A group of scientists at the ADA Forsyth Institute has identified a mechanism used by host cells to fight back against common oral bacteria Fusobacterium nucleatum (F. nucleatum). A microorganism implicated in periodontal disease, F. nucleatum is also associated with many other systemic conditions including colorectal cancer and pregnancy complications.
A new study, published in the International Journal of Oral Science, is the latest advancement in ongoing research into F. nucleatum by a team of researchers including ADA Forsyth Institute K99 Postdoctoral Fellow Pu-Ting Dong, Ph.D. and Professor Xuesong He, D.D.S., Ph.D.
“We are learning more about the specific way by which host cells interact with Fusobacterium nucleatum,” said Dr. Dong, the paper’s first author. “A full understanding of this mechanism could help us selectively target F. nucleatum in a therapeutic application addressing periodontitis and, in turn, many more systemic conditions.”
A commensal-turned pathogen
Fusobacterium nucleatum, a key microbial component of dental plaque, is commonly present in the oral cavity of most individuals. It colonizes the subgingival space, where low-oxygen conditions favor its growth, and is often enriched in people with periodontitis.
While typically harmless in a healthy oral environment, it can contribute opportunistically to periodontitis by promoting biofilm formation, facilitating the co-aggregation of other pathogenic bacteria, and promoting inflammation through the recruitment of immune cells and the stimulation of pro-inflammatory cytokines. Its ability to disrupt epithelial barriers and modulate host immune responses further amplifies tissue destruction and disease progression.
But elsewhere in the body, F. nucleatum is a pathogen associated with colorectal cancer, preterm birth, Alzheimer’s disease, inflammatory bowel disease, and rheumatoid arthritis. Dental plaque buildup can promote the transmission of F. nucleatum to other areas of the body, including the gut microbiome, underscoring one of the most pertinent connections between oral and overall health.
“We are always saying, brush your teeth well, not only for oral health, but potentially even to prevent colorectal cancer,” Dr. He said. Colorectal cancer has been identified by the National Cancer Institute as one of the most common types of cancer in the U.S.
How host cells fight back
A naturally occurring mechanism can lead the way toward new ideas about controlling F. nucleatum.
In a previous paper, the ADA Forsyth team identified two specific types of human tRNA-derived small RNAs (tsRNAs), which are small fragments of ribonucleic acids (RNAs). Researchers found that these host-produced tsRNAs specifically inhibited the growth of F. nucleatum.
In a key finding detailed in their latest report, the researchers identified P-type ATPase Transporter (PtaT), a membrane transporter protein that binds to the tsRNAs and may carry the tsRNAs into F. nucleatum to exert their antimicrobial effect.
Epithelial cells in the mouth use this mechanism to fend off the harmful effects of F. nucleatum. However, when F. nucleatum becomes too abundant, it is more likely to travel via saliva or host cells to other parts of the body and become a dangerous pathogen.
Testing on F. nucleatum strains isolated from colorectal cancer samples demonstrated the effectiveness of these tsRNAs in inhibiting bacterial growth. This suggests that a similar PtaT-dependent mechanism in the intake of tsRNAs exists in host cells in the colon.
Potential to aid systemic disease therapies
The study of tsRNAs is relatively new, but AFI researchers are steadily elucidating a topic that has previously been considered a “black box.”
A potential therapeutic application would involve strengthening the body’s response to F. nucleatum. The team of researchers plans to explore this possibility in further detail through in vivo testing.
“With a comprehensive understanding of all the pathways involved in host modulation of F. nucleatum, we can think of ways to make it more effective,” said Dr. He. “For now, we are still in the stage of fully understanding, at the molecular level, how human cells interact with this bacterium.”
Additional collaborators on this project included Lujia Cen (ADA Forsyth Institute), Mengdi Yang (Northeastern University), Jie Hu, Difei Xu, Peng Xiong (University of Science and Technology of China), Peng Zhou (University of Texas), and Jiahe Li (University of Michigan).
