For Microbes, There’s No Place Like HOM(e)

by Sophia Swartz
figures by Nicholas Lue

Welcome HOM(e)!

Your mouth isn’t too different from a city. Like a city, your mouth contains hundreds of different inhabitants and communities. However, these inhabitants are not humans or animals. Instead, your mouth contains hundreds of thousands of microbes.

Microbes are small organisms—like bacteria or fungi—that cannot be seen by the human eye. For example, 100 bacterial cells could attach to a single grain of salt. But with the help of a microscope, we can observe microbes in virtually any ecosystem on the planet, including the human mouth. And in the mouth, bacteria are the most common microbes to find.

Whenever you wake up in the morning with bad breath or scrape gunk off your tongue with your toothbrush, you are interacting with microbes. The group of microbes living in your mouth is called the human oral microbiome—or HOM, for short—and is a vibrant and diverse ecosystem, containing anywhere from 500 to 600 different microbial species.

Oral microbes can exert both helpful and harmful effects on human health. Certain oral microbes enrich our diets with nutrients we could not process by ourselves. In particular, oral microbes appear to play a beneficial role in using nutrients like nitrate. Nitrate is found in leafy greens and, when metabolized by your body, can slightly lower blood pressure. In people who regularly use a mouthwash—which kills more nitrate-metabolizing oral microbes than just brushing your teeth—nitrate consumption no longer affects blood pressure.

However, other oral microbes can harm your overall oral health. When we consume sugary foods or drinks, cavity-causing microbes on teeth metabolize the sugar and produce acid. The acid then dissolves the tooth surface and creates a painful cavity. Without regular brushing and dental check-ups, cavity-causing microbes can build up on teeth and cause discomfort.

How to best promote a healthy oral microbiome is an important and understudied question. One of the strongest indicators of a healthy society is dental health. Just imagine: What if you could supercharge your mouth with nitrate-metabolizing oral microbes, but reduce the number of cavity-causing oral microbes?

Off the map

As the primary gateway into the human body, the oral microbiome is of particular interest. Everyone has a unique microbiome based on their lifestyle and genetic background. This microbial fingerprint supports your overall health, but is also capable of causing disease. Many diseases such as diabetes or cardiovascular disease are linked to the oral microbiome.

In an ideal world, scientists would precisely tweak your oral microbiome to maximize beneficial microbes and prevent disease. But today, if your doctor prescribed an oral probiotic, there is no way to tell whether the good bacteria in the probiotic stick around in your mouth or pass through with no effect.

Personalized microbiome therapies hold great promise in resolving this issue. However, at the moment, no one fully understands how oral microbes map to the HOM. For these therapies to progress, it is essential to understand where oral microbes localize. How do microbes find their home?

Location, location, location

Microbes do not just live anywhere in your mouth. Your mouth is a complex ecosystem containing many different specialized areas referred to as oral structures. For example, the tongue, plaque on teeth, and cheek are all different oral structures in the human mouth. Each different oral structure has different conditions that make it a better or worse place for certain microbes to live.

**Figure 1: Location is key.** Every day, the human mouth (top) comes into contact with thousands of different microbes. However, only a small subset of these microbes can bind in the mouth. Which microbes live in which oral site is largely determined by environmental conditions. For example, oral microbes that bind strongly and grow quickly can thrive on the cheek (bottom right), while less resilient oral microbes colonize more stable environments like supragingival plaque (bottom left).

The cheek in particular is a dangerous place for a microbe to live. When eating or drinking, we often abrade our cheek cells. Any microbes that live on the cheek must attach strongly to cheek cells and grow quickly before they are unintentionally swallowed or destroyed.

Streptococcus are one of the few abundant microbes on the cheek oral structure, likely due to their versatility. Streptococcus microbes attach quickly to cells, grow rapidly, and can live in high- or low-oxygen environments. They can be found on the cheek, tongue, or in supragingival plaque and thrive where other microbes can’t get a foothold. Unfortunately, Streptococcus microbes also degrade sugars into acid and create an acidic environment, promoting the development of cavities.

The mouth contains other oral environments that are much more stable and densely-populated. Supragingival plaque forms on a solid tooth surface. Teeth, unlike the cheek, have no shedding cells and are subject to less disruption. Even after tooth brushing, a base layer of microbes stays anchored to the tooth and regrows throughout the day.

Actinomyces are oral microbes that often form the base layer on supragingival plaque. Unlike Streptococcus, Actinomyces microbes are less resilient and tend to stick to supragingival plaque or the tongue. Actinomyces microbes are important because they help process nitrate and create alkaline compounds. However, they can also cause bad breath as a side effect.

