Each year, Clostridioides difficile infection affects 500,000 people in the United States, posing a serious, sometimes life-threatening challenge due to its resistance to treatment. Now, a study explores promising alternative approaches for more effective treatment.

The findings, published in Cell Host & Microbes, suggest that nutrient competition is the main mechanism of C. difficile inhibition, hinting at the potential for targeted therapies.

Until now, the main treatment for C. difficile infection has been fecal microbiota transplants (FMT), which transfer gut microbes from healthy donors to patients. While FMTs have been effective, they come with safety risks.

This prompted Shuchang Tian at Pennsylvania State University and her colleagues to seek safer alternatives. To do so, the researchers analyzed 12 studies with a total of 899 samples. 

Fighting infection

C. difficile colonization was linked to a reduced microbial diversity in the gut. Using machine learning models, the team identified key microbial features that could predict whether a person was colonized with C. difficile, based on their microbiota composition alone, with an accuracy of about 80%. Bacteria such as Faecalibacterium prausnitzii and Bacteroides species were associated with low C. difficile levels, while others, including Enterococcus and Lactobacilli, were linked to a high abundance of C. difficile. 

Next, the researchers created a synthetic microbial community with strains associated with low C. difficile levels, which they called sFMT1. Compared with human fecal microbiota transplants, sFMT1 produced higher levels of specific short-chain fatty acids, which have been associated with health benefits.

In cells grown in a dish, sFMT1 reduced C. difficile growth compared to controls. In mice infected with C. difficile, sFMT1 helped reduce the severity of infection. In a model simulating C. difficile recurrence after antibiotic treatment, sFMT1 delayed relapse and reduced infection severity, the researchers found.

Microbiota-targeted therapies

Further experiments showed that Peptostreptococcus anaerobius and other bacteria compete with C. difficile for key nutrients, limiting its growth. Removing these bacteria reduced protection, while colonizing mice with P. anaerobius alone was as effective as traditional FMT. 

“FMT represents perhaps one of the most extreme and effective microbiota-targeted therapies; however, FMT’s greatest strength is also its greatest weakness: complexity,” the authors say. “Hidden within fecal communities may be functional cores of beneficial organisms; however, as we show here, not every microbe common in the healthy human gut may be beneficial, and some may be detrimental.”

Synthetic communities of microbes may offer a more controlled and predictable alternative to traditional FMT, paving the way for future therapies with probiotics, the authors say.