Could the ancient oral microbiome be the key to improving modern health?

Laura Weyrich PhD, remembers vividly the conversation that sparked her interest in oral microbiome transplants. It was on a day she was having drinks with her husband, who suffers from periodontal disease, a progressive inflammation of the gums.

Despite doing everything possible to keep his teeth clean, he was barely able to keep the disease at bay, she says. “He said ‘I'm so proud of all the work that you've done, but when are you going to do something that actually cures diseases like mine?’” she recalls. “At the time, I laughed. My attitude was ‘oh, whatever,’” she quips. But she found herself contemplating his comment.

There is a large body of research linking poor oral health to a higher incidence of cardiovascular disease, diabetes and other chronic conditions. Inflammation and harmful bacteria in the mouth can enter the bloodstream, contributing to systemic health issues. At the same time, there is growing understanding that the oral microbiome is malleable and has changed over time, with diet being a significant contributing factor.

As a microbiologist, Weyrich had been studying the oral microbiomes of people long deceased – Neanderthals and people of ancient times. But then she started brainstorming ideas about how she might use that information to help people today and thus, the oral microbiome transplant project was born.

Oral microbiome transplants involve transferring beneficial microbes from a healthy donor to a recipient to treat diseases like periodontal disease. This is typically done by applying a microbial solution or gel to the patient's gums and teeth, allowing the beneficial bacteria to colonize the mouth. This process requires ensuring microbial compatibility to prevent rejection and establishing long-term stability of the new microbiome.

A microbiome’s turning point

The microbial community that lives in the human mouth, nose, and pharynx is the second-largest in our bodies after the gut. In one of the first studies to track its evolution through history in a single population, Weyrich and her colleagues discovered a change in composition that coincided with the bubonic plague pandemic of the 14th century. 

In the study (1), the researchers examined samples of dental calculus – calcified dental plaque – collected from the remains of 235 British people who lived between 2200 BCE and 1853, and 127 living British adults.

They identified 954 microbial species that broadly fell into two distinct communities. The composition of these communities seems to have shifted sometime after the second plague pandemic in 1348, specifically towards microbial species that are associated with chronic disease.

While it’s difficult to prove the cause of this shift, it’s plausible that the pandemic changed people’s diets, says Weyrich. Bubonic plague killed anywhere from 30% to 60% of the European population. Because so many people died, there is evidence to suggest survivors actually moved up the economic ladder. “There were more jobs, more housing and more foodstuffs available,” she says. However, it’s also possible that the change in oral microbiome was brought on “by other social or cultural shifts.”

The study is most significant, she says, because it compared the oral microbiomes from people in the past to people in the present within a single population. While some studies have used the microbiomes of living Indigenous people as a proxy for the microbiomes of pre-industrialized Western populations, any comparisons between the two are flawed because currently living indigenous populations may not have the same microbes as the ancestors of Western populations, Weyrich says. 

Different community. Different microbiome.

While understanding the evolutionary history of the oral microbiome of British people might help develop oral microbiome therapies for that population, the treatment might not be applicable to other populations, says Weyrich. Health equity is crucial, and treatments should be accessible to all, especially underserved communities, she says.

Weyrich first noticed health inequities among different groups while working with Australian Aboriginal communities as a post-doc at the University of Adelaide. Chronic disease incidence in Aboriginal Australians and Torres Strait Islanders is up to five-fold higher than in people of European descent living in the same Australian cities. Access to healthcare is part of the issue, says Weyrich, but biological factors like the oral microbiome also play a role.

Collaborating with the Indigenous Oral Health Unit at the University of Adelaide, she and her colleagues have found that indeed, the oral microbiomes of Aboriginal Australians are very different, even though the chronic diseases they suffer, such as diabetes and heart disease, are the same. For example, many Aboriginal Australians whose ancestors lived in the central desert still carry microbes typically found in termite guts; the insects were an important source of protein. What surprised her is that the population long ago stopped eating termites, and yet the microbes are still part of their oral flora.

It's not clear whether termite microbes are actually detrimental to health. However, researchers hypothesize that while the microbes at one point served an important function - they may have helped people digest and extract nutrients and energy from plants - they may now be a maladaptation. In other words, in the absence of traditional food sources and on a Western diet, they may negatively impact health. But more research is necessary to test this hypothesis. 

From ancient bones to modern medicine

“There are evolutionary contexts that we need to take into account to understand why we see specific types of oral microbes. We can use that research to better guide us to create biotechnologies and therapies that are equally effective in all people,” says Weyrich.

“If we were to pair someone's evolutionary history with an oral microbiome transplant, we might not have to repeat that transplant because the microbes didn't take,” she explains.

In other words, matching donors and recipients of an oral transplant could be informed by ancient DNA work.

Studying ancient samples poses special challenges in the lab. Contamination is a huge problem, especially since old bones or other tissues tend to be handled by multiple people and may have been improperly stored.

“One thing that's really critical is ensuring our reagents are clean,” says Weyrich. Her lab relies on a few essential QIAGEN reagents, which they have tested extensively. “They have a consistent background signal that we can monitor and manage. In our ancient DNA work, we can rely on QIAGEN reagents to be largely free from handler-associated human microbes,” she adds.

 Weyrich and her colleagues often use the DNeasy PowerSoil Pro Kit from QIAGEN. Because the kit is used by many other labs, it enables cross-comparison of data sets from many different labs, she says, “without worrying about huge changes in contamination signatures because of different reagents.”

Some of the first people to benefit from her research might be those over age 65, almost 70% of whom suffer from periodontal disease. Weyrich and her colleagues have preliminary evidence from animal models suggesting that oral microbiome transplants can prevent dental caries. She is planning human clinical trials to study the therapy further.

“It's really eye-opening to do anthropological and archeological work, reconstructing ancient microbiomes and understanding their diversity today,” says Weyrich. “But at the same time, we have to take that information and use it to improve people's lives.”