Gut check: Health-promoting microbiome also harbors harmful bacteria causing e.g. colorectal cancer

Good news! Turns out the gut microbiome is much more complicated! Cancer is history (soon)!

"In a study published Oct 27 ... identified a novel family of small molecule “genotoxins” produced by specific human gut bacteria that can damage host DNA and may contribute to the development of colorectal cancer. And there are probably many additional bacterial genotoxins that remain to be discovered, the authors say. ...
Previous research had identified the microbiota-derived genotoxin colibactin as a contributor to the formation of colorectal tumors in mice and humans. But colibactin is produced by just a few species of bacteria among the hundreds that populate the human gut. ...
For the new study ... analyzed bacteria from patients with inflammatory bowel disease, a known risk factor for the development of colorectal cancer. After screening more than 100 bacterial isolates, they found that three unique species produced small molecules that could directly damage host DNA.
The researchers went on to identify and characterize a family of novel genotoxins — chemicals or agents that can damage DNA — that are produced by Morganella morganii, a bacterial species found in the intestinal tract of humans and other mammals. Intriguingly, M. morganii   has been found to exacerbate colorectal cancer in mice, but this effect was eliminated when the researchers prevented M. morganii from producing genotoxins. ..."

"Individuals with inflammatory bowel disease are at increased risk of developing colorectal cancer compared with the general population. The gut microbiome is among the many factors that can influence tumorigenesis, in part by modulating the immune system and producing microbial metabolites. Cao et al. developed a functional screen to test whether gut bacteria from patients with inflammatory bowel disease have genotoxic effects (see the Perspective by Puschhof and Sears). The authors discovered a family of DNA damage–inducing microbial metabolites called indolimines, which were produced by the Gram-negative bacteria Morganella morganii. In a mouse model of colon cancer, M. morganii exacerbated tumor burden, but a mutant form of the bacteria unable to produce indolimine did not. This diverse series of genotoxic small molecules from the human microbiome may play a role in intestinal tumorigenesis."

"Studies over the past two decades indicate that genotoxic gut bacteria, which damage or mutate DNA, are critical drivers of colorectal cancer (CRC) pathogenesis (1). Moreover, the notable increase in early-onset CRC incidence highlights the urgency to discover responsible exogenous factors that are amenable to therapeutic intervention. On page 369 of this issue, Cao et al. (2) report that individuals with inflammatory bowel disease (IBD), a common CRC precursor state, display diverse gut bacterial strains that potentially exert genotoxic activity. Pursuing Morganella morganii, a Gram-negative bacterium enriched in the gut microbiota of people with IBD and CRC, the authors identify a class of bacterial genotoxins called indolimines. They find evidence that indolimines promote tumor development in mice, thereby expanding the role of bacterial genotoxic metabolites in colorectal carcinogenesis."

From the (structured) abstract:

"INTRODUCTION

Gut microbiota can potentially contribute to the development and progression of colorectal cancer (CRC) by producing small-molecule genotoxins. For example, select commensal Escherichia coli strains produce the canonical microbiota-derived genotoxin colibactin, which engenders the formation of DNA double-strand breaks (DSBs) in intestinal epithelial cells and exacerbates CRC in mouse models. Furthermore, human CRCs harbor colibactin-associated mutational signatures, implying a direct role for microbiota-induced DNA damage in CRC. However, the impacts of microbiota-derived genotoxins beyond colibactin remain largely unexplored.

RATIONALE

Given the extensive diversity of small-molecule metabolites produced by bacteria, we hypothesized that additional taxa from the human gut microbiome might produce previously undiscovered small molecules that cause DNA damage in host cells. Identifying and characterizing such genotoxins and their respective biosynthetic pathways may reveal causal roles of gut microbes in shaping host biology and disease susceptibility. Thus, we designed a large-scale electrophoresis-based DNA damage screening pipeline to evaluate the genotoxicity of a collection of more than 100 gut commensals isolated from patients with inflammatory bowel disease (IBD).

RESULTS

We identified diverse bacteria from the human microbiota whose small-molecule metabolites caused genotoxicity in both cell-free and cell-based DNA damage assays. For example, small-molecule metabolites from gram-positive bacteria (including Clostridium perfringens and Clostridium ramosum strains) and gram-negative bacteria (including multiple Morganella morganii strains) directly damaged DNA in cell-free assays and induced the expression of the DSB marker γ-H2AX and cell-cycle arrest in epithelial cells. However, the DNA damage patterns caused by these metabolites were distinct from colibactin-induced cross-links, and these isolates lacked the biosynthetic machinery to produce colibactin or other known genotoxins. These data thus implied the existence of previously unrecognized microbiota-derived genotoxins.

M. morganii is enriched in the gut microbiota of both IBD and CRC patients. Using a combination of comparative metabolomics and bioactivity-guided natural product-discovery techniques, we discovered a family of M. morganii-derived small-molecule genotoxins—termed the indolimines—that elicited DNA damage in cell-based and cell-free assays. Furthermore, we identified a previously uncharacterized bacterial decarboxylase (annotated as an aspartate aminotransferase encoded by the aat gene) that was essential for indolimine synthesis and constructed an isogenic aat mutant M. morganii that lacked genotoxicity in both cell-free and cell-based DNA damage assays.

Compared with the non–indolimine-producing mutant, wild-type M. morganii caused increased intestinal permeability and induced transcriptional signatures associated with abnormal DNA replication and intestinal epithelial cell proliferation in gnotobiotic mice. Furthermore, indolimine-producing M. morganii induced increased colonic tumor burden in the context of a mock microbial community in a mouse model of CRC.

CONCLUSION

By leveraging function-based assessments of the microbiome, we uncovered the existence of a broader universe of microbiota-derived small-molecule genotoxins. We found that diverse bacterial strains isolated from IBD patients exhibited DNA-damaging activities and discovered a previously undescribed family of genotoxins, termed the indolimines, produced by the IBD- and CRC-associated species M. morganii. Indolimine-producing M. morganii caused increased intestinal permeability and exacerbated colon tumorigenesis in gnotobiotic mice. Overall, these studies imply an expanded role for microbiota-derived genotoxins in shaping host biology and disease susceptibility."

Gut check: Health-promoting microbiome also harbors harmful bacteria | YaleNews: A team of Yale scientists identified a novel family of “genotoxins” produced by human gut bacteria that can damage DNA and may contribute to colorectal cancer.

Microbial metabolites damage DNA Unexpected members of the gut microbiota produce diverse host cell genotoxins (no public access)

Commensal microbiota from patients with inflammatory bowel disease produce genotoxic metabolites (no public access)