Essentially, microbial localization is the dilemma of satisfying certain biological constraints within a limited set of oral environments. These oral environments differ hugely. To use the city analogy, the human cheek is like a parking lot, while supragingival plaque is like a bustling downtown square. Environmental conditions and basic organizational principles—like resilient versus sensitive, aerobic or anaerobic—strongly influence where oral microbes live.

“Endless forms most beautiful”
–Charles Darwin

Just as a city is composed of different structures—ranging from skyscrapers to college campuses—the HOM contains consortia with many different structures, too. Research has identified that distinct structures form among microbes depending on where you are located in the HOM.

If we look at the ways bacteria form communities in plaque, we will notice different consortia than if we look at bacteria on the tongue. For example, scientists find that bacteria tend to create “hedgehog” structures in plaque. These hedgehog consortia have anaerobic microbes at the center and aerobic microbes along the exterior of the structure.

“Corncobs” are also observed, where a thin layer of aerobic microbe cells surround a core of anaerobic microbe cells in long strands stretching out from the tooth. Scientists have also identified “cauliflower” structures, where patches of different aerobic bacteria collect on the outside of a consortia cluster.

**Figure 2: From disorder to order.** The human mouth is a volatile and disordered environment, subject to regular tooth brushing, drinking, and eating. The oral microbes that are able to survive these stresses create communities with an astonishing degree of order. In supragingival plaque on a single tooth, many distinct structures have been observed, ranging from dense cauliflowers (pink, top left) to elongated corncobs (orange, top right) to elaborate hedgehogs (blue, bottom).

The specificity of consortia structures can yield valuable insights into how these microbes interact with the human mouth. For example, Actinomyces microbes form the base layer of hedgehog consortia in supragingival plaque. But Actinomyces isn’t the only microbe in the base layer; Streptococcus microbes also grow along the tooth.

Streptococcus microbes are aggressive colonizers, preventing Actinomyces from forming a homogeneous base layer on the tooth. But Streptococcus microbes also produce acid and could erode away the stable tooth environment if the hedgehog base layer consisted only of streptococci.

Since Actinomyces produce alkaline compounds, a base layer of Streptococcus and Actinomyces together ensures that the acid and alkaline compounds neutralize each other. In this way, the stable tooth environment is maintained and less resilient oral microbes—like Actinomyces—can continue growing.

Despite the volatility and complexity of the HOM, a staggering degree of structure may be observed. At the moment, this is an active area of research. Although no definitive conclusions have been made, many researchers are investigating biological pathways where microbes may supplement human diets or vice versa, such as riboflavin synthesis or nitrate metabolism.

For microbes, there’s no place like HOM(e)

Your mouth is the interface for many important processes, ranging from metabolism to immune system function. When any of these processes go wrong, there can be dire health consequences. Good oral health is critical to good quality of life, and dysbiosis of the HOM can exacerbate risk of heart attack, stroke, and diabetes. The insights that can be gained from microbial mapping research are far-reaching and topical: toothpaste that better prevents cavities or probiotics that effectively colonize the microbiome. As a result, there is a clear human health motivation to study healthy HOM community structures.

For personalized microbiome therapies to be effective, researchers must understand how microbes colonize the mouth. How to make a “microbial GPS”—a tool to chart a patient’s microbial communities and how they change—is an important and ongoing question. Hopefully, with the future development of a microbial GPS, navigating the complex, wonderful city that oral microbes call HOM(e) will be a little easier.

For More Information:

To learn more about the current research attempting to resolve the questions raised in this article, take a look at this Knowable Magazine article.
For more in-depth discussions of recent research mapping the tongue microbiome, listen to this Science Friday podcast.
If you want to check out research at the bleeding edge of microbial localization, read this scientific paper in Annual Reviews of Microbiology articulating the site-specialist hypothesis.
For videos and images of what these oral microbe communities look like through the microscope, check out this StatNews article and these videos (Tongue consortium flythrough and Tongue consortium in three dimensions) from the Marine Biological Laboratory at Woods Hole.
If you were wondering what steps you could take to improve your oral microbiome and keep your microbial friends happy, skim this Micropia article.
If you want a better sense of the size of different microbes and objects you might encounter in the HOM, check out the Cell Size and Scale website from Learn Genetics Utah.

Sophia Swartz is a junior at Harvard University studying Molecular and Cellular Biology.

Nicholas Lue is a fourth-year Ph.D. student in the Chemical Biology program at Harvard University. You can find him on Twitter as @nicklue8.