For more than 15 years, scientists have known that a toxin produced by a common gut bacterium could damage the cells lining the human colon, but the precise mechanism by which it entered those cells remained a stubborn mystery. A new discovery, published in the journal Nature in 2025 by researchers at Johns Hopkins Medicine, has finally solved that puzzle, opening a concrete path toward potential new treatments for colorectal cancer, the third most common cancer in the United States.
How a Gut Bacterium’s Toxin Gains Entry
The human gut is home to trillions of bacteria, most of which are harmless or even beneficial. However, certain strains of one common resident, Bacteroides fragilis, produce a toxin known as BFT. Since the early 2000s, scientists have understood that this toxin can damage the delicate lining of the colon, triggering chronic inflammation that has long been suspected of paving the way for cancer. What they could not determine was exactly how the toxin got inside human colon cells to begin its destructive work.
The Johns Hopkins team has now identified the answer. They found that the BFT toxin must first latch onto a specific protein called claudin-4 on the surface of colon cells.
Only after this binding occurs can the toxin slip inside the cell and cause damage. Claudins are a family of proteins that normally act as gatekeepers, serving as the main components of tight junctions—the seals that control what passes between cells in the lining of the gut and other organs. These small proteins span the cell membrane four times, with both ends inside the cell, and their job is to maintain the barrier that keeps harmful substances out.
The discovery that one particular claudin, claudin-4, serves as the entry point for the BFT toxin turns that protective function on its head.
A Clear Target for Drug Developers
The finding gives drug developers a clear and concrete target. If researchers can design a therapy that blocks the handshake between BFT and claudin-4, they could potentially prevent the toxin from ever entering a cell.
This could stop the chronic inflammation that the toxin triggers before it starts, interrupting the chain of events that begins when a common gut bacterium releases its harmful payload. Dr. Rosario Ligresti, a gastroenterologist at Hackensack University Medical Center who was not involved in the study, said the findings strengthen the evidence for a causal link between the bacterial toxin and colorectal cancer. The research solves a puzzle that has frustrated scientists since the early 2000s.
They knew the BFT toxin was dangerous, but they could not figure out exactly how it entered colon cells. The identification of claudin-4 as the gateway protein changes the picture entirely.
Colorectal cancer is the third most common cancer in the United States. Chronic inflammation has long been suspected as a key driver of the disease, and the BFT toxin triggers exactly that kind of inflammation in the gut lining. By identifying claudin-4 as the gateway, researchers now have a clear target for intervention.
Future Research and Potential Therapies
So what comes next? Future research, Dr. Ligresti noted, could focus on targeting claudin-4 itself or going after the BFT toxin directly. Both approaches aim to reduce cancer risk by interrupting the chain of events that begins when a common gut bacterium releases its harmful payload.
The implications are direct: blocking the binding between the toxin and this protein could prevent the toxin from ever entering a cell, potentially stopping the inflammatory process before it starts. For now, the work remains in the research phase.
The finding solves a puzzle that has persisted for more than 15 years, giving drug developers a concrete place to aim. Future therapies could target claudin-4 itself or the BFT toxin directly. For patients and doctors, that means the possibility of a treatment that addresses one root cause of colorectal cancer rather than just managing its symptoms.
Consult your doctor for medical advice.
