An international research team headed by scientists at Vanderbilt University Medical Center has shown how an intestinal pathogen reshapes the gut environment to fuel its own colonization and cause disease. The team’s studies found that enterotoxigenic Bacteroides fragilis (ETBF) uses a toxin it produces, Bacteroides fragilis toxin (BTF), to reprogram intestinal cell metabolism and generate conditions that support its growth. ETBF is a classically anaerobic bacterium that causes diarrhea and has been implicated in inflammatory diseases, including colitis and colorectal cancer. The study findings point to potential new therapeutic strategies for disrupting the growth of pathogens such as ETBF.

“Our findings suggest that disease-associated microbes don’t just respond to inflammation—they can actively drive it by reshaping host metabolism,” stated Wenhan Zhu, PhD, assistant professor of pathology, microbiology and immunology. “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.

Zhu is lead corresponding author of the team’s published paper in Cell, titled “An anaerobic pathogen rewires host metabolism to fuel oxidative growth in the inflamed gut.” In their paper the team wrote, “Here, we demonstrate that ETBF leverages its virulence factor, BFT, to reprogram epithelial cell metabolism, thereby reshaping the gut nutritional landscape. This reprogramming leads to increased levels of lactate and oxygen, which fuel ETBF’s unique oxidative metabolism.”

Independent studies have implicated ETBF in both inflammatory diarrheal diseases and in colorectal cancer, the authors noted. “These pathogenic effects are primarily driven by the virulence factor Bacteroides fragilis toxin (BFT), which elicits a range of physiological alterations in host cells.” However, the team noted, “… the specific mechanisms by which BFT facilitates ETBF niche establishment and promotes persistent colonization in the gut remain largely undefined.”

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, BFT, that interacts with intestinal host cells, causing inflammation and increasing oxygen and oxidative stress—conditions that are usually harmful to anaerobes such as 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. Through their newly reported study the investigators found that ETBF uses its toxin, BFT, to reprogram intestinal epithelial cell metabolism.

The researchers 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. “BFT manipulates colonic epithelial signaling and the bile acid recycling pathway, inducing a metabolic shift in the epithelium from oxidative phosphorylation to glycolysis,” they wrote.

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. “This shift increases local concentrations of lactate and oxygen, nutrients that support oxidative metabolism in ETBF,” they continued. 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 team is 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. In their report the investigators stated, “… by sculpting an oxidative niche, ETBF both fuels its own growth and suppresses its microbial competitors. Importantly, this distinct metabolic program could potentially be leveraged to selectively target and remove ETBF.” Zhu added, “Ultimately, we hope to identify strategies to disrupt these disease-promoting niches before they lead to long-term pathology.”

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