Intestinal Microbes as Carcinogens
Fecal microbiota from patients with colorectal cancer (CRC) have carcinogenic properties, researchers report in the December issue of Gastroenterology. Feeding mice stool from patients with colorectal cancer (CRC) increased numbers of polyps, levels of intestinal dysplasia and proliferation, and markers of inflammation in colon, compared with stool from individuals without CRC, the scientists found.
Intestinal microbes can promote intestinal carcinogenesis by producing toxins, inducing inflammation, creating a microenvironment that promotes tumorigenesis, and activating toll-like receptor and beta-catenin signaling.
To investigate the mechanisms by which microbes promote colorectal carcinogenesis, Sunny H. Wong et al fed mice stool samples from patients with CRC or from healthy individuals (controls), and studied the phenotypic and molecular changes in colonic tissues.
In these experiments male C57BL/6 mice were given a course of antibiotics in their drinking water follwed by azoxymethane to induce colon neoplasia (conventional mice). Mice were gavaged twice weekly with stool from 5 patients with CRC or 5 healthy individuals (controls) for 5 weeks. Germ-free C57BL/6 mice were gavaged once with stool from 5 patients with CRC or 5 controls.
In mice given antibiotics and azoxymethane, the prevalence and number of colonic polyps were significantly higher among those fed stool samples from patients with CRC than from contols or no microbiota after 9 weeks. Germ-free mice fed stool samples from patients with CRC or from controls for as long as 32 weeks did not develop polyps. However, intestinal tissues from mice fed the CRC patients’ stool samples did have increased proliferation, compared to mice fed control fecal samples.
Taxonomic analysis by 16S rRNA gene sequencing revealed decreased microbial diversity and increased relative abundance of Fusobacterium nucleatum, Peptostreptococcus anaerobius, Peptostreptococcus stomatis, Parvimonas micra, Solobacterium moorei, and Gemella morbillorum in fecal samples from mice fed the stool samples from patients with CRC vs mice fed control stool.
Reduced microbial diversity was also found in fecal samples from germ-free mice fed stool from patients with CRC compared to germ-free mice fed control stool.
Intestines from mice (conventional or germ-free) fed stool from patients with CRC had increased expression of cytokines that modulate inflammation, including C-X-C motif chemokine receptor 1 (CXCR1), CXCR2, interleukin 17A (IL17A), IL22, and IL23A. Their intestines also contained significantly higher proportions of T-helper 1 (Th1) cells (2.25% vs 0.44%) and Th17 cells (2.08% vs 0.31%) than mice fed with stool from controls.
Real-time polymerase chain reaction arrays revealed up-regulation of genes involved in cell proliferation, stemness, apoptosis, angiogenesis, invasiveness, and metastasis in mice fed with stool from patients with CRC.
Wong et al state that their findings provide evidence for the direct tumorigenic effects of the intestinal microbiota of patients with CRC in conventional and germ-free mouse models of colorectal carcinogenesis.
They explain that most of the time, the intestinal microbiota provide their host with important nutrients and help regulate the immune response. However, an altered microbiota can promote development of diseases, including cancer. It has not been clear whether the tumorigenic effects of the microbiota require different combinations of bacterial phyla or are specific to a defined set of bacteria. Wong et al propose that, based on their findings, a defined set of microbiota appear to be involved in colorectal carcinogenesis.
Wong et al also believe the status of the immune response to be involved in microbiota-induced, colorectal carcinogenesis. This is because the mice that developed polyps (conventional mice) had a mature immune system, whereas the germ-free mice, which had only intestinal hyperplasia after exposure to the CRC microbita, have deficient immune systems, including underdevelopment of the gut-associated lymphoid tissues.
In an editorial that accompanies the article, Christian Jobin provides a model by which the fecal microbiota from patients with CRC might promote neoplastic lesions after oral transfer into mice. Jobin states that studies are needed to determine the mechanisms that cause changes to the microbiota of patients with vs without CRC.