New study shows many inflammatory diseases start in the mouth

 In Writing
graphic of a colorful bacterium
Published research finds bacterium is playing major role in oral abscesses

A bacterium that is widely recognized for its association with inflammatory diseases and cancer—such as head and neck and colorectal cancers—has caught the attention of OHSU School of Dentistry researchers and colleagues with whom they collaborated.

Fusobacterium nucleatum, or F. nucleatum, is a type of bacterium that appears in the mouth and can easily travel throughout the body. When people experience oral inflammation, all types of organisms can travel through their bloodstream and gastrointestinal tract, spreading bacteria and potentially causing illness.

F. nucleatum comes in four different flavors known as subspecies. Up to now, these different subspecies have generally been considered synonymous organisms that are essentially interchangeable.

However, an OHSU study on Fusobacterium nucleatum reveals that these subspecies behave differently than originally believed. The organisms also have a habit of settling into their favorite niches in the mouth, according to co-authors from the School of Dentistry.

The discovery was published online March 12 in the journal Cell Host and Microbe. The print edition was published April 10.

The paper is titled “Stratification of Fusobacterium nucleatum by Local Health Status in the Oral Cavity Defines its Subspecies Disease Association.”

Authors and funding

The paper was co-authored by School of Dentistry faculty members and members of OHSU-Portland State University School of Public Health, OHSU School of Medicine, OHSU Knight Cancer Institute, private practice and private industry for cancer research.

The co-authors are Madeline Krieger, Ph.D., Yasser AbdelRahman, Ph.D., Dongseok Choi, Ph.D., Elizabeth Palmer, D.M.D., M.S., Anna Yoo, D.M.D., Sean McGuire, D.M.D., Jens Kreth, Ph.D., and Justin Merritt, Ph.D.

Palmer is an associate professor of pediatric dentistry for the School of Dentistry, and clinical site director for the pediatric dentistry graduate program. Kreth and Merritt are professors in the division of biomaterial and biomedical sciences for the School of Dentistry and affiliate professors in the molecular microbiology and immunology department in the School of Medicine.

Krieger is a postdoctoral researcher for the computational biology group with CEDAR, OHSU Knight Cancer Institute and OHSU School of Medicine. Choi is a professor at the OHSU-Portland State University School of Public Health.

AbdelRahman is a scientist at Predicine, a California-based cancer research facility. Yoo and McGuire are practicing pedodontists (treating dental problems in infants, children and teenagers).

Funding was provided by the National Institutes of Health-National Institute of Dental and Craniofacial Research—grants R35DE028252 (Justin Merritt); R21DE029612 and R01DE029492 (Jens Kreth); and T90DE030859 (Madeline Krieger; PI Hui Wu). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The following are questions asked by the School of Dentistry and answers provided by Justin Merritt, Ph.D.

Note on terminology

The subspecies terminology used in this story is the current convention. No official species names have been assigned to the four organisms. The authors have proposed using the current subspecies names as the species names for the four organisms. Taxonomists will make that determination.

School of Dentistry (SOD): Who will find the research presented in this paper most relevant?

Justin Merritt (JM): The target audience is geared toward basic science and clinical researchers, especially those with an interest in infectious disease and/or the microbiome. This includes dentist-scientists and those interested in the cancer tumor microbiome. While this study does not focus on cancer per se, the organism is receiving a lot of press in recent years due to its prevalence inside tumors, especially colorectal cancer. There is compelling evidence to indicate that the Fusobacterium nucleatum found in these tumors originates in the oral cavity.

SOD: Does this advance or change oral care?

JM: This study does not change clinical care directly, but its impact is likely to be much larger in basic and clinical research. For decades, it has been known that the bacterial oral microbiome species Fusobacterium nucleatum comes in four different flavors. The four subspecies are F. nucleatum subsp. animalisF. nucleatum subsp. nucleatum, F. nucleatum subsp. polymorphum, and F. nucleatum subsp. vincentii.

In basic science and clinical studies, these different F. nucleatum subspecies have generally been considered as essentially interchangeable and largely synonymous organisms.

Our study reveals that these subspecies prefer different niches in the oral cavity. F. nucleatum subspecies animalis dominates the inflammatory abscess environment, while polymorphum subspecies dominates within dental plaque. F. nucleatum subsp. animalis is also the same subspecies that is most prevalent in colon cancer tumors and several other extraoral conditions.

