Probiotic Propionibacterium freudenreichii requires SlpB protein to mitigate mucositis induced by chemotherapy.

Fillipe Luiz Rosa Do Carmo,Valbert Nascimento Cardoso,Ana Maria Caetano Faria,Houem Rabah,Vasco Azevedo,Bruna Savassi,Yves Le Loir,Alessandra Figueiroa,Gwénaël Jan,Martine Deplanche,Maria Izabel Alves Queiroz,Valérie Gagnaire,Rafaela Miranda Pessoa,Álvaro Cantini Nunes,Ênio Ferreira,Simone Odılia Antunes Fernandes ,Cláudio César Fonseca ,S.h.c Sandes ,Luísa Lemos ,N.m Rodrigues ,Sara Heloísa Da Silva ,Emiliano R Oliveira ,Bárbara Fernandes Cordeiro ,Juliana Dias Alves

doi:10.18632/oncotarget.27319

Fillipe Luiz Rosa Do Carmo, Valbert Nascimento Cardoso + Show 22 more

Open Access

https://doi.org/10.18632/oncotarget.27319

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Abstract

Propionibacterium freudenreichii CIRM-BIA 129 (P. freudenreichii wild type, WT) is a probiotic bacterium, which exerts immunomodulatory effects. This strain possesses extractable surface proteins, including SlpB, which are involved in anti-inflammatory effect and in adhesion to epithelial cells. We decided to investigate the impact of slpB gene mutation on immunomodulation in vitro and in vivo. In an in vitro assay, P. freudenreichii WT reduced expression of IL-8 (p<0.0001) and TNF-α (p<0.0001) cytokines in LPS-stimulated HT-29 cells. P. freudenreichii ΔslpB, lacking the SlpB protein, failed to do so. Subsequently, both strains were investigated in vivo in a 5-FU-induced mucositis mice model. Mucositis is a common side effect of cytotoxic chemotherapy with 5-FU, characterized by mucosal injury, inflammation, diarrhea, and weight loss. The WT strain prevented weight loss, reduced inflammation and consequently histopathological scores. Furthermore, it regulated key markers, including Claudin-1 (cld1, p<0.0005) and IL-17a (Il17a, p<0.0001) genes, as well as IL-12 (p<0.0001) and IL-1β (p<0.0429) cytokines levels. Mutant strain displayed opposite regulatory effect on cld1 expression and on IL-12 levels. This work emphasizes the importance of SlpB in P. freudenreichii ability to reduce mucositis inflammation. It opens perspectives for the development of probiotic products to decrease side effects of chemotherapy using GRAS bacteria with immunomodulatory surface protein properties.

Highlights

Propionibacterium freudenreichii represents the main species of dairy propionibacteria
The aim of this study is to evaluate the probiotic ability of P. freudenreichii CIRM-BIA 129 to protect mice against inflammatory mucositis damages induced by 5-FU, and to further investigate the impact of slpB gene mutation on such a protection
We investigated the anti-inflammatory potential of P. freudenreichii WT, and the impact of the mutation of the slpB gene on this potential

Summary

Introduction

Propionibacterium freudenreichii represents the main species of dairy propionibacteria It is a grampositive, non-motile, non-spore forming and anaerobic to aerotolerant beneficial bacterium, which plays an important role in food transformation, in cheese ripening [1]. Non-motile, non-spore forming and anaerobic to aerotolerant beneficial bacterium, which plays an important role in food transformation, in cheese ripening [1] It has been listed in the Qualified Presumption of Safety list by the European food safety authority [2]. Dairy propionibacteria are peculiar bacteria with a great probiotic potential. They produce the short chain fatty acids (SCFAs) acetate and propionate, and other beneficial metabolites, such as vitamin B9 and B12, as well as 1,4-dihydroxy-2-naphthoic acid (DHNA) and 2-amino3-carboxy-1,4-naphthoquinone (ACNQ), which were described as bifidogenic growth stimulators [1]

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