Synthetic Microbiome Therapy Offers Safer Alternative to Fecal Transplants

Researchers from Penn State University have developed a novel synthetic microbiome therapy for Clostridioides difficile (C. difficile), a bacterium that can cause severe diarrhea, abdominal pain and colon inflammation. C. difficile is difficult to treat and potentially life-threatening in humans.

The findings from the study – which was conducted in mice – could lead to the development of new probiotic strategies to treat infections as an alternative to antibiotics and conventional fecal microbiota transplants.

The study was published in Cell Host & Microbe.

Synthetic microbiome therapies: The new fecal transplants?

Organisms within the microbiome usually keep each other in check. C. difficile is often carried in the gut but typically remains dormant, going unnoticed. However, when the balance of the gut microbiome is disrupted, as can happen when receiving antibiotic treatment, C. difficile can flourish.

C. difficile mostly affects older adults in hospitals or long-term care settings, however, some strains of the bacterium are more likely to cause serious infection in younger people.

Treating these infections is challenging as antibiotics aren’t effective against C. difficile – the bacteria are drug-resistant. Administering antibiotics can also cause further disruption of the gut microbiome, creating a positive feedback loop that leads to recurrent infections.

Previous therapies attempting to treat C. difficile have involved human fecal transplants, a medical procedure where bacteria from a healthy donor’s stool are transferred to a patient’s gastrointestinal tract. However, it’s not without risks.

“To a certain extent, a fecal transplant is almost like going to the pharmacist where they take a little bit of everything off the shelf and put it into one pill, assuming that something will probably help,” said senior author Dr. Jordan Bisanz, assistant professor of biochemistry and molecular biology at Penn State University, and Dorothy Foehr Huck and J. Lloyd Huck Early Career Chair in host–microbiome interactions. “But we don’t know 100% what’s in there.”

Fecal transplants may even, unknowingly, contain disease-causing bacteria. The newly developed synthetic microbiome therapy, however, does not require any fecal matter.

Using fewer but more precise bacteria strains that were linked to C. difficile suppression, the microbiome therapy was as effective as human fecal transplants against infection, in mice, and with fewer safety concerns.

“We need to be much more targeted in our microbiome interventions,” said Bisanz. “This project is a first step in trying to understand how complex microbial communities function to affect the host, then turning that around to learn how to develop microbiome-targeted therapies,” he continued.

C. difficile “foes” provide a targeted therapy approach

Bisanz and the team first identified microorganisms that tend to co-occur with C. difficile and those that may suppress the bacterium's growth. They then aimed to reconstruct that mixture and design a targeted treatment with this selective community of bacteria.

“The idea was to take our understanding of basic microbiome sciences and turn it into precision-like therapies that take what we’ve learned from fecal transplants but doesn’t actually require a fecal transplant,” Bisanz said.

Bisanz and team used machine learning to identify the key features of microorganisms that were positively and negatively associated with C. difficile in 12 previous human microbiome studies.

In total, 37 strains of bacteria were negatively correlated with C. difficile, meaning there was no infection when these microorganisms were present. However, 25 bacteria were positively correlated and presented alongside C. difficile infection.

The results identified from the machine learning model enabled researchers to combine the bacteria that appeared to suppress C. difficile and create a targeted synthetic microbiome therapy.

When tested in vitro and given orally to mice, the synthetic microbiome therapy significantly reduced the growth of C. difficile, resisted infection and was as effective as a traditional human fecal transplant. The therapy also demonstrated protection against severe disease, delayed relapse and decreased severity of recurrent infection caused by antibiotic use.

Interestingly, just one bacterial strain was found to be critical for suppressing C. difficile.

“If you have this Peptostreptococcus strain, you don’t have C. difficile. It’s a very potent suppressor and is better than all 37 strains combined,” Bisanz said.

Peptostreptococcus is particularly good at scavenging proline, an amino acid that C. difficile needs to grow, highlighting new potential avenues for therapeutic treatment not originally available.

Looking to the future

The development of a synthetic microbiome therapy represents a significant advancement in the fight against C. difficile infections.

Bisanz and team’s approach to microbiome science could be used to understand complex host–microbial interactions in other conditions, such as inflammatory bowel disease, with the potential to develop novel therapies.

“The goal is to develop the microbes as targeted drugs and therapies,” he concluded.

Investigating alternative delivery methods, long-term effects and potential combinations with existing treatments could also enhance therapeutic outcomes. Ultimately, the integration of microbiome-based precision medicine into mainstream healthcare could revolutionize the management of antibiotic-resistant bacterial infections and improve overall gut health.

Reference: Tian S, Kim MS, Zhao J, et al. A designed synthetic microbiota provides insight to community function in Clostridioides difficile resistance. Cell Host & Microbe. 2025. doi: 10.1016/j.chom.2025.02.007

This article is a rework of a press release issued by Penn State University. Material has been edited for length and content.