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Chemically Induced Bladder Cancer Risk Influenced by Gut Microbe Metabolism, Study Finds

NEW YORK – New research suggests metabolic processes in certain gut microbes can mediate the ways carcinogenic compounds are processed and distributed in the body, influencing the risk of developing cancers like bladder cancer.

"We describe a new mechanism of how the gut microbiota impacts chemically induced tumorigenesis outside of the intestine," senior and co-corresponding author Michael Zimmermann, a structural and computational biologist at EMBL in Heidelberg and a member of the University of Heidelberg and EMBL Molecular Medicine Partnership Unit, said in an email.

Building on findings from past studies that found a potential role for gut bacteria in modifying the activity and distribution of xenobiotics and other compounds, Zimmermann and colleagues from EMBL, the University of Split in Croatia, and elsewhere examined potential ties between gut microbiome features and bladder cancer in mouse models exposed to N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), a bladder cancer-related carcinogen found in, for example, cigarette smoke. The work appeared in Nature on Wednesday.

While it was known that chronic BBN exposure consistently leads to bladder cancer in rodent models, the team suspected that certain gut microbes may contribute to the "biotransformation" of BBN to an oxidative product that prompts DNA adduct formation in urothelial tissue.

"Although the molecular mechanisms of microbial contributions to cancer development remain largely unknown, recent studies have demonstrated that gut bacteria have a large potential to chemically modify diverse classes of compounds, changing their activity and distribution in the body," Zimmermann said. "This led us to investigate whether the gut microbiota could contribute to tumor onset and development through the metabolism of nitrosamine carcinogens that are commonly found in cigarette smoke and processed food."

Indeed, the researchers found that BBN-exposed mice treated with antibiotics were less likely to develop bladder cancer than their BBN-treated, antibiotic-free counterparts. In addition, they noted that the tumors tended to be less aggressive when they did form in the antibiotic-treated group.

Consistent with those findings, their liquid chromatography-mass spectrometry analyses of samples taken from a range of mouse tissues showed lower-than-usual levels of the BBN oxidation product in bladder, cecum, and colon tissues and urine samples from the antibiotic-treated animals.

Based on this, the authors suggested that "gut microbiota carcinogen metabolism may be a contributing factor for chemical-induced carcinogenesis," and argued that results from the study "could open avenues to target the microbiome for improved predisposition risk assessment and prevention of cancer."

With that in mind, the team set out to flag the specific gut bacteria involved in processing BBN and used targeted 16S ribosomal RNA gene sequencing to identify a dozen microbial species that appeared to contribute to BBN biotransformation. Those findings were further backed up by biotransformation experiments they conducted using cultured mouse and microbial cells.

In additional studies in germ-free mice, meanwhile, the investigators found evidence that microbes found in human fecal samples can perform similar BBN biotransformation, while highlighting that there is person-to-person microbiome variation that would be expected to impact the risk of tumor development after exposure to the carcinogen.

Together, the results "could explain why some people, despite being exposed to potential carcinogens, do not develop cancers while others do," co-corresponding author Janoš Terzić, at the University of Split in Croatia, said in a statement.

Zimmermann, Terzić, and their colleagues noted in their paper that the findings may ultimately help to come up with cancer-prevention strategies that rely on manipulating the microbes in an individual's body and suggested "[f]uture investigations will build on these findings aiming at identifying microbiome-encoded predisposition risk factors for chemical-induced cancer development."