Patients with colitis are particularly susceptible to infection by the toxin-producing bacteria Clostridium difficile, but the reason remained unknown. Now, researchers have discovered that changes in the immune system, namely high levels of Th17 immune cells, are the key drivers worsening the infection.
Moreover, levels of a cytokine called interleukin (IL)-6 help identify those at higher risk of severe infection.
“When you look at how much bacteria are growing or how much toxin is being produced, a lot of time there is no direct correlation,” Mahmoud Saleh, the study’s first author, said in a press release. “Now we know that what’s making that difference is this immune response.”
The study, “Colitis-Induced Th17 Cells Increase the Risk for Severe Subsequent Clostridium difficile Infection,” was published in the journal Cell Host & Microbe.
C. difficile infection is currently the most common hospital-acquired infection, but it is more common and severe among patients with inflammatory bowel disease (IBD), especially those with colitis.
However, the cause of increased incidence and severity of the infection among IBD patients was unknown.
Scientists had long believed that the severity of C. difficile infection was simply linked with the bacteria’s ability to secrete toxins that damage the body. As so, more bacteria would mean increased toxins and more damage.
Researchers at the University of Virginia School of Medicine, however, hypothesized that the abnormal gut inflammation seen in IBD could increase the severity of C.difficile infection.
“When we, as a lab, started working on this, we were actively discouraged from working on C. difficile because [some] people in the field thought, ‘Oh, this is a toxin-mediated disease. You don’t need to understand anything more than the fact that the bacteria make toxins,’ ” said William A. Petri Jr., the study’s lead author.
Their work shows that colitis patients have an excessive immune response against the bacteria and that this actually causing more tissue damage.
“It’s been a wonderful opportunity for us because we went in and we sort of countered the prevailing wisdom. Yes, the toxins are important, but the toxins are important because they affect the immune system in dramatic ways,” he said.
Researchers used a mouse model of colitis where the animals were treated with dextran sulfate sodium (DSS), recovered for two weeks, followed by infection with C. difficile.
They saw that the DSS treatment changed the animals’ immune system. Specifically, a type of immune cells called Th17 became hyperactive and primed to cause a severe reaction in a subsequent C. difficile infection.
“If we infect a [mouse] a month later, we see that these [T helper cells] alone can cause severe infection,” Saleh said. “[These] cells are sufficient for that increased severity of C. difficile infection.”
Isolating Th17 cells and transferring them to mice before C. difficile was sufficient to increase the infection’s severity.
To know whether these findings were also relevant for humans, researchers analyzed levels of two cytokines (immune signaling molecules), called IL-6 and IL-23, which mediate the activity of Th17 cells.
Analysis of blood samples showed that patients with severe infection had significantly higher levels of IL-6 and IL-23 compared to those with milder infections.
Patients with high levels of IL-6 had almost eight times the risk of death associated with C.difficile infection compared to patients with low levels.
“Now we know from Mahmoud’s work that if I, as a physician, measure IL-6 in one of my patients with inflammatory bowel disease, I’ll be able to know how severe disease will be in that person and I can make the decision about whether the person needs to be admitted to the hospital … or even go to the intensive care unit,” Petri said.
These results suggest that targeting Th17 cells could have therapeutic potential for colitis patients infected with C. difficile.
“These findings establish a central role for Th17 cells in [Clostridium difficile infection development] following colitis and identify them as a potential target for preventing severe disease,” the researchers stated.
“We know that in mice by targeting T cells we protect from disease, and that leads to the question, could we do something similar and people to provide better therapy?” Petri said.
“It is an interesting and terrible situation right now that C. diff is not resistant to antibiotics, but is resistant to treatment. And so even though we have very, very good antibiotics for this, the [body’s] response is so severe that even though we’re killing the bacteria with the antibiotics, patients are suffering from their own immune response,” he added.
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