title: Secretion of biologically active pancreatitis-associated protein I (PAP) by genetically modified dairy Lactococcus lactis NZ9000 in the prevention of intestinal mucositis.
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 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.
authors.affiliation: Federal University of Minas Gerais (UFMG-ICB), Av. Antônio Carlos, 6627, CP 486, Belo Horizonte, MG, 31270-901, Brazil.
authors.forename: Rodrigo D
authors.initials: RD
authors.lastname: Carvalho
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-En-Josas, France.
authors.forename: Natalia
authors.initials: N
authors.lastname: Breyner
authors.affiliation: Federal University of Minas Gerais (UFMG-ICB), Av. Antônio Carlos, 6627, CP 486, Belo Horizonte, MG, 31270-901, Brazil.
authors.forename: Zelia
authors.initials: Z
authors.lastname: Menezes-Garcia
authors.affiliation: Federal University of Minas Gerais (UFMG-ICB), Av. Antônio Carlos, 6627, CP 486, Belo Horizonte, MG, 31270-901, Brazil.
authors.forename: Nubia M
authors.initials: NM
authors.lastname: Rodrigues
authors.affiliation: Federal University of Minas Gerais (UFMG-ICB), Av. Antônio Carlos, 6627, CP 486, Belo Horizonte, MG, 31270-901, Brazil.
authors.forename: Luisa
authors.initials: L
authors.lastname: Lemos
authors.affiliation: Federal University of Minas Gerais (UFMG-ICB), Av. Antônio Carlos, 6627, CP 486, Belo Horizonte, MG, 31270-901, Brazil.
authors.forename: Tatiane U
authors.initials: TU
authors.lastname: Maioli
authors.affiliation: Federal University of Minas Gerais (UFMG-ICB), Av. Antônio Carlos, 6627, CP 486, Belo Horizonte, MG, 31270-901, Brazil.|Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-En-Josas, France.
authors.forename: Danielle
authors.initials: D
authors.lastname: da Gloria Souza
authors.affiliation: Federal University of Minas Gerais (UFMG-ICB), Av. Antônio Carlos, 6627, CP 486, Belo Horizonte, MG, 31270-901, Brazil.
authors.forename: Denise
authors.initials: D
authors.lastname: Carmona
authors.affiliation: Federal University of Minas Gerais (UFMG-ICB), Av. Antônio Carlos, 6627, CP 486, Belo Horizonte, MG, 31270-901, Brazil.
authors.forename: Ana M C
authors.initials: AM
authors.lastname: de Faria
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-En-Josas, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Langella
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-En-Josas, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Chatel
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-En-Josas, France.
authors.forename: Luis G
authors.initials: LG
authors.lastname: Bermúdez-Humarán
authors.affiliation: Federal University of Minas Gerais (UFMG-ICB), Av. Antônio Carlos, 6627, CP 486, Belo Horizonte, MG, 31270-901, Brazil.
authors.forename: Henrique C P
authors.initials: HC
authors.lastname: Figueiredo
authors.affiliation: Federal University of Minas Gerais (UFMG-ICB), Av. Antônio Carlos, 6627, CP 486, Belo Horizonte, MG, 31270-901, Brazil.
authors.forename: Vasco
authors.initials: V
authors.lastname: Azevedo
authors.affiliation: Federal University of Minas Gerais (UFMG-ICB), Av. Antônio Carlos, 6627, CP 486, Belo Horizonte, MG, 31270-901, Brazil. marcela.spachecoazevedo@gmail.com.
authors.forename: Marcela S
authors.initials: MS
authors.lastname: de Azevedo
mesh_terms: D000818:Animals; D000898:Antibiosis; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D013293:Enterococcus faecalis / Q000502:physiology; D005472:Fluorouracil; D006801:Humans; D007079:Ileitis / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000517:prevention & control; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D013294:Lactococcus lactis / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D037181:Lectins, C-Type / Q000235:genetics* / Q000378:metabolism*; D008089:Listeria monocytogenes / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D052016:Mucositis / Q000139:chemically induced / Q000188:drug therapy / Q000382:microbiology / Q000517:prevention & control*; D000073718:Pancreatitis-Associated Proteins
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D005472:Fluorouracil
keywords: 5-Fluoracil; Lactococcus lactis; Mucositis; Pancreatitis-associated protein