombinant CRAMP-producing Lactococcus lactis attenuates dextran sulfate sodium-induced colitis by colonic colonization and inhibiting p38/NF-κB signaling
title_sort recombinant cramp-producing lactococcus lactis attenuates dextran sulfate sodium-induced colitis by colonic colonization and inhibiting p38/nf-κb signaling
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494263/
https://www.ncbi.nlm.nih.gov/pubmed/34650393
http://dx.doi.org/10.29219/fnr.v65.5570
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