Our study also reveals the diversity of F. nucleatum subspecies that are found in healthy human oral cavities and in diseased sites.

Lastly, we provide a deep dive into the genetic content of these F. nucleatum subspecies and show that they are actually different species of Fusobacterium, rather than different F. nucleatum subspecies, as they have been classified for the past 30 years. Accordingly, we show that these organisms are quite different in their behaviors and environmental preferences in the oral cavity.

The results provide a strong rationale for future research and clinical studies to distinguish which variety of Fusobacterium is being examined. This is rarely done in research today.

SOD: How is this research important to dentistry?

JM: The field needs to understand how organisms in the oral microbiome contribute to oral health and disease before we can expect to develop new therapeutic strategies to prevent oral disease.

If we are to move beyond the current approach of surgical intervention for dental diseases, studies like this must continue to probe new solutions.

Specifically, this research provides insights into the role of different fusobacteria in the oral cavity. Fusobacterial species play central roles in the ecology of the human oral microbiome. Whether we’re healthy or have diseases, the species have a purpose and play central roles.

For example, F. nucleatum is well-known to transit throughout the human body, where it is associated with a range of pathologies. Current evidence indicates that the oral cavity is the likely entry point to these distant sites. Once it’s in the mouth, the mode of transportation to the rest of the body is via the gastrointestinal tract and/or the bloodstream.

The oral microbiome is unique in terms of its impact on systemic health because oral bacteria enter the bloodstream from the oral cavity daily. Even heathy mouths inject lots of bacteria into the body every day from activities like eating or toothbrushing.

When people experience inflammation like periodontitis, there is an increased quantity of organisms that enter the bloodstream. If you’re healthy, the composition of bacteria that enters your bloodstream will be different.

Oral inflammatory conditions—like tooth abscesses—tend to promote the growth of more tissue-destructive bacteria. The bacteria in these soft tissue infections are then transmitted to other sites in your body.

Our study does not indicate whether F. nucleatum subsp. animalis is the primary Fusobacterium in periodontitis, but it does provide a strong rationale to examine this question in future clinical studies.

However, our comparison of patient-matched dental plaque versus abscess specimens provides strong evidence that the animalis subspecies can outcompete other fusobacteria present in abscesses. In fact, it may even grow better in an inflammatory environment.

SOD: How might the research affect people’s lives?

JM: F. nucleatum has recently been associated with a wide range of pathologies outside of the oral cavity and is especially prevalent in colon cancer tumors and other malignancies. Since the oral cavity is the likely reservoir for the bacteria found in these sites, it is especially important to know which type of Fusobacterium is involved.

Presently, most studies do not differentiate between the four varieties of F. nucleatum. Our study shows how this may result in misleading conclusions that can cascade into basic research. Are the appropriate organisms being examined for these different conditions?

In a broader sense, microbiome research attempts to understand the interplay between the microbiome and the host. As we learn more about how this works, we hope new therapeutic strategies will arise, allowing us to manipulate the interplay in a way that promotes oral and systemic health.

Read the full Cell Host and Microbe journal article.

Abstract

The ubiquitous inflammophilic oral pathobiont Fusobacterium nucleatum (Fn) is widely recognized for its strong association with inflammatory dysbiotic diseases and cancer. Fn is subdivided into four subspecies, which are historically considered functionally interchangeable in the oral cavity. To test this assumption, we analyzed patient-matched dental plaque and odontogenic abscess clinical specimens and examined whether an inflammatory environment selects for/against particular Fn subspecies. Dental plaque harbored a greater diversity of fusobacteria, with Fn. polymorphum dominating, whereas odontogenic abscesses were exceptionally biased for the largely uncharacterized organism Fn. animalis. Comparative genomic analyses revealed significant genotypic distinctions among Fn subspecies that correlate with their preferred ecological niches and support a taxonomic reassignment of each as a distinct Fusobacterium species. Despite originating as a low-abundance organism in dental plaque, Fn. animalis typically outcompetes other oral fusobacteria within the inflammatory abscess environment, which may explain its prevalence in other oral and extraoral diseases.


Illustration by Mohammed Haneefa Nizamudeen, Getty Images

Story by Rhonda Morin, APR

First published April 11, 2024, on OHSU Now

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