By Paul Nicolaus
June 6, 2018 | In recent years, the gut microbiome has garnered plenty of attention as scientists look to learn how the bacteria in this part of our body influences health and risk of disease. While the gut may be a central location for many of our microbes, trillions of bacteria, fungi, and viruses reside all over our bodies. They live in our mouths, inhabit our noses, and even populate the surface of our largest organ. So some researchers are taking aim at the skin microbiome.
Skin is not the same across the human body, however. We have dry skin areas like our hands and forearms. We have moist skin regions like our feet or armpits. We have oily sites like our face or scalp. And our skin’s microbiome varies based on these different skin properties, Julia Oh, assistant professor at The Jackson Laboratory explains in a brief video clip.
Why does this matter? Because skin disease tends to occur in specific areas. We get eczema in our arm or leg creases, fungus on our feet, and acne on our face. According to Oh, understanding the different ways our microbes interact with our skin could help determine how to develop targeted therapeutics that are specific to the skin or the microbes found at certain sites.
Decade of Findings
Huiying Li, associate professor of Molecular & Medical Pharmacology at UCLA, is one researcher working to better understand the role of the human microbiome in relation to different diseases at different body sites. In addition to the oral and vaginal microbiome, her lab studies the skin and has zeroed in on acne—the most common skin condition in the United States that, according to the American Academy of Dermatology, affects up to 50 million Americans each year and over 8 in 10 adolescents.
As she reflects on her research journey, Li points back to the late stages of her PhD work when she studied microbial genomics. “At that time, the microbiome field was still very, very early,” she said. “So mostly we studied the genomes one by one.” Later, during her post-doc work, she analyzed data from communities. When she began her own independent position as a researcher roughly a decade ago, she started looking at the human skin microbiome in particular.
By that point, the National Institutes of Health (NIH) had just started the Human Microbiome Project (HMP), and her group was funded to study the role of the skin microbiome in acne. In general, the first wave of human microbiome studies took a look at the composition of the microbiome. Then, research sought to reveal what these microbes do and how they influence human physiology in health and disease states. Nowadays, Li said, researchers are largely trying to understand the mechanisms involved and figure out how a change in microbial activities could influence health.
This is the same sort of trajectory Li’s work has followed. At the beginning of her study of the skin microbiome, little was known about the microbial communities on the skin. Major microorganisms were known from previous traditional microbiology research, but overall, in terms of the community structure and how they change over time, it was not well studied, she said.
At the time, it was known that certain bacteria, especially the Propionibacterium acnes (P. acnes), are involved in acne development. “But we didn’t really understand whether the microbiome is different in acne patients versus healthy individuals,” she said. After comparing study participants, they came to realize that healthy individuals have just as much P. acnes, in terms of relative abundance, as acne patients.
Looking at the microbiome at the species level didn’t reveal any noticeable differences between the two groups, but an in-depth review of the data did reveal differences on a deeper level. Certain strains—groups of microorganisms that are genetically distinct from other groups of the same species—were highly associated with acne, while other strains were associated with healthy skin.
“I think this opened the door to a better understanding of the skin microbiome—not only just at the species level but at the strain level, which could potentially explain certain diseases,” she said. A similar concept can be found with E. coli. Almost everybody has E. coli in their gut, but only certain strains of it can cause disease. In other words, not every E. coli or every P. acnes is harmful.
In their first follow-up study, the researchers sequenced different strains of bacteria, analyzed that information, and revealed that certain genes were found in the disease-associated strains. The next logical step, Li said, was to figure out what these bacteria do on the skin and learn why certain microbes are associated with disease. After looking at the gene expression of the microbiome on human skin, they found that the activity of these bacteria differed between healthy individuals and acne patients.
Along the way, the vitamin B12 biosynthesis pathway caught the researchers’ attention. Bacteria on acne skin represses this pathway, which can lead to increased porphyrin production and trigger inflammation in acne development. This finding, she said, helped shed light on why some people develop acne while taking B12 supplements—a clinical phenomenon that had been recorded in literature for decades.
