Bladder cancer ranks as the tenth most prevalent cancer globally and is frequently associated with exposure to harmful substances, particularly those found in tobacco smoke. Recent research indicates that gut bacteria may significantly influence the development of bladder cancer. The study demonstrates that particular gut microbes can alter a specific group of carcinogens present in cigarette smoke, transforming them into related chemicals that build up in the bladder and potentially lead to tumor formation.
Our intestines are home to more than 10 trillion microbes at any moment. These microorganisms play a vital role in various bodily functions, from digesting food to enhancing our immune defense against diseases. A recent study conducted by researchers from EMBL, alongside their colleagues from the University of Split in Croatia, highlights the role these microbes may have in how our body deals with carcinogens and cancer development.
Carcinogens are substances that can cause normal cells to change into cancerous cells, resulting in tumors. Tobacco smoke is one of the best-known sources of these harmful chemicals. Prior research indicated that when mice were exposed to BBN, a nitrosamine found in tobacco, they regularly developed a severe form of bladder cancer, making this a common model for studying carcinogen-related cancer.
During their research, JanoÅ¡ Terzić’s team at the University of Split observed something intriguing. Mice that received antibiotics—at a dose effective enough to eliminate 99.9% of their gut bacteria—while being exposed to BBN had a considerably lower risk of developing tumors.
“While 90% of mice exposed to BBN developed bladder tumors, only 10% of those treated with antibiotics did,” stated Blanka Roje, a co-author of the study and PhD student at the Laboratory for Cancer Research, University of Split School of Medicine in Croatia. “The sight of BBN and BCPN bands on thin-layer chromatography plates after incubating bacteria and BBN overnight is something I’ll always remember.”
“The reduction in tumor occurrence was so significant that I questioned our results at first, suspecting a potential error in our experiments. We repeated the study five times before we became convinced of our findings,” Terzić remarked. “It was remarkable to find that by using a simple treatment—antibiotics—we could stop cancer development.”
While attending a conference at EMBL Heidelberg, Terzić connected with Michael Zimmermann, a group leader at EMBL, whose team focuses on using high-throughput techniques to investigate gut microbiome functions, specifically in the area of biotransformation. Biotransformation refers to how microorganisms can modify or degrade chemicals in their environment.
This initial interaction led to a productive collaboration. The two groups collaborated to examine the influence of gut bacteria on how the mice reacted to the carcinogen. By applying various microbiology and molecular biology techniques, the researchers found that the gut bacteria in mice could convert BBN into BCPN. Like BBN, BCPN is also a type of nitrosamine, but unlike BBN, BCPN accumulates in the urinary bladder and can lead to cancer based on the microbiome present.
Next, the team researched over 500 isolated and cultured bacterial strains to pinpoint the specific species responsible for converting BBN to BCPN. “We identified 12 species capable of performing this transformation,” noted Boyao Zhang, co-author of the study and a former PhD student in the Zimmermann group. “Sequencing these showed that many were typically found on the skin and existed in lower quantities in the gut. We theorized that such bacteria could transiently move from the skin to the gut during grooming. However, it was crucial to determine if these findings were applicable to humans as well.”
Following their initial experiments in mice, the researchers utilized human fecal samples to demonstrate that human gut bacteria could similarly convert BBN to BCPN. As a proof of concept, they transplanted human stool into the intestines of germ-free mice, confirming that the bacteria could convert BBN to BCPN.
However, the study also revealed significant variability in how different individuals’ gut microbiomes influenced BBN metabolism and the bacterial species involved in this transformation. “We believe this sets the stage for further studies to determine whether an individual’s gut microbiome could indicate a susceptibility to cancer from chemical exposure and potentially help predict cancer risk and develop preventive strategies,” Zimmermann explained.
“These differences in gut microbiota may help clarify why some individuals, despite being exposed to carcinogens, do not develop cancer while others do,” Terzić added.
But does this mean that antibiotics can serve as a universal cancer prevention method? Zimmermann clarifies that this is not the case. “More studies are necessary, including some we are currently conducting, to understand how the microbiome affects the processing of various carcinogens. It is also crucial to keep in mind that cancer arises from multiple factors—there seldom exists a single cause.”
This research is in line with EMBL’s themes on Microbial Ecosystems and Human Ecosystems as part of its 2022-26 Programme titled ‘Molecules to Ecosystems’. The Microbial Ecosystems theme is focused on investigating microorganisms and their interactions, while the Human Ecosystems theme aims to leverage growing human data to explore how genes and environment interact and impact human traits. For more details on these research initiatives, click here.
