How a Gut Bacterium Rewires Colon Cells to Fuel Colitis and Colorectal Cancer
核心洞察
Enterotoxigenic Bacteroides fragilis (搜索) (ETBF) uses its BFT toxin to reprogram colon epithelial cells from oxygen-consuming metabolism toward glycolysis, causing oxygen accumulation and lactate secretion in the gut.
The metabolic shift creates an oxidative niche that ETBF exploits via a complete TCA cycle and lactate oxidation, generating energy more efficiently than competing anaerobic microbes.
In mouse models, restoring normal colonocyte metabolism with tributyrin or blocking bile acid recycling with maralixibat reduced infection and tumor burden.
A bacterial pathogen long implicated in colitis (搜索) and colorectal cancer (搜索) actively engineers a favorable metabolic environment in the inflamed gut rather than merely surviving within it, according to a study published in Cell. The findings, which detail how Enterotoxigenic Bacteroides fragilis (ETBF) rewires host epithelial cells, point toward both metabolic and immune-modulatory therapeutic strategies for ETBF-associated disease.
The research was co-authored by Alexandra Grote, PhD, assistant professor of Medicine in the Division of Infectious Diseases at Northwestern University Feinberg School of Medicine, in collaboration with a team led by Wenhan Zhu at Vanderbilt University.
A longstanding paradox resolved
Anaerobic pathogens thrive in oxygen-poor environments such as the human colon. ETBF causes disease by secreting a single virulence factor, B. fragilis toxin (BFT). Yet the pathogen also triggers gut inflammation, which raises local oxygen levels — creating an apparent paradox for an anaerobe.
"ETBF triggers gut inflammation, which raises oxygen levels, so how does a classically anaerobic bacterium survive, and even flourish, in the increasingly oxygenated environment it creates? That was the central question," Grote said.
Metabolic hijacking of colonocytes
Using genomics, metabolomics, mouse models, and hybrid-selection RNA sequencing, the investigators discovered that BFT internally rewires epithelial cells in the colon, shifting them from normal oxygen-consuming metabolism to glycolysis — the breakdown of glucose into energy.
"This has two consequences: oxygen accumulates in the gut lumen, and lactate is secreted as a byproduct. The bacterium is well-positioned to exploit both, expressing enzymes for a complete TCA cycle and coupling lactate oxidation to oxygen respiration, generating energy far more efficiently than competing gut microbes that rely solely on anaerobic fermentation," Grote explained.
BFT also hijacks the gut's bile acid recycling machinery by depleting compounds that normally suppress inflammatory IL-17-producing immune cells. This depletion drives further metabolic reprogramming of colonocytes and sustains ETBF colonization.
Therapeutic interventions in mouse models
The study tested several interventions in mouse models of colitis (搜索) and colorectal cancer (搜索). Restoring normal colonocyte metabolism with tributyrin, a dietary compound known to help repair the intestinal barrier and reduce inflammation, reduced both infection and tumor burden. Mice given maralixibat, a drug currently prescribed for liver disease, demonstrated blocked bile acid recycling and reduced disease.
"This work reframes how we think about anaerobic pathogens: rather than merely tolerating the inflammation they cause, ETBF appears to actively engineer an oxidative niche that it can exploit. The specific enzymes powering ETBF's oxygen-based metabolism are potential drug targets," Grote said. "Together, these findings suggest metabolic and immune-modulatory approaches to preventing or treating ETBF-associated colorectal cancer (搜索)."
The receptor connection: claudin-4 (搜索)
In a separate study published in Nature, researchers led by Cynthia Sears, MD, professor at Johns Hopkins University, identified the receptor through which BFT attaches to human gut cells. Using CRISPR-based screening, the team found that BFT binds to claudin-4 (搜索), a receptor found on human cells. When claudin-4 was lost, BFT could not attach to gut cells.
"We've made several attempts over time to identify the receptor, so this is an exciting moment," said Sears. "Understanding how bacterial toxins work can open doors to new approaches for detection and therapy for associated diseases, including diarrhea, colorectal cancer (搜索), and bloodstream infections."
The Johns Hopkins team also demonstrated a protective strategy in mouse models: a decoy molecule with similarities to claudin-4 (搜索) successfully bound to gut cells in place of BFT, shielding mice from toxin-induced gut damage. At least 20% of healthy people are thought to carry BFT, underscoring the potential population-level impact of such preventive strategies.
Next steps
Grote indicated that future work will focus on identifying the mechanisms by which BFT promotes the bacterium's own oxygen tolerance and further validating potential therapeutic approaches. "Our team also aims to develop more physiologically realistic infection models and to explore whether the therapeutic strategies identified here, particularly tributyrin and targeted inhibition of ETBF's oxidative metabolism, can be translated toward clinical use," she said.
The Cell study was supported in part by a Jane Coffin Childs Memorial Fund for Medical Research postdoctoral fellowship.