The skin is home to a menagerie of microbes. The bustling community contains some fungi and viruses, but a diverse collection of bacteria make up the majority (1). Through its interactions with immune and skin cells, the skin microbiome helps keep not only the skin but also the entire body healthy.

“They function as a community, so as a real ecosystem, a little bit like in a rain forest,” said Sarah Lebeer, a microbiome researcher at the University of Antwerp. “The little bit of more diversity that you have, the better you are protected against an invasion with unwanted bad bacteria.”

Sometimes, however, harmful bacteria that normally live in harmony with other skin microbes can overgrow and dominate the population. This can lead to infection in the case of the common skin bacteria, Staphylococcus aureus, or acne with the bacteria Cutibacterium acnes.

Lebeer studies the dynamics of different microbiomes, including the vaginal, respiratory, and skin microbiomes. From her early research of the vaginal microbiome, she knew that Lactobacillus bacterial species play important roles in the vaginal microbiome to promote vaginal health (2). She wondered whether lactobacilli could also benefit the skin microbiome by counteracting the inflammatory effects of acne-causing bacteria.

After years of work and fruitful collaborations with academic and industry partners, Lebeer and her team spun out their research into the company YUN and developed a cream formulated with live lactobacilli to treat acne. Building off of this success, she and her team now investigate how to use lactobacilli to help treat other chronic inflammatory skin conditions such as atopic dermatitis.

How did you become interested in studying different microbiomes?

Since I started my research career, I’ve been intrigued by beneficial bacteria and how they can promote human and environmental health. I did my PhD research on inflammatory bowel disease, and I investigated how specific probiotic bacteria such as Lactobacillus and Bifidobacteria could protect the gut epithelium against inflammation. I wanted to know which lactobacilli genes and molecules could block inflammation and protect the gut barrier, but that was really in the premicrobiome era, so there were no sequencing tools available yet.

Then I conducted my postdoctoral research on the vaginal microbiome and how specific lactobacilli could protect against viral infections such as HIV because the vagina is the port of entry for this virus. Around that time, many microbiome sequencing studies started to pop up, and I had the opportunity to start my own lab in Antwerp. I thought, I want to do microbiome research, but which microbiome shall I focus on? So many great scientists were already working on the gut microbiome. There are a lot of other mucosal microbiomes — on the skin, in the mouth, in the nose, in the vagina — that are also important. I decided to focus on these underexplored microbiomes. 

Why did you want to study Lactobaccillus in the context of the skin microbiome specifically?

I was working on the vaginal microbiome, which I often say is even more important than the gut microbiome. As babies move through the birth canal, the vagina gives them their first bacteria. Because the vaginal microbiome has a dominance of lactobacilli, these bacteria are the first colonizers of the baby and the skin.

I always wanted to study whether the skin maintains a population of lactobacilli. I thought that they were probably rapidly out competed by other bacteria on the skin, but maybe we could still detect them. I knew from my previous research that they could be beneficial, so the first question I had was if I could see them on the skin.

We took cheek samples from volunteers in the lab, and we found lactobacilli (3). They were not the most dominant species, but there were more of them than we expected to see. We thought that maybe we saw so many because we are a Lactobacillus lab. But when we checked the publicly available microbiome databases, we saw that lactobacilli form a consistent part of the skin microbiome.

Where did the idea come from to use lactobacilli on the skin as an acne treatment?

Because we had found lactobacilli on the skin, we thought that instead of developing probiotics for the gut and the vagina, maybe we could develop lactobacilli probiotics for the skin. We thought that we might find a suitable Lactobacillus strain that could fight Staphylococcus aureus and Cutibacterium acnes. If we could find a way to put lactobacilli in a live form in a cream, maybe we could develop a novel therapy for conditions such as acne. It was a really ambitious project, but it turned out to be more successful than I thought.

After you identified promising lactobacilli strains to target acne, how did you formulate them into a skin cream?

We thought that we should make a formulation to keep the lactobacilli in an inactive form in the skin cream, so we designed a capsule to enclose them. When someone applies the capsules onto the skin, the bacteria need to be resuscitated so that they can become active, so we had to make sure that the capsule would break open when it encountered the skin. We had very talented chemistry graduate students who played around with the capsule material and with the preservation components to prevent the growth of unwanted bacteria. We tested hundreds of different types of formulations.

It's one of the few occasions that we could show — from the lab to the patients — that the probiotic had a benefit. 
– Sarah Lebeer, University of Antwerp

In the end, we developed a lactobacilli-containing capsule in the cream, and when someone presses on the capsule by rubbing the cream between their hands, the bacteria come out. People can then put the cream with active lactobacilli onto the skin where the acne is. In the paper, we reported that the cream had a six-month shelf life, but now we have 18 months or even longer shelf lives. We’re still improving the process.

How did you test the live lactobacilli acne treatment?

We first had an open label pilot study with volunteers from our university hospital. They all had reduced inflammation on the skin, but we had no placebo control in that trial. So we conducted a randomized placebo-controlled trial, and that showed even more positive results than we expected because we saw reduced inflammation in all of the people participating if they applied the cream twice daily. It's one of the few occasions that we could show — from the lab to the patients — that the probiotic had a benefit.

What challenges did you face in developing this acne cream?

A very important challenge was the regulatory environment. In cosmetics, we cannot have live microbes in a skin cream because it looks like contamination. We developed a quality control system to show that we only had the live beneficial bacteria and no pathogens in the cream. We can show that if a test detects live bacteria, they are only the ones that we actually want there. We were very happy that the European Regulatory Authority was willing to approve this innovation.

Are you interested in using lactobacilli to treat other inflammatory skin conditions?

We're continuing to look at other inflammatory skin conditions in my lab, and the most important one we are studying now is atopic dermatitis or eczema. We have done one trial with the same formulation, but we discovered that for eczema, we need an even more moisturizing formulation because it's often a very dry skin condition. We also discovered that there are different types of atopic dermatitis, and a host factor also seems to be involved as well as some other things. We're still working on that.

We also did a microbiome study to look at the possible causes of atopic dermatitis. Acne often occurs on the more fatty regions of the skin that have a lot of sebum secretion, while eczema shows up on the elbows or knees, which are much drier. There is a different microbiome on this body site, so we need to have a different strategy to block the inflammation and the pathogens there.

What do you find most exciting about studying the beneficial effects of lactobacilli?

In my group, we make comparisons between lactobacilli in the vagina, on the skin, and in the nose as well as compare their activities in fermented foods and yogurts. So it's quite a helicopter picture. But what I liked about the skin microbiome project was that we got to make a product and do a clinical trial. We showed that lactobacilli have a causal role in a person’s skin microbiome ecosystem. If people have fewer of these beneficial bacteria, we can put them on their skin, and they can really see the benefit. 

For me, it was one of the first times that we could prove that the concept works. If we add a lot of beneficial bacteria, there is less skin inflammation. Now it's a product on the market. I have a teenage daughter, and she and her friends are using it. When we were writing the paper, one of the reviewers said that we should highlight the safety of the treatment because it's not often that there are so few adverse events in an acne treatment. With lactobacilli, it's like a friendly way of using nature to protect the skin.

References

1. Byrd, A., Belkaid, Y., and Segre, J. The human skin microbiome. Nat Rev Microbiol  16, 143–155 (2018).
2. Petrova, M.I. et al. Lactobacillus species as biomarkers and agents that can promote various aspects of vaginal health. Front Physiol  6 (2015).
3. Lebeer, S. et al. Selective targeting of skin pathobionts and inflammation with topically applied lactobacilli. Cell Rep Med  3, 100521 (2022).