Scientists have known for some time that inflammation influences the development of colorectal cancer, but now, a new study suggests that gut microbes may also play a role.
Writing in the latest online issue of the journal mBio, the researchers describe how they transferred gut microbes from mice with colon tumors to germ-free mice and found it made them prone to getting tumors as well.
The human gut harbors trillions of bacteria, fungi and other tiny organisms – known collectively as the gut microbiome – that are important for a healthy gut.
While the known risk factors for developing colorectal cancer include eating too much red meat, drinking too much alcohol and chronic gut inflammation (such as that seen in patients with chronic inflammatory bowel diseases like ulcerative colitis), patients with colorectal cancer also show signs of “dysbiosis,” or changes to their gut microbiome.
But while there is growing evidence that disruption to the gut microbiome is strongly linked to the development of colorectal cancer, it is not clear if it actually drives the cancer or results from it.
The researchers suggest their findings show dysbiosis drives colorectal cancer:
“We demonstrate using a mouse model of inflammation-driven colon cancer that there are dramatic, continual alterations in the microbiome during the development of tumors, which are directly responsible for tumor development.”
Study author Patrick Schloss, professor of Microbiology and Immunology at the University of Michigan, says he was surprised how clear their results were:
“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]. 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.”
For their study, the researchers induced colorectal tumors in a group of mice, then transferred their feces and bedding to a group of germ-free mice (mice eat their droppings, so this was an easy way to inoculate the germ-free group with a new microbiome).
Meanwhile, another group of germ-free mice were similarly inoculated with a new microbiome from healthy mice.
Both sets of mice were then induced to develop colorectal tumors, with stark results: the mice that had received a microbiome from the tumor-ridden mice had more than twice as many colon tumors as the mice inoculated with a healthy microbiome.
The researchers also inoculated normal mice with gut bacteria from the tumor-ridden mice. One half of this group received antiobiotics before and after inoculation, while the other half received no antibiotics. When induced to develop tumors, the half that had been given antibiotics had fewer, smaller tumors.
This second experiment suggests specific populations of microbes are involved in tumor formation, so in a final phase of the study, the team set out to identify them.
They discovered that the guts of the tumor-ridden mice contained more bacteria in the genera Bacteroides, Odoribacter and Akkermansia, and fewer in the Prevotellaceae and Porphyromonadaceae families.
Prof. Schloss says they see the process as a “feed-forward” system, where the inflammation changes the balance of the gut bacteria, and the gut bacteria induce inflammation:
“They make each other worse to the point that you have higher rates of tumor formation.”
The team is now investigating which bacteria are and are not associated with tumor formation.
Prof. Schloss says:
“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.”
Earlier this year, systems biologists at the University of Washington reported in PNAS how environment strongly influences microbiome composition.