After digging further, the researchers learned that the disease-associated bacteria strains produce greater amounts of porphyrins than health-associated strains. And the health-associated strains don’t respond to B12 by producing more porphyrins, which may explain why some people don’t develop acne even while taking a vitamin B12 supplement.
Nowadays, Li’s work is focused on understanding how the microbiome changes over time and how treatment could change its composition.
Future Possibilities
Although the microbiome is not currently being harnessed as a means of diagnosing disease, Li does envision a future where microbiome-based diagnostics have moved from hope to reality. The microbiome can reflect the host status, and there are many studies showing that there are differences in the microbiome between a healthy state and a disease state, she said, so it could be used to identify the markers of disease.
A microbiome profile could also help stratify patients into different treatments. Some acne patients have antibiotic resistant strains, for example, so it would not be helpful to treat these individuals with certain types of antibiotics. Profiling the microbiome could help arrive at alternative treatment options instead of keeping the resistant strain while killing other commensal or potentially helpful bacteria.
Li is quick to point out that this anticipated future won’t come easy. While traditional microbiology tests often involve the detection of a single organism, a microbiome approach would mean looking at an entire community, she explained. And individual variation presents a huge challenge considering that even two healthy individuals can have radically different microbiomes.
When Lloyd Miller considers the possibilities of harnessing the skin microbiome for diagnostic purposes, the associate professor of dermatology at the John Hopkins University School of Medicine sees both hope and hardship down the road.
He studies the immune mechanisms involved in host defense and inflammatory skin conditions, and most of his lab’s research has centered on atopic dermatitis (eczema), psoriasis, and healing versus non-healing wounds, although he noted that there are many other skin diseases to evaluate for microbiome differences.
Different inflammatory processes in the skin have different skin microbiomes than normal skin microbiomes, he said, and these abnormal microbial communities can contribute to inflammatory skin diseases. If you take a disease like eczema, for example, it is known that the microbiome goes through dysbiosis (microbial imbalance) during flares. The bacterial communities on the skin become much less diverse, and most of the population is taken over by a species called staphylococci, especially Staphylococcus aureus.
“It’s not currently used as a diagnosis,” he said of the microbiome alterations, “but it tracks with disease flares.” And this means down the road it could potentially be used to track a flare or monitor the response to treatment because the flare is associated with a less diverse microbiome and the resolution of inflammation has a more diverse microbiome that more closely resembles the degree of diversity seen in normal, healthy skin.
And yet, the DNA sequences of all of the different microbial ribosomal subunits need to be sequenced and analyzed, so it’s an expensive and labor-intensive way to diagnose a flare. “I think that’s why they’re not routinely used in clinical practice right now,” he said. Beyond that, flares can typically be identified by patient history and visual inspection.
For these reasons, Miller isn’t so sure that the use of the microbiome will ever take over as a way to diagnose a particular skin disease, but he does believe enhanced understanding of the skin microbiome could offer up diagnostic and prognostic clues. “As we learn more about the microbiome, whether it be on the skin or in the gut, I think there’s an opportunity to figure out what the healthy microbiome is and what a disease microbiome looks like,” he said.
A healthy skin microbiome prevents pathogens that cause infection from getting into the skin, and a normal microbiome could prevent skin barrier defects resulting in water loss and dry skin that contributes to inflammatory skin diseases like eczema or psoriasis. The composition of the microbiome could also either help or hinder the healing of skin wounds.
If it became possible to promote a healthier microbiome on a patient with skin disease, that might just be a difference-maker. Who knows? Eventually, he said, a cream could emerge that promotes a healthy microbiome on the skin similar to the way a probiotic could prevent a disease-associated microbiome in the gut.
It’s the type of ambitious what-if that Oh is taking on at the moment. She was recently named the recipient of a New Innovator Award—part of the NIH High-Risk, High-Reward Research program—to the tune of $2.8 million. The plan? Learn how to harness the skin microbiome to develop probiotic treatments for a variety of skin and infectious diseases. Perhaps the outcome will transform the skin microbial therapeutic landscape as we know it.
Paul Nicolaus is a freelance writer specializing in science, nature, and health. Learn more at www.nicolauswriting.com.