Treatments That Leverage SCFAs May Be Effective in Clostridioides difficile Infection

Exploring how short-chain fatty acids (SCFA) affect Clostridioides difficile infection (CDI), researchers of a new study suggest that these molecules may have potential as therapeutic targets for CDI treatment.

Citing outbreaks of CDI in both America and Europe, the researchers emphasized the need for more effective treatments. They note that while antibiotics are the preferred treatment for the infection, they interfere with intestinal microbiota, which increases the risk of recurrent infection.

“Fecal microbiota transplantation (FMT) has received much attention in recent years and is safer and more effective for [recurrent] CDI than antibiotics,” explained the group.

They continued, “Some studies suggest that FMT can restore the richness and diversity of the intestinal microbiota, increasing the production of short-chain fatty acids (SCFAs), regulating bile acid metabolism, and improving intestinal barrier function and host immune function. SCFAs reduce intestinal inflammation, inhibit intestinal tumors, and regulate intestinal homeostasis. Moreover, SCFAs reduce CDI or directly inhibit C. difficile growth through multiple pathways in vivo and in vitro, respectively.”

The researchers outlined the effect of different types of SCFAs on C. difficile, including acetate, which improves immune function and stimulates immune cells to secrete anti-inflammatory cytokines to reduce CDI.

According to the researchers, the acetyl group in potassium acetate is able to mitigate toxicity to colonocytes by C. difficile toxin A, a toxin that activates histone deacetylase-6 (HDAC-6) in intestinal epithelial cells and results in mucosal damage. By also binding to HDAC-6, the acetyl group in potassium acetate is able to inhibit toxin A-induced tubulin deacetylation and subsequent microtubule disassembly.

The group also described the SCFA butyrate’s ability to enhance innate antimicrobial immunity and cytokine-mediated immune response. Previous work has found that butyrate treatment is able to hinder intestinal inflammation and bacterial translocation by reducing intestinal permeability. While the most effective application of butyrate for CDI has not been determined, the researchers note that several butyrate-increasing interventions improve infection.

Other research has shown that in patients with CDI, FMT was able to increase levels of valerate levels, which dropped significantly during treatment with clindamycin and remained diminished after treatment. Following FMT, C. difficile total viable counts dropped by 94% and spore count dropped by 86%.

The researchers also described certain intestinal SCFAs, such as succinate, that actually promote CDI.

“Succinate is a byproduct of primary fermenters such as Bacteroides thetaiotaomicron and is utilized by secondary fermenters in the gut. Antibiotic treatment significantly decreased the levels of acetate and butyrate while increasing succinate levels in mice,” explained the researchers.

“The genes involved in the use of succinate were highly expressed under conditions that favored C. difficile growth, and an increase in succinate levels following antibiotic treatment favored the proliferation of C. difficile,” they said.

The researchers cited a mouse study that suggested inhibiting C. difficile’s ability to utilize succinate can potentially prevent and treat CDI. The study showed that viable counts and butyrate levels were lower in a C. difficile mutant strain that lacked putative succinate transporter than in a wild-type strain.

Reference:

Ouyang Z, Niu X, Wang W, Zhao J. The role of short-chain fatty acids in Clostridioides difficile infection: A review. Anaerobe. Published online May 8, 2022. doi:10.1016/j.anaerobe.2022.102585