ETBF is a subtype of Bacteroides fragilis that carries the gene for Bacteroides fragilis toxin, known as BFT. The bacterium has been linked to diarrheal disease, inflammatory bowel disease and colorectal cancer, and colonization is known to be associated with long-term disturbances of intestinal motility. What remained unclear was precisely how a toxin famous for cleaving epithelial junctions could leave the gut’s movement machinery permanently impaired. The Shanghai team approached the question using mouse colonization models in which animals were inoculated with ETBF and followed over weeks, allowing the researchers to track both the microbial load and the structural integrity of the colonic myenteric plexus, the network of neurons embedded in the gut wall that orchestrates peristalsis.

The answer was stark. ETBF colonization triggered the loss of colonic myenteric neurons, and the effect depended entirely on BFT: mice colonized with a genetically engineered ETBF strain lacking the bft gene were largely protected. The toxin did not merely stun the neurons; it drove them into apoptosis, a programmed cell death routine. Critically, the neuronal loss and the accompanying motility dysfunction persisted even after the bacteria themselves had been cleared from the gut, a finding that echoes the clinical phenomenon of post-infectious gut disorders, in which symptoms linger long after the offending pathogen has disappeared. The researchers measured this dysfunction using gastrointestinal transit time and ex vivo recordings of colonic strip contractions, both of which deteriorated in colonized animals.

Having established that BFT kills enteric neurons, the team dissected the molecular pathway inside the cells. The toxin’s lethal signal, they found, runs through NOD1, an intracellular pattern-recognition receptor, which recruits its adaptor protein RIPK2 and then activates a caspase cascade: caspase-9, the initiator of the intrinsic apoptotic pathway, followed by caspase-3, the executioner. When the researchers knocked out Nod1 in mice, the BFT-induced neuronal apoptosis and dysmotility were markedly attenuated, confirming that this receptor, better known for sensing bacterial peptidoglycan and driving inflammatory responses, also functions as a death switch in enteric neurons when provoked by BFT. The pathway is notable because NOD1 has previously been identified as a functional receptor for BFT in cancer contexts, suggesting the toxin may have co-opted a host surveillance system for destructive purposes across multiple cell types.

The second half of the study addresses a question that has intrigued microbiome researchers for years: why do ETBF and Fusobacterium nucleatum so often appear together in diseased guts? Analyses of patient cohorts with inflammatory bowel disease and colorectal cancer revealed a positive correlation between the abundance of the two organisms, hinting at a cooperative rather than coincidental relationship. To test this directly, the researchers co-colonized mice with both species. The result was dramatic: the presence of F. nucleatum significantly aggravated the ETBF-induced loss of myenteric neurons and worsened gut dysmotility, and the effect again required bft, indicating that the oral pathobiont was not adding its own toxin but rather turning up the volume on ETBF’s.

The mechanism behind this microbial collusion proved to be a small molecule. F. nucleatum produces 2-hydroxybutyric acid, or 2HB, a metabolite generated through lactate dehydrogenase activity. When ETBF is exposed to 2HB, the toxin gene bft is transcribed at far higher levels. The team showed that 2HB physically binds to RprY, a regulatory protein in ETBF that normally represses bft transcription. By occupying RprY, the metabolite lifts this repression, derepressing the toxin gene without altering other virulence genes controlled by the regulator. In other words, one bacterium’s metabolic waste product acts as a molecular key that unlocks another bacterium’s most dangerous weapon. Administering 2HB to mice colonized with ETBF alone reproduced the aggravating effect, while F. nucleatum strains engineered to overproduce the metabolite intensified neurotoxicity further, and the researchers confirmed that multiple F. nucleatum subspecies produce 2HB in culture.

