Cover story THESE BUGS ARE GREAT!
In brief Cosmetic formulators have begun to explore the relationship between the human microbiome and healthy skin. Taking lessons gleaned from the Human Microbiome Project, a five-year, $157 million U.S. endeavor launched in 2008, they are embracing, rather than rejecting, microbes. The project teased out tantalizing details on the astounding variety of microbial communities living on human skin. Companies are now trying to nurture beneficial microbes to treat skin conditions such as acne and eczema as well as more minor maladies such as dryness and wrinkles. Skeptics wonder if the project’s lessons can be scientifically applied in cosmetics. Still, a number of startup firms are already incorporating bacteria into skin creams with the promise of “rebalancing” the community of bacteria that live on the human body and delivering healthier, more radiant-looking skin.
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MARC S. REISCH, C&EN NEW YORK CITY
CREDIT: YANG H. KU/C&EN/SHUTTERSTOCK
ove your bacteria.” That’s the tagline for Yun Probiotherapy’s line of skin cosmetics directed at those who have acne or athlete’s foot or who just want to keep their skin looking healthy. Yun’s product line, now entering the personal care market, incorporates “friendly” bacteria to help correct skin microbe imbalances. Scientists have known for some time that the skin, like the human gut, is teeming with bacteria, fungi, yeast, and viruses, all actors in what is known as the microbiome. Some are beneficial, others are not, and some considered “good” may become harmful under the right conditions. There’s also long-standing evidence of a connection between a healthy gut and the consumption of Lactobacillus-containing supplements and foods such as yogurt. Research firm Global Market Insights estimates that the food market for the beneficial microorganisms known as probiotics exceeded $36 billion in 2015. However, little was known about the diversity of the “bugs” among us or their impact on human health until the Human Microbiome Project, a five-year, $157 million endeavor launched in 2008 and overseen by the National Institutes of Health. The effort teased out tantalizing details on the astounding variety of microbial communities living in our guts and on our bodies. Now, cosmetic formulators are taking tentative first steps toward applying some of the lessons learned from the project to develop their own microbiome franchises. They are designing health-enhancing skin
care products that contain live bacteria, bacteria extracts, or ingredients meant to enhance skin microbe activity. Skeptics say not enough evidence exists to verify the benefits of creams and butters meant to farm the bugs living on human skin. They especially question the benefit of placing live microorganisms on the body without thorough testing, and they wonder how formulations containing live actors can even exist when regulations generally forbid the sale of “contaminated” products. Personal care product formulators like Yun aren’t put off by such questions about the skin microbiome. They see many opportunities emerging from research that suggests a strong connection between a balanced microbiome and healthy skin. Others targeting consumers with skin-microbiome-enhancing formulas include start-up firms such as AOBiome, maker of skin care products containing the ammonia-oxidizing bacteria Nitrosomonas eutropha, and Gallinée, a supplier of products containing probiotics as well as so-called prebiotics that feed skin microorganisms. And the small innovators are not alone. Some of the big personal care firms are MAY 8, 2017 | CEN.ACS.ORG | C&EN
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Microbiome skeptics Not surprisingly, the concept of microbiome-enhancing cosmetics has its doubters. Wilfried Petersen, managing director of the German preservatives specialist Dr. Straetmans, wonders if the developing fascination with the skin microbiome will amount to more than a hill of beans. “The story of the microbiome sounds nice, but the proof of benefit is lacking,” he says. European Union regulations, Petersen points out, don’t allow for the intentional addition of bacteria to cosmetics. In addition, he asks, if beneficial bacteria are added, how do you preserve the formula and how can you be sure it won’t become unstable and spoil? Dermatologist Patricia K. Farris points out that skin microbiome imbalances, such as the overgrowth of Propionibacterium acnes, are prevalent in many skin diseases. Correcting those conditions, perhaps with lactic acid or other bacterial derivatives, can provide relief for people with those conditions. “But can we make people look 20 years younger by putting probiotics on their face? I’m not sure we’re there yet,” says Farris, who is on the board of the American Academy of Dermatology. More study is needed to determine if pre- and probiotics are worthy of the hype they are getting, she says. Studies carried out as part of the Human
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Skin deep The composition of the microbiome varies widely depending on location.
Note: Microbes named represent the most common types.
