Clostridioides Difficile Thrives in Inflamed Environment

Clostridioides difficile thrives in an inflamed environment by generating toxins that support prolonged infection, according to a study from North Carolina State University.

The study, published in Nature Communications, showed how C. diff produces toxins that cause inflammation, eliminating competing bacteria and releasing peptides and amino acids that support growth of C. diff.

“C. diff thrives when other microbes in the gut are absent – which is why it is more prevalent following antibiotic therapy,” corresponding author Casey Theriot, PhD, associate professor of infectious disease at North Carolina State University, said. “But when colonizing the gut, C. diff also produces two large toxins, TcdA and TcdB, which cause inflammation. We wanted to know if these inflammation-causing toxins actually give C. diff a survival benefit – whether the pathogen can exploit an inflamed environment in order to thrive.”

Investigators examined two variants of C. diff in vitro and in an antibiotic-treated mouse model. The variants included a wild type C. diff that produces toxins and a genetically modified variant that does not. They found that the wild type C. diff, associated with toxin production, generated more inflammation and tissue damage than the mutant.

Investigators also found changes in the expression of metabolic genes, with C. diff in the inflamed environment expressing more genes related to carbohydrate and amino acid metabolism that sustains growth.

“C. diff’s toxins damage the cells that line the gut,” Theriot said. “These cells contain collagen, which is made up of amino acids and peptides. When collagen is degraded by toxins, C. diff responds by turning on expression of genes that can use these amino acids for growth.”

Inflammation provided a second benefit to C. diff by creating an inhospitable environment for other bacteria that compete for nutrients. Bacteroidaceae were present in control groups that weren’t infected with toxin-producing C. diff, which was consistent with previous studies that found negative associations between C. diff and Bacteroidaceae.

“I always found it interesting that C. diff causes such intense inflammation,” first author Josh Fletcher, PhD, former postdoctoral researcher at North Carolina State University, said. “Our research shows that this inflammation may contribute to the persistence of C. diff in the gut environment, prolonging infection.”

C. diff is the most significant cause of hospital-acquired diarrhea, causing more than 223,900 infections and 12,800 deaths in the US in 2017, according to a recent report.

The disease has two phases, a spore phase and vegetative phase. Toxins are released during the vegetative phase, causing the diarrhea and other symptoms. But the pathogen is often transmitted during the spore phase, during which it is hardy and isn’t susceptible to gastric acids and alcohol-based hand sanitizer, experts explained during a recent discussion of the disease.

Risks for infection include exposure to C. diff spores and antibiotic use. An investigational drug to prevent the disruption of the gut microbiota by antibiotics is among the most recent developments in the fight against C diff infection.