In a study published in the prestigious scientific journal Science, a team of researchers from Yale University (New Haven, USA) discovered that the gut bacteria Morganella morganii can produce a class of genotoxic compounds, which can damage DNA, thus can promote genome instability. These compounds are microbial metabolites called indolimines, and genome instability is linked to colorectal cancer development. The authors demonstrated microbiome indolimines’ capability to elicit DNA damage and to increase colonic cancer burden in a mouse model.
Colorectal cancer and gut microbiome: the link
Colorectal cancer development can be associated with gut microbiome composition. In particular, specific bacterial strain can affect colorectal cancer development by producing small molecules, called genotoxins, able to induce DNA damage, thus promoting genome instability, which is the principal cancer diver factor.
For example, specific strains of Escherichia coli, a highly-represented gut bacteria, can produce colibactin, which promotes the formation of DNA double-strand breaks in the cells of the intestinal epithelium. Colibactin exacerbates colorectal cancer in mouse models, and human colorectal cancer is characterized by colibactin-associated mutational signatures, demonstrating a direct role for gut microbiota-induced DNA damage in colorectal cancer development.
Indolimines from M. morganii: the discovery
Looking for other microbiota-derived molecules potentially involved in colorectal cancer development Yale researchers, led by Yiyun Cao, evaluated the genotoxicity of more than 100 gut microbiota bacteria isolated from inflammatory bowel disease patients. In fact, long-standing inflammatory bowel disease patients are at increased risk of colorectal cancer.
«We identified diverse bacteria from the human microbiota whose small-molecule metabolites caused genotoxicity», Cao and colleagues explains on Science’s pages, adding that the small molecules produced by these bacteria «induced the expression of the DSB [Double Strand Breaks] marker γ-H2AX and cell-cycle arrest in epithelial cells». However, the damage induced by these molecules was different from the damage promoted by colibactin; what is more, these bacteria could not synthesize nor colibactin nor other previously known genotoxins.
Among identified bacteria was M. morganii, which is enriched in both inflammatory bowel disease and colorectal cancer patients. Cao and colleagues discovered it produces indolimines, small molecules able to elicit DNA damage. They also identified a gene (aat, aspartate aminotransferase) that is essential for the synthesis of indolimines, and demonstrated that mutant aat prevents indolimine synthesis and M. morganii genotoxicity. In mouse models, «compared with the non–indolimine-producing mutant, wild-type M. morganii caused increased intestinal permeability [which is associated with colorectal cancer] and induced transcriptional signatures associated with abnormal DNA replication and intestinal epithelial cell proliferation», and «indolimine-producing M. morganii induced increased colonic tumor burden».
Gut microbiome and genome instability
«These studies reveal the existence of a previously unexplored universe of genotoxic small molecules from the microbiome that may affect host biology in homeostasis and disease», the authors conclude. «These results add evidence to the link between gut microbiome composition and colorectal cancer risk», Silvia Soligon, PhD, nutritionist, microbiome expert, and Bioscience Institute Scientific Consultant, comments. «What is more, they highlight gut microbiome’s role in promoting DNA damage, thus the first cancer driver factor – that is, genome instability».
Genome instability develops in a timespan ranging from years to decades, during which other factors, including gut dysbiosis, promote or insist on it, creating the ideal microenvironment for cancer development. «During this phase, called the prodromal stage of cancer, we can do a lot to counteract cancer development», Soligon explains. «Among other things, we can promote a healthy gut microbiota composition by acting on several actionable lifestyle factors, such as our diet and our physical activity. What is more, clinical studies suggest that selected patients could undergo chemopreventive treatments. For example, in the case of colorectal cancer, people with Lynch syndrome could benefit from aspirin treatment».
How to analyze gut microbiome
Nowadays, gut microbiome can be easily analyzed by means of Next-Generation Sequencing-based approaches requiring only a simple stool sample. MICROBALANCE is Bioscience Institute’s solution aimed at this scope. It can be combined with the analysis of genome instability by HELIXBALANCE and with the analysis of other cancer driver factors (low-grade chronic inflammation and immune imbalance) thanks to HELIXAFE, Bioscience Institute’s program for cancer driver interception.
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- Burn J et al. Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial. Lancet. 2020 Jun 13;395(10240):1855-1863. doi: 10.1016/S0140-6736(20)30366-4
- Cao Y et al. Commensal microbiota from patients with inflammatory bowel disease produce genotoxic metabolites. Science. 2022 Oct 28;378(6618):eabm3233. doi: 10.1126/science.abm3233
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