Microbiome Project suggest that a person isn’t so much an individual as a complex organism composed of both human and microbial cells. Trillions of microorganisms inhabit the body, outnumbering human cells by 10 to 1. In all, those microorganisms make up 1 to 3% of the body’s mass, or anywhere from 1 to 3 kg on the body of a 100-kg adult. But the challenge is to translate that general knowledge into health and disease conditions and then to specific treatments. Mapping out and sequencing the genetic identity of microbes at various locations on the skin is a complex undertaking, notes Nava Dayan, a skin research consultant to
The Human Microbiome Project by the numbers ▸ $157 million: Amount invested
by the National Institutes of Health in microbiome research between 2008 and 2013 ▸ 2 kg: Average weight of microorganisms living in and on a 100-kg human body ▸ 10 to 1: The ratio of microorganisms to human cells in the body ▸ 10,000: Number of microbial species inhabiting the human body ▸ 8 million: Number of microbial protein-coding genes found in the body, 360 times the number of human genes
pharmaceutical and personal care firms. Even with the work undertaken to date, “we don’t fully understand the baseline of what a healthy skin microbiome is because it varies from person to person and even differs depending on a person’s age and environment,” she says. Without a full understanding of what the baseline is, developing a personal care product to influence the skin microbiome “is like shooting a moving target,” Dayan says. Even if scientists learn how the skin microbiome changes and shifts over time, they are still missing a lot of information about how microbes influence human cells. Testing personal care formulations for their effects on the skin poses another problem, Dayan says. Cultured human cell models now used in labs “are inherently sterile.” It will be some time before scientists can develop a human cell model that also incorporates skin microbes.
Probiotic possibilities Still, cosmetic firms such as Yun, the company that exhorts customers to love their bacteria, see value in harnessing what is now known about the microbiome. The firm has worked with scientists at the University of Antwerp to develop its product line, which incorporates live Lactobacillus. It promises to make its research public soon.
CREDIT: DARRYL LEJA/NATIONAL HUMAN GENOME RESEARCH INSTITUTE
staking out a claim to the microbiome. Johnson & Johnson, for instance, is helping the biotech firm S-Biomedic develop a bacterial treatment for both therapeutic and cosmetic applications. The firm is now a resident of J&J’s JLINX start-up incubator in Beerse, Belgium. Procter & Gamble has taken an interest in the skin microbiome, applying for a patent on a prebiotic composition to “improve the health of the skin microbiome.” L’Oréal, meanwhile, has patented the bacteria-derived ingredient vitreoscilla ferment, intended to “balance” the microbiome of dry skin. The firm has incorporated it into cosmetics sold under its La Roche-Posay label. Forward-looking personal care ingredient makers are also looking into what could be the next big thing in cosmetics. For instance, prominent ingredient suppliers such as BASF and Givaudan have introduced products to enhance the microbiome and, along with it, skin health. Smaller firms such as Azitra, Greenaltech, and Vantage Specialty Ingredients are also looking to provide microbiome-focused ingredients.
