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Gut Microbiome Community Changes Exacerbate Tumorigenesis in Mouse Model

NEW YORK (GenomeWeb News) – Shifts in the composition of the gut microbiome associated with inflammation can promote tumorigenesis, according to a paper appearing this week in mBio.

University of Michigan researchers characterized gut microbiome changes that took place during tumorigenesis in a mouse model of colon cancer and found that significant population shifts occurred. They also transplanted those cancer-related microbiomes and microbiomes from healthy mice into mouse donors, and discovered that mice that had received microbiomes from mice with cancer were more likely to develop the disease.

"We saw more than two times the number of tumors in mice that received the cancerous community [than in mice that received a healthy gut community]," senior author Patrick Schloss, an associate professor at the University of Michigan, said in a statement. "That convinced us that it is the community that is driving tumorigenesis. It's not just the microbiome, it's not just the inflammation, it's both."

Colorectal cancer was diagnosed in some 131,600 people in the US in 2010, and about 52,000 died from the disease, according to the US Centers for Disease Control and Prevention. Risk factors for colorectal cancer include eating red and processed meat, drinking alcohol, as well as chronic inflammation of the gastrointestinal tract. The UMich researchers noted that those risk factors are closely associated with changes to the community structure of gut microbes.

Turning to an inflammation-based mouse model of colorectal cancer, Schloss and his colleagues examined how the gut microbiome community structure changes during tumorigenesis. Tumorigenesis was initiated through the administration of the carcinogen azoxymethane and dextran sodium sulfate.

Using 16SrRNA gene sequencing performed on the 454 Titanium platform, they noted shifts in the microbiome, including enrichment of OTUs affiliated with members of the Bacteroides genus and declining numbers of OTUs linked to members of the genus Prevotella and unclassified genera in the family Porphyromonadaceae. They also noted a late-in-the-process bloom of a member of the Erysipelotrichaceae family.

Overall, the mice developed a median 14.5 tumors each. Further, they found that if the mice received an antibiotic cocktail they had fewer tumors.

At the same time, the researchers reported that there was increased infiltration by immune cells, epithelia damage, and submucosal edema, and other hallmarks of inflammation during the tumor-generating process.

To determine whether the observed changes to microbial gut community structure were enough to promote tumorigenesis, Schloss and his colleagues also inoculated germfree mice with feces and bedding from both healthy mice and the colon-cancer model mice. Those newly inoculated mice were then administered the same azoxymethane and dextran sodium sulfate tumor-generating cocktail.

The researchers noted that the microbiomes of the recipient mice contained all bacterial phyla and about 90 percent of the genus-level taxa that were in their donor samples.

Mice that received the microbiota from donors with cancer had a two-fold increase in tumor burden — and tumors that were larger in size — as compared to mice that were conventionalized with a healthy microbiome.

These tumor-bearing mice also exhibited enrichment in OTUs associated with Bacteroides, Odoribacter, Turicibacter, and a bloom of Erysipelotrichaceae alongside a corresponding decrease of OTUs associated with the genus Prevotella and the family Porphyromonadaceae.

"These results demonstrate that alterations to the gut microbiome that were associated with chronic inflammation and tumorigenesis in [the first set of] mice were transmitted to germfree mice and can exacerbate colon tumorigenesis," Schloss and his colleagues write.

Changes to the gut community structure occur prior to the development of macroscopic tumors, the researchers noted, indicating that the gut microbiome could be altered therapeutically to decrease the formation of tumors in the colon.

"If you can better understand what functions in the microbial community are important for protecting against tumor formation or making it worse, we can hopefully translate those results to humans to understand why people do or do not get colorectal cancer, to help develop therapeutics or dietary manipulations to reduce people's risk," Schloss said.