Cancer is commonly linked to both chemical-induced tumor development—exposure to environmental pollutants which are typically metabolized in the body, and can change their ability to be carcinogenic—and the composition of the microbiome. But the link between these two is not well understood.
Now, a collaboration that started from a chance meeting at a conference, has uncovered how gut bacteria affect the way mice respond to a carcinogen. A new paper shows that gut bacteria can metabolize carcinogens and cause them to accumulate in distant organs, leading to tumor development. The depletion of the gut microbiota, they wrote, “affects the toxicokinetics of nitrosamines, which markedly reduces the development and severity of nitrosamine-induced urinary bladder cancer in mice.”
This work is published in Nature in the paper, “Gut microbiota carcinogen metabolism causes distal tissue tumours.”
Researchers have previously shown that if mice are exposed to N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) (one of the chemicals found in tobacco smoke) they reliably develop an aggressive form of bladder cancer. This method is used as a common laboratory model of carcinogen-induced cancer.
The lab of Janoš Terzić, PhD, from the University of Split in Croatia, found that when mice were fed antibiotics at a dose that kills 99.9% of their gut bacteria, at the same time as they were exposed to BBN, the chances of them forming tumors were much lower.
The team uncovered that bacteria living in the mouse gut could convert BBN into N-butyl-N-(3-carboxypropyl) nitrosamine (BCPN). And, unlike BBN, BCPN concentrates in the urinary bladder and triggers tumor formation in a microbiome-dependent manner.
“While 90% of mice exposed to BBN went on to develop bladder tumors, only 10% of those that also received antibiotics did so. This led us to hypothesize that the gut bacteria might be involved in regulating the way BBN is processed in the body,” said Blanka Roje, PhD student at the University of Split School of Medicine.
“The decrease in tumor incidence was so dramatic that at first I doubted the results, thinking we must have made a mistake somewhere in the experiment,” Terzić said. “Consequently, we repeated the experiment five times before we finally became ‘believers.’ It was fantastic to realize that with a treatment—in this case, antibiotics—we were able to abolish cancer development.”
The team then causally linked the carcinogen biotransformation to specific bacteria using bacterial culture collections and gnotobiotic mouse models. The researchers analyzed over 500 bacteria to identify the specific bacterial species involved in converting BBN to BCPN. “We found 12 species that can carry out this carcinogen biotransformation,” said Boyao Zhang, former PhD student in the lab of Michael Zimmermann, PhD, a group leader at EMBL Heidelberg. “We sequenced them and were surprised to find that many of those species were skin-associated and found at relatively low abundance in the gut. We speculated that there might be some transient transfer of such bacteria from the skin to the gut as a consequence of the animals’ grooming. But it was important to figure out whether these findings would also be true for humans.”
Human fecal samples showed that human gut bacteria can also convert BBN to BCPN. As a proof of concept, they showed that if human stool was transplanted into the intestine of a mouse, they could also convert BBN to BCPN.
However, the researchers also observed large individual differences in the ability of the human gut microbiome to metabolize BBN, as well as in the bacterial species involved in the biotransformation. “We think this lays the foundation for further research to see whether a person’s gut microbiome represents a predisposition for chemically induced carcinogenesis and could hence be used to predict the individual risk and potentially prevent cancer development,” said Zimmermann.
“This difference in interindividual microbiota could explain why some people, despite being exposed to potential carcinogens, do not develop cancers while others do,” Terzić added.