CREDIT: PIERO GEMELLI/GIVAUDAN
At a microbiome workshop last month at the In-Cosmetics personal care ingredients show in London, Yun cofounder Tom Verlinden said the company avoids contaminating other ingredients in its formula by housing the dormant Lactobacillus inside a protective microcapsule. When the cream is rubbed on the skin, the capsule breaks open and the bacteria are activated, according to Verlinden, who is trained as a pharmacist. The firm uses a “natural” pH-activated preservative system that turns off when it hits the skin’s pH, he added. Asked if he thinks the market is ready for skin care products that contain bacteria, Verlinden said he would not have thought so two years ago on the basis of surveys his firm conducted. “Now, given the fear of chemicals,” he said, consumers are ready for a more “natural” product. Some consumers have already given Yun a vote of confidence. The firm raised more than $20,000 on Indiegogo, a crowdfunding website, earlier this year. Regulators are ready for live probiotics too, Verlinden claimed. The regulators Yun has spoken with gave the firm the go-ahead after they saw data indicating its products “can’t hurt,” he says. Also adding live bacteria to its formulas is Cambridge, Mass.-based AOBiome, maker of a product called Mother Dirt. Speaking at the London workshop, Elsa Jungman, a product manager for the firm, explained that company founder David Whitlock uncovered the ammonia-oxidizing bacteria after being challenged to explain why horses roll in the dirt. Whitlock, a Massachusetts Institute of Technology-trained chemical engineer, took a look at the dirt and eventually isolated Nitrosomonas. While studying the bacteria, he found they consume the ammonia in sweat and produce nitric oxide and anti-infective compounds that have a role in regulating inflammation, Jungman explained. Whitlock concluded that horses roll in the dirt for its skin-soothing benefits. Nitrosomonas were once common on human skin, AOBiome theorizes, but with the widespread use of surfactants to clean skin, they have all but disappeared. Reestablishing them on the body promotes skin health and reduces the occurrence of skin pathologies such as acne, Jungman claimed. Mother Dirt drew attention the year before it was launched when a 2014 New York Times Magazine article detailed reporter Julia Scott’s experience testing a spray mist containing AOBiome’s active
A Givaudan scientist at the firm’s Toulouse research labs where the firm does microbiome research. ingredient. After a month of using the mist instead of showering, Scott said, she didn’t smell and her skin changed for the better. The mist and other preparations containing the bacteria contain no preservatives and must be refrigerated, Jungman said. “Our customers tend to be afraid of chemicals,” she said, and they tend to have very sensitive and problematic skin. To date, she noted, “we have had no adverse event reports involving our product.” The biotech firm Azitra, a 2014 spinoff from Yale University, has developed a skin-soothing recombinant microbe based on Staphylococcus epidermidis, a normal part of the skin microbiome. Azitra’s bacteria express filaggrin, a structural protein often missing or underexpressed in people who have skin problems such as eczema, explains Travis Whitfill, a Yale School of Medicine research scientist and Azitra’s chief science officer. The protein binds to keratin fibers in the skin’s epithelial cells, regulating skin lipids and helping the skin retain moisture, he says. Whitfill says filaggrin production is designed to be short-lived. After a day or two, the bacteria “kick out” the designer DNA Azitra inserted as they reproduce on the skin. The bacteria are still there, but the altered DNA decays in the environment, he says. Azitra is struggling with how to keep the bacteria viable until the consumer uses a product containing them. Whitfill says the firm is considering drying the bacteria so they go dormant and delivering them in a waterless emollient to the consumer. Moisture on the skin would revive them. So far, Azitra has raised nearly $4 million from the venture capital firm Bios Partners, in which Whitfill is also a partner. Azitra aims to qualify a consumer product for sale by 2019, hopefully with another firm, Whitfill says. Longer term, it wants to develop its
recombinant bacteria to treat skin conditions such as eczema and rare genetic skin diseases, he says. Gallinée distributes a cream in France and the U.K. that contains what the company describes as “deactivated bacteria from the Lactobacillus family” along with prebiotic fibers and sugars to support the growth of good bacteria, and lactic acid to optimize skin pH. The combination of ingredients is intended to repair the skin barrier and support the microbiome. The firm’s founder, Marie Drago, who like Verlinden is a pharmacist, also spoke at the London conference. Changing her diet to include prebiotic and probiotic ingredients alleviated the gluten intolerance she had for years, she claimed. That led her to reason that “if such a treatment worked inside, it could work outside too.” “We’re cleaner than we used to be, and that’s why you see so much disease,” Drago said.
