First name
Elena
Last name
Zagato
Year of Study
Thesis Title
Role of bacteria and the mucus system in intestinal tumorigenesis
Thesis Abstract
Studies on human colorectal cancer (hCRC) samples have documented a dysbiosis associated with the tumor, but a clear picture of the microorganisms whose abundance
is altered during has not yet emerged. This study is aimed at dissecting the role of bacteria in CRC development by focusing on the intestinal mucus barrier as a key
mediator in microbiota-host interaction. We used the ApcMin/+ murine model to demonstrate that in tumor-bearing mice the mucus and the intestinal barrier have altered properties. Mucin expression is altered at the level of dysplastic crypts, strictly relating mucus changes with neoplastic transformation. We further observed that bacterial penetrance was compromised in tumor-prone mice with increased Salmonella penetration in the intestine and mesenteric lymph nodes. To address the potential role of mucus alteration in the tumorigenic process we exogenously modified the mucus barrier. Mucus disruption in both the ApcMin/+ and the AOM/DSS models led to increased colonic tumorigenesis. We did also investigate whether there was a dysbiosis associated with tumor progression. Metagenomic analysis in the faeces of mice at different ages highlighted a dysbiosis already at 4 weeks of age in ApcMin/+ mice when tumors are not yet established. In particular, Lactobacillus genus was expanded in ApcMin/+ mice concomitantly with a contraction in the Clostridium genus. Finally since epigenetic mechanisms have been hypothesised to contribute to the loss of heterozygosity of the normal apc allele and bacteria can alter miRNA expression we analysed miRNA profiles in WT and ApcMin/+ intestinal tissue observing alterations in ApcMin/+ ilei.
is altered during has not yet emerged. This study is aimed at dissecting the role of bacteria in CRC development by focusing on the intestinal mucus barrier as a key
mediator in microbiota-host interaction. We used the ApcMin/+ murine model to demonstrate that in tumor-bearing mice the mucus and the intestinal barrier have altered properties. Mucin expression is altered at the level of dysplastic crypts, strictly relating mucus changes with neoplastic transformation. We further observed that bacterial penetrance was compromised in tumor-prone mice with increased Salmonella penetration in the intestine and mesenteric lymph nodes. To address the potential role of mucus alteration in the tumorigenic process we exogenously modified the mucus barrier. Mucus disruption in both the ApcMin/+ and the AOM/DSS models led to increased colonic tumorigenesis. We did also investigate whether there was a dysbiosis associated with tumor progression. Metagenomic analysis in the faeces of mice at different ages highlighted a dysbiosis already at 4 weeks of age in ApcMin/+ mice when tumors are not yet established. In particular, Lactobacillus genus was expanded in ApcMin/+ mice concomitantly with a contraction in the Clostridium genus. Finally since epigenetic mechanisms have been hypothesised to contribute to the loss of heterozygosity of the normal apc allele and bacteria can alter miRNA expression we analysed miRNA profiles in WT and ApcMin/+ intestinal tissue observing alterations in ApcMin/+ ilei.
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