The clinical implications extend beyond motility. The study found that the enteric neuron loss and dysmotility induced by ETBF increased susceptibility to dextran sulfate sodium-induced colitis in mice, linking the neural damage to a weakened mucosal defense. This connects with a growing body of evidence that the enteric nervous system is not merely a passive conduit for brain signals but an active participant in intestinal immunity and barrier maintenance. Previous work has shown that other pathogens, from Shigella to Clostridioides difficile, can target enteric neurons, and that neuronal loss in conditions such as Chagas disease and Hirschsprung disease produces profound motility defects. The new study adds a bacterial cooperation model to this landscape, in which the composition of the microbiome determines how much toxin a colonizing pathogen actually delivers.

Human relevance was reinforced by tissue analyses. In colonic specimens from ulcerative colitis patients, the researchers detected the bft gene in mucosal tissue and observed myenteric neurons positive for NOD1, RIPK2, cleaved caspase-9 and cleaved caspase-3, the same molecular signature seen in the mouse model, with the staining pattern more prominent in patients suffering from constipation. While such observational data cannot prove causation in humans, the concordance between the animal pathway and the human tissue findings strengthens the case that the mechanism operates in clinical disease.

Perhaps the most immediately actionable finding concerns therapy. The researchers tested Bifico, a commercially available probiotic formulation containing Bifidobacterium species, in their mouse model. Treatment attenuated the neuronal toxicity, improved intestinal motility and reduced the severity of subsequent colitis. Bifidobacterium longum alone recapitulated much of the protective effect, and the probiotic did not simply eradicate ETBF; rather, it appeared to interfere with the processes that drive toxin production and neuronal death. Given that probiotics are inexpensive, widely available and generally safe, the finding suggests a plausible strategy for preventing the long-term neurological consequences of ETBF colonization, although the authors and independent observers caution that mouse models do not always translate to human therapy and that controlled clinical trials would be needed.

The study, published in Nature Microbiology with the DOI 10.1038/s41564-026-02497-y, is likely to resonate across several fields at once. For microbiome researchers, it provides a textbook example of metabolic cross-feeding with pathological consequences, in which a diffusible small molecule from one species reprograms virulence gene expression in another. For neurogastroenterologists, it identifies a specific toxin-receptor-caspase axis that destroys the neurons governing bowel movement, offering potential drug targets in NOD1, RIPK2 or the caspases themselves. And for clinicians treating patients with post-infectious bowel dysfunction, irritable bowel symptoms or inflammatory bowel disease, it raises the possibility that screening for ETBF and F. nucleatum co-colonization, and perhaps manipulating the microbiome to reduce 2HB production or boost protective Bifidobacterium, could one day prevent the slow, silent loss of the gut’s own nervous system. The data and bacterial strains underlying the work have been deposited in public repositories, including a Zenodo archive of the neuronal RNA-sequencing data, allowing other laboratories to build on the findings immediately.

Subject of Research: Bacterial cooperation between Fusobacterium nucleatum and enterotoxigenic Bacteroides fragilis in enteric neuron loss and intestinal dysmotility

Article Title: Fusobacterium nucleatum enhances enterotoxigenic Bacteroides fragilis-mediated neuron loss and intestinal motility dysfunction

Article References: Zhang, Y., Zhao, Y., Zhang, L., Xuan, B., Wang, Z., Yu, B., Li, W., Huang, X., Zhou, Y., Ning, L., Ding, J., Jiang, Y., Hu, M., Shao, Y., Li, L., Gao, X., Chen, S., Chen, H., Wang, F., … Hong, J. (2026). Fusobacterium nucleatum enhances enterotoxigenic Bacteroides fragilis-mediated neuron loss and intestinal motility dysfunction. Nature Microbiology. https://doi.org/10.1038/s41564-026-02497-y

Image Credits: AI Generated

DOI: 10.1038/s41564-026-02497-y

Keywords: Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, Bacteroides fragilis toxin, enteric nervous system, gut dysmotility, 2-hydroxybutyric acid, NOD1, apoptosis, gut microbiota, inflammatory bowel disease, probiotics, Bifidobacterium