A Microbe from Poo Suppresses Bacterial Infection

Bacteria in the human gut microbiome maintain a delicate balance, where beneficial bacteria keep potentially harmful microbes in check. Antibiotic treatment can disrupt this harmony, allowing pathogens like Clostridium difficile to wreak havoc, causing diarrhea, stomach cramps, and colon inflammation.¹ Antibiotics also deplete the healthy microbiome, which paves the way for reinfection. Infection recurrences are difficult to treat, with one recurrence increasing the risk of repeated reinfections.²

In the past decade, researchers have shown that transplanting fecal material from healthy donors can prevent recurrent C. difficile infections.³However, this procedure is 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 Jordan Bisanz, a biochemist and molecular biologist at The Pennsylvania State University, in a press release. “But we don’t know 100 percent what’s in there.”

Now, in research published in Cell Host & Microbe, Bisanz and his colleagues have identified which gut bacteria can suppress C. difficile infections, laying the foundation for probiotic-based strategies as an alternative to antibiotics and fecal microbiota transplants.⁴

Bisanz and his team started out by investigating C. difficile’s “friends,” microbes that coexist with it, and its “enemies,” those that may suppress the bacterium. They performed a meta-analysis of previously published studies containing information about C. difficile load in people alongside gut microbiome sequencing data. With the help of machine learning, they identified 25 bacterial strains that cooccurred with C. difficile, and 37 strains that were negatively correlated with its presence.

The researchers then created a community of bacteria by coculturing the 37 strains negatively linked to C. difficile. Treating a C. difficile culture with this synthetic version of a fecal microbiota transplant (sFMT) reduced its growth. When the researchers exposed sFMT-colonized mice to C. difficile, the animals had significantly less weight loss and toxin abundance compared to control mice that received bacteria-free media.

To investigate whether a sFMT protected mice from antibiotic-induced C. difficile reinfection, the researchers treated mice with an antibiotic, infected them with C. difficile, and then treated them with another antibiotic before subjecting them to a sFMT. Compared to controls, sFMT-treated mice showed delayed infection relapse and reduced disease severity.

The researchers sought to identify the pathways through which sFMT may suppress C. difficile. Compared to mice that received human-derived fecal microbiota, those treated with sFMT exhibited higher levels of 5-aminovalerate, a metabolite produced when some microbes ferment proline, an amino acid important for C. difficile growth and virulence.⁵Consistent with this, the researchers observed reduced proline levels in sFMT-colonized mice.

Removing known proline fermenters from the sFMT abolished its protective activity on C. difficile infections and resulted in severe disease symptoms in mice, establishing that proline scavenging by sFMT suppresses C. difficile. The researchers found that the bacterium Peptostreptococcus anaerobius made up a majority of the synthetic microbial community members that ferment proline.

C. difficile-exposed mice treated with P. anaerobius had reduced disease severity. The effect was comparable to what was observed in mice treated with human-derived fecal microbiota transplants, suggesting that a single bacterium could help treat C. difficile infection. Since P. anaerobius is an opportunistic pathogen, the researchers noted that other microbes with similar features could be explored as potential treatments.

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