C. diff uses toxic compounds to gain competitive advantage in the intestine

Pathogen C. diff – the most common cause of medically related infectious diarrhea – survives and grows using compounds that kill microorganisms in the human intestine, giving them a competitive advantage in infected intestines.

The team led by investigators at Vanderbilt University Medical Center is C. We have discovered how Diff (Clostridioides difficile) converts the toxic compound 4-thiouracil, which can arise from foods like broccoli, into usable nutrients. Their findings were published in the journal on March 25th Cell hosts and microorganismsC. It enhances understanding of molecular drivers for diff infection and points to new treatment strategies.

C. DIFF causes approximately 500,000 infections in the United States each year, according to the Centers for Disease Control and Prevention. Factors that increase the risk of C. diff infection include antibiotic use, age 65 and over, and recent stays in hospitals and other medical facilities.

Like other pathogens, C. Diffs need to acquire nutrients to survive and grow.

“I'm interested in trying to understand the nutrients that C. diff needs during an infection, and how what you eat affects what C. diff eats in your gut,” said first author of the study, Dr. Eric Scarle, MPH, and Matthew Munneke, Goodpasture Director at the Goodpasture Institute at the Goodpasture Institute at the Vandabilt Institute, the study's first author. inflammation.

This group focused on nucleotides, the building blocks of DNA and RNA. This is C. A class of nutrients that has not been well studied for diff.

The researcher is C. Discover that diff must acquire certain types of nucleotides (pyrimidines) to cause infection, C. We discovered an enzyme named Tuds (thiouracil desulfurase) that dif uses to recover pyrimidine nucleotide uracil from related compounds: 4-thiouracil.

They showed that 4-thiouracil was incorporated into RNA and was toxic to resident gut microorganisms that did not carry the TUDS enzyme. But C. In Diff, Tuds modify and detoxify 4-Thiouracil and become available as a nutrient. Researchers have demonstrated that TUD contributes to C. diff “fitness” to a new minibioreactor model containing mice fed 4-thiouracil and bacterial communities isolated from human feces by adding 4-thiouracil.

We consider 4-thiouracil metabolism to be beneficial for C. diff. Because it acts as a nutrient to burn fuel to bacteria and can inhibit adjacent bacteria, C. Gives Diff an even more competitive advantage within the intestinal environment. ”

Matthew Munneke, the first author of the study

TUDS enzyme is C. It may represent a new therapeutic target to treat Diff infections. C, as it is not present in the gut microorganisms (or human cells) of many residents. Antibiotics that target it to kill diffs may help maintain healthy gut microbiota, he noted.

The researchers also showed that adding C. diff tuds to the probiotic strain in the E. coli model blunts the fitness benefits of C. diff in the in vitro model.

“It may be possible to use probiotics with this enzyme to reduce the ability of C. diff to flourish and push out in the gut,” Munneke said.

Researchers have shown that 4-thiouracil is present in the human intestine, but the source of this compound is unknown. Livestock that consume dietary rich diets in cruciferous vegetables (such as kale and other lush greenery, broccoli, cauliflower) have increased levels of 4-thiouracil, suggesting that nutrient sources may contribute to the presence of 4-thiouracil in human GUT.

“More research is needed to understand the cause of 4-thiouracil, but if it comes from the diet, it can inform the dietary intervention of C. diff infection,” Munneke said.

However, it is not time to give up on eating cruciferous vegetables. In healthy intestines, some resident microorganisms contain TUDS-related enzymes, which may convert 4-thiouracil into nutrients. Munneke said these microorganisms may be missing in the intestines of C. diff infections.

Other VUMC authors Cell hosts and microorganisms The paper includes Dr. Katherine Shelton, Dr. Darian Carroll, Nicole Kirkoff, Ph.D., Martin Douglas, Ph.D., M. Wade Calcutt, Ph.D., Katherine Gibson Corey, DVM, Ph.D., Maribeth Nicholson, MD, MPH, Mariana Bynus, DVM, PHD. Collaborators from the University of Florida and Baylor School of Medicine contributed to the research.

This study was supported by grants from the National Institutes of Health (R01AI164587, U19AI174999, R01GM070641, T32ES007028, F31AI172352, K23AI156132, U19AI157981).