Prevotella is one of the most common groups of bacteria in the healthy mouth and respiratory tract. Earlier research found that higher levels of Prevotella correlate with better outcomes in people with respiratory infections. What scientists did not know was how the bacterium might actually protect against pneumonia.

How did the researchers test it?

Clark and her colleagues exposed mice to P. melaninogenica, then challenged them with S. pneumoniae. To see what changed inside the lungs, the team used single-cell RNA sequencing — a technique that measures gene activity in individual cells one by one — to examine thousands of lung cells and track how their behavior shifted.

The results showed that Prevotella exposure essentially reprogrammed several types of immune cells involved in fighting infection. Two cell types stood out:

• Neutrophils — immune cells that quickly swarm infection sites — became better at engulfing and killing the pneumonia bacteria.
• Macrophages — the lungs' resident "garbage-eating" cells — showed the same improved bacteria-killing capacity.

The mice exposed to Prevotella also carried significantly smaller amounts of S. pneumoniae in their lungs than unexposed mice.

"The immune cells were present in greater numbers and behaving differently," Clark said. "They had been functionally reprogrammed to do a better job of clearing bacteria."

Is the lung microbiome part of the body's first line of defense?

The study adds to growing evidence that bacteria normally living in the respiratory tract are not simply passive passengers. They may actively shape how the immune system responds to disease.

The researchers note that clinical studies have already linked greater respiratory microbial diversity — and the presence of anaerobic bacteria such as Prevotella, which grow without oxygen — with better outcomes in people with severe respiratory illness. The new mouse data provide a possible biological explanation for those earlier observations.

"We're interested in understanding whether we can harness this natural interaction between the microbiome and the immune system," Clark said. "If we can figure out how these bacteria educate immune cells to respond more effectively, it could open up entirely new approaches to preventing respiratory infections."

What are the limits?

The findings come from experiments in mice, so they do not yet prove that the same immune-cell reprogramming happens in human lungs. Whether Prevotella exposure could be turned into a practical pneumonia-prevention strategy — through probiotics or another intervention — remains an open question that will require further research, including clinical studies in people.

Still, the work gives researchers a concrete mechanism to investigate: commensal bacteria training the immune system, cell by cell, before disease strikes.

Publication details: Sara N. Stoner et al., "Myeloid cell reprogramming drives enhanced defense against Streptococcus pneumoniae lung infection following exposure to commensal Prevotella," Proceedings of the National Academy of Sciences (2026). DOI: 10.1073/pnas.2623525123