Abstract
BackgroundInflammatory bowel disease (IBD) increases the risk of colorectal cancer. Probiotic bacteria produce immunoregulatory metabolites in vitro such as conjugated linoleic acid (CLA), a polyunsaturated fatty acid with potent anti-carcinogenic effects. This study aimed to investigate the cellular and molecular mechanisms underlying the efficacy of probiotic bacteria in mouse models of cancer.Methodology/Principal FindingsThe immune modulatory mechanisms of VSL#3 probiotic bacteria and CLA were investigated in mouse models of inflammation-driven colorectal cancer. Colonic specimens were collected for histopathology, gene expression and flow cytometry analyses. Immune cell subsets in the mesenteric lymph nodes (MLN), spleen and colonic lamina propria lymphocytes (LPL) were phenotypically and functionally characterized. Mice treated with CLA or VSL#3 recovered faster from the acute inflammatory phase of disease and had lower disease severity in the chronic, tumor-bearing phase of disease. Adenoma and adenocarcinoma formation was also diminished by both treatments. VSL#3 increased the mRNA expression of TNF-α, angiostatin and PPAR γ whereas CLA decreased COX-2 levels. Moreover, VSL#3-treated mice had increased IL-17 expression in MLN CD4+ T cells and accumulation of Treg LPL and memory CD4+ T cells.Conclusions/SignificanceBoth CLA and VSL#3 suppressed colon carcinogenesis, although VSL#3 showed greater anti-carcinogenic and anti-inflammatory activities than CLA. Mechanistically, CLA modulated expression of COX-2 levels in the colonic mucosa, whereas VSL#3 targeted regulatory mucosal CD4+ T cell responses.
Highlights
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States [1]
VSL#3 probiotic bacteria treatment was more effective than conjugated linoleic acid (CLA) in decreasing inflammation and reducing disease activity in both models (Figure 1A and Figure 2A)
Chronic intestinal inflammation occurring in Inflammatory bowel disease (IBD) induces persistent damage and enhanced mucosal permeability along the gastrointestinal tract, playing an important role in the development of colorectal cancer (CRC) [29]
Summary
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States [1]. Probiotics are live microbial feed supplements which beneficially impact on host health They rely on introducing particular exogenous strains into the gut microflora [8,9]. These strains are often chosen for specific beneficial activities, like the production of lipids such as conjugated linoleic acid (CLA) and conjugated linoleic acid isomers (CLNA) [10,11]. These lipids vary in chemical structure from short fatty acids such as propionate, acetate and butyrate to polyunsaturated fatty acids (PUFA) and are involved in regulating apoptosis and the immune response [10,12,13,14]. Inflammatory bowel disease (IBD) increases the risk of colorectal cancer. This study aimed to investigate the cellular and molecular mechanisms underlying the efficacy of probiotic bacteria in mouse models of cancer
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