Scientists Identify Gut Microbes as Key Players in Cancer Development

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Scientists Identify Gut Microbes as Key Players in Cancer Development

Scientists Identify Gut Microbes as Key Players in Cancer Development

Bladder cancer ranks as the tenth most common cancer worldwide, often linked to exposure to harmful chemicals, such as those found in tobacco smoke.

However, groundbreaking research by scientists at EMBL Heidelberg, in collaboration with the University of Split in Croatia, has revealed that bacteria residing in our gut may also play a crucial role in the development of bladder cancer.

Reference: Gut microbiota carcinogen metabolism causes distal tissue tumors

In a series of experiments, researchers demonstrated that certain gut bacteria can transform carcinogens, commonly found in cigarette smoke, into related chemicals that accumulate in the bladder and contribute to tumor formation.

Our gut is home to over 100 trillion microorganisms at any given time. These microbes are essential to our interaction with the world, from breaking down nutrients in our food to bolstering our immune response against pathogens. The recent study conducted by EMBL researchers and their Croatian collaborators has highlighted another critical role of these microorganisms: influencing the body’s response to carcinogens and the subsequent development of cancer.

Carcinogens are chemicals that can convert normal cells into cancerous ones, initiating tumors and cancer. They are found in many places, with tobacco smoke being a prominent source. Previous research had shown that exposure to the tobacco smoke-derived chemical BBN (N-butyl-N-(4-hydroxybutyl)nitrosamine) in mice invariably led to the development of aggressive bladder cancer. Consequently, BBN has become a standard model in laboratory studies for carcinogen-induced cancer.

However, researchers at the University of Split’s Janoš Terzić Laboratory observed something unusual while studying this model. When mice were administered antibiotics—doses sufficient to kill 99.9% of their gut bacteria—and simultaneously exposed to BBN, their likelihood of developing tumors was significantly reduced.

“While 90% of mice exposed to BBN developed bladder tumors, only 10% of those treated with antibiotics did,” said Blanka Roje, a doctoral student at the University of Split School of Medicine and one of the study’s lead authors. “This led us to hypothesize that gut bacteria might play a role in how BBN is processed in the body.”

“The reduction in tumor incidence was so striking that I initially doubted the results, thinking we must have made a mistake somewhere in the experiment. So, we repeated the experiment five times before we were completely convinced. It’s incredible that we could prevent cancer development with just one treatment—in this case, antibiotics.”

At a conference held at EMBL Heidelberg, Terzić met with Michael Zimmermann, a group leader at EMBL specializing in high-throughput methods to study gut microbiota functions, with a particular focus on biotransformation. Biotransformation refers to the ability of microorganisms to modify or break down chemicals in their environment.

This meeting led to a productive collaboration between the two groups. They combined their expertise to investigate whether and how gut bacteria influence mice’s response to carcinogens. Using various microbiological and molecular biology techniques, the researchers discovered that bacteria in the mouse gut could convert BBN into BCPN, another nitrosamine compound. Unlike BBN, however, BCPN accumulates in the bladder and triggers tumor formation in a microbiome-dependent manner.

The researchers then studied over 500 isolated and cultured bacterial species to identify the specific strains responsible for converting BBN to BCPN. “We identified 12 species capable of this carcinogen biotransformation. To our surprise, many of these species are commonly associated with the skin and are relatively rare in the gut. We speculate that these bacteria may transiently migrate from the skin to the gut in animals. However, it is crucial to determine whether these findings also apply to humans,” said Boyao Zhang, one of the study’s lead authors.

Following these initial studies in mice, the scientists used human fecal samples to show that human gut bacteria can also convert BBN into BCPN. As proof of concept, they demonstrated that transplanting human feces into germ-free mice enabled these mice to carry out the same conversion.

However, the researchers observed significant individual differences in the human gut microbiome’s ability to metabolize BBN, as well as in the bacterial species involved in the biotransformation.

“We believe this sets the stage for further research into whether a person’s gut microbiome represents a susceptibility to chemical carcinogenesis. This could potentially be used to predict individual risk and possibly prevent cancer development,” said Zimmermann.

“These differences in the microbiome between individuals might explain why some people develop cancer despite exposure to potential carcinogens, while others do not,” Terzić added.

Does this mean antibiotics could be used universally to prevent cancer? “No, certainly not,” Zimmermann cautioned. “More research is needed, including studies we’re currently conducting, to understand how the microbiome affects the metabolism of different types of carcinogens. It’s also important to remember that cancer is a multifactorial disease, rarely caused by a single factor.”

This research aligns with EMBL’s transversal themes on microbial ecosystems and human ecosystems, introduced in its 2022-26 program “Molecules to Ecosystems.” The microbial ecosystems theme aims to explore microbes and their interactions with the environment, while the human ecosystems theme seeks to leverage rapidly expanding human datasets to explore gene-environment interactions and their effects on human phenotypes.