Modulation of 5-fluorouracil activation of toll-like/MyD88/NF-κB/MAPK pathway by Saccharomyces boulardii CNCM I-745 probiotic

Cytokine. 2020 Jan;125:154791. doi: 10.1016/j.cyto.2019.154791. Epub 2019 Aug 8.

Abstract

Background and aim: Chemotherapy drugs that act via Toll-like receptors (TLRs) can exacerbate mucosal injury through the production of cytokines. Intestinal mucositis can activate TLR2 and TLR4, resulting in the activation of NF-κB. Intestinal mucositis characterized by intense inflammation is the main side effect associated with 5-fluorouracil (5-FU) treatment. Saccharomyces boulardii CNCM I-745 (S.b) is a probiotic yeast used in the treatment of gastrointestinal disorders. The main objective of the study was to evaluate the effect of S.b treatment on the Toll-like/MyD88/NF-κB/MAPK pathway activated during intestinal mucositis and in Caco-2 cells treated with 5-FU.

Methods: The mice were divided into three groups: saline (control), saline + 5-FU, and 5-FU + S.b (1.6 × 1010 colony forming units/kg). After 3 days of S.b administration by gavage, the mice were euthanized and the jejunum and ileum were removed. In vitro, Caco2 cells were treated with 5-FU (1 mM) alone or in the presence of lipopolysaccharide (1 ng/ml). When indicated, cells were exposed to S.b. The jejunum/ileum samples and Caco2 cells were examined for the expression or concentration of the inflammatory components.

Results: Treatment with S.b modulated the expressions of TLR2, TLR4, MyD88, NF-κB, ERK1/2, phospho-p38, phospho-JNK, TNF-α, IL-1β, and CXCL-1 in the jejunum/ileum and Caco2 cells following treatment with 5-FU.

Conclusion: Toll-like/MyD88/NF-κB/MAPK pathway are activated during intestinal mucositis and their modulation by S.b suggests a novel and valuable therapeutic strategy for intestinal inflammation.

Keywords: Inflammatory pathways; Mucositis; Probiotics; Side effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caco-2 Cells
  • Chemokine CXCL1 / genetics
  • Chemokine CXCL1 / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Fluorouracil / adverse effects
  • Fluorouracil / pharmacology*
  • Humans
  • Ileum / metabolism
  • Immunohistochemistry
  • Inflammation / metabolism
  • Interleukin-1beta / genetics
  • Janus Kinases / metabolism
  • Jejunum / metabolism
  • Lipopolysaccharides / pharmacology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • Male
  • Mice
  • Mucositis / drug therapy
  • Mucositis / metabolism*
  • Myeloid Differentiation Factor 88 / metabolism*
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Probiotics / administration & dosage
  • Probiotics / pharmacology*
  • Saccharomyces boulardii / metabolism*
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / metabolism*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Chemokine CXCL1
  • Cytokines
  • Interleukin-1beta
  • Lipopolysaccharides
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • Janus Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Fluorouracil