Secretion of biologically active pancreatitis-associated protein I (PAP) by genetically modified dairy Lactococcus lactis NZ9000 in the prevention of intestinal mucositis. Issue 1 (December 2017)

• Record Type: Journal Article
• Authors: Carvalho, Rodrigo; Breyner, Natalia; Menezes-Garcia, Zelia; Rodrigues, Nubia; Lemos, Luisa; Maioli, Tatiane; Gloria Souza, Danielle; Carmona, Denise; Faria, Ana; Langella, Philippe; Chatel, Jean-Marc; Bermúdez-Humarán, Luis; Figueiredo, Henrique; Azevedo, Vasco; Azevedo, Marcela
• Is Part Of: Microbial cell factories. Volume 16:Issue 1(2017)
• Page Start: 1
• Page End: 11
• Publication Date: 2017-12
• Subjects: Pancreatitis-associated protein -- Mucositis -- Lactococcus lactis -- 5-Fluoracil; Microbial biotechnology -- Periodicals; Recombinant proteins -- Synthesis -- Periodicals; 660.62
• DOI: 10.1186/s12934-017-0624-x
• Languages: English
• ISSNs: 1475-2859

Abstract

Abstract 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 ofLactococcus 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-recombinantL. lactis NZ9000 have antagonistic activity, in vitro, against the enteroinvasive gastrointestinal pathogenL. monocytogenes and confirmed PAP inhibitory effect against OpportunisticE. 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 thatL. lactis NZ9000 by itself, is able to prevent 5-FU-induced intestinal inflammation in BALB/c mice. Moreover, PAP delivered by recombinantL. lactis strain showed additional protective effects in mice epithelium, revealing to be a promising strategy to treat intestinal mucositis.