An intestinal pathogen reshapes the gut environment to fuel its own colonization and cause diseases, a multi-institutional team including researchers at Vanderbilt Health has discovered.
The investigators showed that enterotoxigenic Bacteroides fragilis (ETBF), which causes diarrhea and has been implicated in colitis (inflammation of the colon) and colorectal cancer, uses a toxin it produces to reprogram intestinal cell metabolism and generate conditions that support its growth. The study, published April 30 in the journal Cell, points to new therapeutic strategies for disrupting the growth of pathogens like ETBF.
"Our findings suggest that disease-associated microbes don't just respond to inflammation — they can actively drive it by reshaping host metabolism. This opens up new possibilities for intervention, such as by targeting metabolic interactions between host and microbes to prevent or disrupt diseases like infectious diarrhea and colorectal cancer," said Wenhan Zhu, PhD, assistant professor of Pathology, Microbiology and Immunology and lead corresponding author of the study.
Zhu has long been interested in how pathogens succeed in the competitive intestinal environment.
"The gut is one of the most densely populated microbial environments in the body, with heavy competition for nutrients, yet certain microbes can still take hold and drive disease," he said. "These microbes are ultimately competing for nutrients, and processes like inflammation and cancer may be ways they alter the environment to gain access to those resources."
Though the percentage of people who carry ETBF varies from study to study, it can be a common member of the gut microbiota and is considered a classical anaerobe, a type of bacteria that requires low-oxygen conditions (such as those in the large intestine) to survive. It produces a toxin that interacts with intestinal host cells, causing inflammation and increasing oxygen and oxidative stress — conditions that are usually harmful to anaerobes like ETBF.
Zhu and colleagues are exploring how ETBF navigates and exploits these conditions, to gain insight into microbial physiology and host-microbe interactions, he said. In the current study, researchers showed in an animal model that:
- ETBF uses its toxin to reprogram intestinal epithelial cell metabolism.
- This metabolic shift reduces oxygen consumption by host cells, increasing oxygen availability in the gut.
- The resulting environment supports the growth of ETBF, despite it being traditionally considered an anaerobe.
- These changes also create conditions that promote disease-associated microbial communities linked to colorectal cancer.
"One of our most surprising findings was that a classically anaerobic bacterium can benefit from, and even help create, an oxygen-rich environment," Zhu said. " This challenges the traditional view that anaerobic microbes simply cannot tolerate oxygen."
The researchers also discovered that ETBF reshapes the intestinal landscape in unexpected ways, for example by driving epithelial cell proliferation and manipulating immune signaling pathways and bile acid biology.
They are continuing to explore how ETBF modifies its environment to successfully colonize and cause disease; how broadly the mechanisms apply across other microbes and disease settings; and whether these interactions can be therapeutically targeted.
"Ultimately, we hope to identify strategies to disrupt these disease-promoting niches before they lead to long-term pathology," Zhu said.
Four researchers contributed equally to the studies and are co-first authors: Luisella Spiga, PhD; Ryan Fansler; and Yifan Wu, PhD; all at Vanderbilt Health; and Alexandra Grote, PhD, at Northwestern University Feinberg School of Medicine. Also making significant contributions to the study were Madison Butler at Vanderbilt Health; Cynthia Sears, MD, at Johns Hopkins University; and co-corresponding author Ashlee Earl, PhD, at the Broad Institute of MIT and Harvard.
The research was supported by the National Institutes of Health (grants F31AI178950, R35GM147470, R01DK134692, R35GM150625, U19AI110818, U2CDK119886, OT2OD030544, U2CDK119889, P30CA068485 and P30DK058404); V Foundation; Colorectal Cancer Alliance; The G. Harold & Leila Y. Mathers Foundation; and the Jane Coffin Childs Memorial Fund for Medical Research.
