Dataset Information

Immunoregulatory mechanisms underlying prevention of colitis-associated colorectal cancer by probiotic bacteria.

ABSTRACT:

Background

Inflammatory 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 findings

The 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-?, angiostatin and PPAR ? 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/significance

Both 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.

SUBMITTER: Bassaganya-Riera J

PROVIDER: S-EPMC3325233 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Immunoregulatory mechanisms underlying prevention of colitis-associated colorectal cancer by probiotic bacteria.

Bassaganya-Riera Josep J Viladomiu Monica M Pedragosa Mireia M De Simone Claudio C Hontecillas Raquel R

PloS one 20120412 4

<h4>Background</h4>Inflammatory 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.<h4>Methodology/principal findings</h4>The immune modulatory mechanisms of VSL#3 probiotic b ...[more]

PMID: 22511958

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Project description:Gut microbiota dysbiosis with increased pathogenic bacteria and decreased beneficial bacteria is associated with colorectal cancer (CRC) development. This study examined the effect of a newly developed probiotic formula in modulating CRC-related bacteria. We developed a probiotic formula containing three bifidobacteria (B. adolescentis, B. longum, and B. bifidum) based on the identification of bacterial species that showed significant correlations with CRC-related bacteria including Fusobacterium nucleatum (Fn), Lachnoclostridium sp. m3, Clostridium hathewayi (Ch), and Bacteroides clarus (Bc). We co-cultured Fn with each bifidobacterium or the combined formula and examined the growth of Fn by qPCR. The three individual bifidobacteria significantly inhibited the growth of Fn compared to the control treatment (24~65% inhibition; all p < 0.001). The combination of the three bifidobacteria showed a greater inhibitory effect on Fn growth (70% inhibition) than the individual bifidobacteria (all p < 0.05). We further examined the effect of the probiotic formula in a pilot study of 72 subjects (40 on probiotics; 32 with no intervention) for 4 weeks and followed them up for 12 weeks. The relative fecal abundances of the bifidobacteria in the formula and the CRC-related markers (Fn, m3, Ch, and Bc) were quantitated by qPCR before and after the intervention, and the combined CRC risk score (4Bac; Fn, m3, Ch, and Bc) was evaluated. Subjects with probiotics intervention showed significantly increased abundances of the bifidobacteria from week 2 to week 5 compared to baseline (p < 0.05), and the abundances dropped to baseline levels after the cessation of the intervention. There were significant decreases in the levels of CRC-related markers (Fn and m3) and the CRC risk score (4Bac) from week 2 to week 12 compared to baseline levels (p < 0.05) in the intervention group but not in the control group. A novel probiotic formula containing B. adolescentis, B. longum, and B. bifidum was effective in inhibiting the growth of F. nucleatum in vitro and improving the gut microbial environment against CRC development.

Project description:BackgroundColorectal cancers develop through several pathways, including the adenoma-carcinoma sequence and colitis-associated carcinogenesis. An altered intestinal microflora has been reported to be associated with the development and progression of colorectal cancer via these pathways. We identified Lactobacillus casei-derived ferrichrome as a mediator of the bacterial anti-tumor effect of colorectal cancer cells through the upregulation of DDIT3. In this study, we investigated the anti-tumor effects of ferrichrome on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer.MethodsSRB and MTT assays were performed to assess growth inhibition in vitro. Eighteen organoids were prepared from biopsy specimens obtained by colonoscopy. An AOM-DSS carcinogenesis model and xenograft model of colorectal cancer cells were generated for the assessment of the tumor suppressive effect of ferrichrome in vivo.ResultsFerrichrome inhibited the cell growth of colorectal cancer cells in vitro and in in vivo xenograft models. Ferrichrome exerted a strong tumor-suppressive effect that was superior to that of currently available anti-tumor agents, including 5-FU and cisplatin, both in vitro and in vivo. The tumor-suppressive effect of the combination of ferrichrome and 5-FU was superior to that of single treatment with either drug. The tumor suppressive effects of ferrichrome were confirmed through the upregulation of DDIT3 in patient-derived organoids of adenoma and carcinoma. Ferrichrome inhibited the tumor progression in the AOM-DSS model while exhibiting no anti-inflammatory effect in the DSS-colitis model, suggesting that ferrichrome inhibited cancer cells, but not a precancerous condition, via the colitis-associated pathway.ConclusionsFerrichrome exerts a tumor suppressive effect on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer. The anti-tumor effect of ferrichrome was mediated by the upregulation of DDIT3, and was superior to that of 5-FU or cisplatin. These results suggest that Lactobacillus brevis-derived ferrichrome may be a candidate anti-tumor drug for the treatment of colorectal neoplasms.

Dataset Information

Immunoregulatory mechanisms underlying prevention of colitis-associated colorectal cancer by probiotic bacteria.

Background

Methodology/principal findings

Conclusions/significance

Publications

Immunoregulatory mechanisms underlying prevention of colitis-associated colorectal cancer by probiotic bacteria.

Similar Datasets

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