A common mouth microbe might contribute to colon cancer.
Originally published for MicroBites on May 6, 2024
The colon contains the densest population of microbes in our bodies with an estimated count of 1013 bacteria in approximately 0.4L of space. So, scientists have been asking for a long time whether the colon microenvironment is different in the presence of cancerous tumors. Studies from as early as 2012 have been looking at the colorectal cancer microbiome, and they showed using early genomic analysis techniques that patients with colon cancer have a higher proportion of bacteria in the Fusobacterium genus compared to patients without colon cancer. Since then, scientists have been investigating whether Fusobacterium, specifically Fusobacterium nucelatum, has a more causative role in colon cancer development.
Fusobacterium nucleatum is commonly found in the mouth, which is why its presence in the colon was initially puzzling. While it is usually harmless, it can cause periodontal disease when given the opportunity. Since the initial identification in 2012, researchers have linked an abundance of Fusobacterium in the colon with worse outcomes for patients.
Most recently, researchers at the Fred Hutchinson Cancer Center published a paper where they used genomic analysis techniques to pinpoint with high specificity the specific subgroup of F. nucleatum that contributes to the worsening of colon cancer. To do this, they collected 55 strains of F. nucleatum from the tumors of patients with colon cancer. To compare to a non-cancer control group, they also gathered 80 strains of F. nucleatum from healthy oral microbiomes.
From these collections, they sequenced the entire genome of each strain, including the epigenetic markers which provide an added layer of specificity to each strain’s bacterial behavior. Through comparing the two different niches of F. nucleatum (Fn), they found that in the oral microbiome, the strain Fn nucleatum is the most abundant, but in the colorectal cancer microbiome, Fn animalis is more prevalent.
Sequencing the entire genome of each Fn strain revealed that the colorectal cancer niche was more narrow than they had previously thought. Genetic analysis showed two distinct clades of Fn animalis. A clade is a group of organisms that share one common ancestor on the evolutionary tree. While a clade can encompass a wide variety of species, it can also refer to evolution within a species.
The researchers labeled the clades within Fn animalis “clade 1” and “clade 2”. In the oral microbiome, the proportion of clade 1 and clade 2 are approximately the same; however, in the colorectal cancer microbiome, clade 2 dominates. While many of the core components of their genomes are largely the same, there are some important differences. For example, clade 2 contains genes that are essential for withstanding the low pH of the stomach, which is essential for bacteria moving from the oral microbiome to the colon. Clade 1 and clade 2 are also distinct in their epigenetic patterns, specifically in the highly conserved 16S ribosomal RNA gene, which implicates it as a potential target for diagnostics to differentiate between clades in patients at risk for colorectal cancer.
With Fn animalis clade 2 and colorectal cancer correlation identified, the researchers set out to see if the clade could promote tumor growth in vivo. To do this, they used mice that are prone to developing intestinal tumors and treated them with either Fn animalis clade 1 or Fn animalis clade 2 with an additional no bacteria control group. To quantify the effect that the bacteria had on tumor development, they infected the mice with the bacteria every day for six weeks then counted how many tumors each mouse had in their large intestine by the end. Only three of the no bacteria group developed any tumors at all, and the mice treated with clade 1 had a median of only one tumor. But the clade 2 treated mice showed a statistically significant increase in tumor production with a median of 3 tumors, with one mice in the treatment group developing up to eight.
While this seemed like a promising finding, mouse experiments are not the end all be all. So, the researchers went one step further to observe whether Fn animalis clade 2 is the specific bacterial agent present in human colorectal cancer tissues. They did this in three main ways:
- by comparing the relative abundance of the two clades in colorectal cancer patients in two independent cohorts,
- by doing side-by-side comparisons of cancerous and adjacent noncancerous tissue, and
- by sequencing stool samples of colorectal cancer patients and comparing them to healthy patients.
Each of these experiments confirmed that Fn animalis clade 2 is indeed present and specific to colorectal cancer tumors.
The specificity of this finding allows researchers to now focus on a specific target to learn more about this relationship between bacteria and cancer. By comparing this clade to genetically similar organisms, researchers can identify specific proteins and genes that this bacterium uses to worsen the outcomes of patients with cancer.
Original Paper: Zepeda-Rivera, M., Minot, S.S., Bouzek, H. et al. A distinct Fusobacterium nucleatum clade dominates the colorectal cancer niche. Nature 628, 424–432 (2024). https://doi.org/10.1038/s41586-024-07182-w