Macrophage-killing bacterial toxin weakens the gut’s defenses against ulcerative colitis

Ulcerative colitis (UC) is one of the most common inflammatory bowel diseases, a lifelong condition that can cause chronic inflammation and ulcers in the lining of the large intestine. This can lead to symptoms such as rectal pain and bleeding, and persistent diarrhea. It is thought to be an autoimmune disease, but exactly what triggers it remains unclear.

However, a team of researchers led by Fangyu Wang, Xuena Zhang, and Minsheng Zhu at Nanjing University has discovered a bacterial toxin that destroys key immune cells that protect the gut, which may explain how the disease takes hold. The study is published in the journal Science.

Previous research has shown that macrophages, a type of immune cell that helps eliminate foreign substances (like pathogens and debris), are crucial for protecting the gut barrier and preventing inflammation. The team’s analysis of tissue samples revealed that these defenders were largely absent from the protective layer just beneath the colon’s surface in UC patients.

Identifying the culprit

To test their theory that something must be actively destroying gut macrophages, the scientists first studied fecal samples from people with UC and healthy individuals. They found a potent substance called aerolysin. This toxin, produced by bacteria of the Aeromonas genus, was found in 72% of samples from UC patients, compared with 12% of healthy individuals.

Aerolysin kills target cells by punching holes in their outer membrane, leading to rapid cell death. Because this toxin is so effective at killing protective immune cells, the study authors dubbed the specific aerolysin-producing strain macrophage-toxic bacteria (MTB).

To see if this bacterium and its toxin were responsible, the researchers infected mice models that had chemically induced colitis with MTB. As a result, symptoms such as weight loss, bleeding and ulcers worsened. When they introduced a genetically engineered version of the bacterium that could not produce aerolysin, there was no worsening of colitis. A final step was administering anti-aerolysin antibodies into MTB-infected mice, which relieved symptoms.

A new therapeutic approach?

The results were found primarily in mice, but if the research translates to humans, it could provide a new way to treat ulcerative colitis. Instead of the current approach of broadly suppressing a patient’s immune system, drugs could target the bacterial toxin, as the scientists discuss in their paper.

“Our findings highlight how microbes may contribute to UC pathogenesis and suggest that targeting bacterial virulence factors could be a therapeutic strategy for UC.”

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