Active ingredient approaches Some personal care ingredient suppliers are leery of diving into materials that contain bacteria, either alive or “deactivated.” But they are interested in developing active ingredients that work to benefit the skin microbiome. “We considered developing live bacteria strains with skin benefits,” says Boris Vogelgesang, a technical manager at BASF, the world’s largest chemical company. But the firm was concerned about regulations on microbial “contamination” of personal care products and the complications inherent in preserving creams and lotions while keeping good bacteria viable. “Maybe we can learn from food regulations,” which do allow active microorganisms in products such as yogurt and cheese, MAY 8, 2017 | CEN.ACS.ORG | C&EN
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Vogelgesang suggests. “Preservative regulations need to evolve to distinguish good from harmful bacteria.” That may happen with time, but for now “it’s a brand new topic,” he says, and BASF is taking a conservative approach. That approach includes establishing a research group that is exploring how microbes are involved in a healthy skin barrier and how active ingredients affect them. “We want to better understand the role of each microorganism in skin beauty and build new skin models to study effects of active ingredients,” says David Herault, BASF’s head of global R&D for bioactives. Together with the International Center for Infectiology Research in Lyon, France, BASF has been developing skin models embedded with bacteria. The firm hopes the models will help it launch active ingredients to treat aging skin, skin with pigment disorders, and skin exposed to pollution as well as to work with different skin types. BASF’s work in skin modeling also involves Poietis, a French firm with which it is developing a three-dimensional printed model of human skin as an alternative to animal testing of cosmetics, which is banned in Europe. Vogelgesang says 3-D printing can layer cells and precisely seed growth factors and cell types. The technique might be adapted to reproduce the cells and bacteria found in wrinkles, Vogelgesang suggests. Such a model could lead to microbiome-inspired techniques to reduce skin wrinkling. “There is a lot to discover about the skin microbiome,” he says. As BASF sees it, exploring the microbiome for personal care opens up a brave new world. “For years we’ve tried to eliminate problematic bacteria by using antibiotics. But killing the bad bacteria could also damage beneficial bacteria,” Vogelgesang says. “We need an approach that recognizes the community of flora on the skin and that preserves beneficial bacteria.” For now the firm is using in vivo methods to look at the effect of active ingredients on skin microbes. In doing so it has come up with an ingredient, called Relipidium, that rebalances the skin microbiome. Vogelgesang says Relipidium works by encouraging growth of the beneficial bacterial S. epidermidis and discouraging growth of Staphylococcus aureus, which is associated with dermatitis and dry skin. Launched late last year, Relipidium is made by feeding a yeast extract to Lactobacillus plantarum, a type of lactic acid bacteria. After filtering out any microbes, what are left behind are beneficial proteins, amino acids, and short-chain fatty acids. BASF expects to develop products that
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complement Relipidium in the future, Vogelgesang says, adding that the firm’s likely next microbiome-inspired targets are ingredients that address oily and sensitive skin. The fragrance ingredient specialist Givaudan is also developing actives to enhance the skin microbiome. Its 2015 acquisition of the active ingredients maker Induchem brought with it an R&D center in Toulouse, France, with expertise in genetic analysis and the microbiome, explains Fabrice Lefèvre, marketing and innovation director. Givaudan initially developed Revivyl, one of its newest ingredients, to “revive” the skin by stimulating cellular differentiation and exfoliation of older skin cells. But
developing ingredients that depend on microbiome activity. Many are betting that getting the skin microbiome into better balance with prebiotics is the first course of action. “We stay strictly with prebiotics and address the skin holistically,” says Michael Anthonavage, technical director of Vantage Specialty Ingredients. The firm’s PreBio Defense is a blend of polysaccharides that “acts as a fertilizer bed” for good skin bacteria, Anthonavage says. Prebiotics in the formula include inulin and β-glucan, which are packed into cellulose microcapsules to make it easy for formulators to blend into their skin care products, he says. Greenaltech, a Barcelona-based bio-
“Can we make people look 20 years younger by putting probiotics on their face? I’m not sure we’re there yet.” —Patricia K. Farris, board member, American Academy of Dermatology then “we also asked how this ingredient would affect the microbiome,” Lefèvre says. Isolated about 10 years ago, Revivyl is an extract from Orobanche rapum, a chlorophyll-free parasitic plant that grows in Europe. Besides its skin-reviving characteristic, Revivyl “protects skin by balancing the skin microbiota” and prevents microbial imbalances. According to the firm’s literature, Revivyl also inhibits the Finegoldia genus of opportunistic skin pathogens. In a concept it calls [Yu] for “you are unique,” Givaudan is promoting the incorporation of Revivyl into fragrances. Such a use would combine a sensory experience with microbiome protection to make users “feel and look beautiful,” Lefèvre says. Beyond ingredients that maintain the skin microbiome, Lefèvre says, Givaudan is developing ingredients that the microbiome turns on. One is Brightenyl, a skin-lightening agent that is activated by the skin’s resident bacteria. Developed two years ago, Brightenyl contains an α-glucoside derivative of trihydroxybenzoic acid that Givaudan calls THBG. When applied to the skin, THBG is converted by certain microbes into trihydroxybenzoic acid, a molecule that evens out and lightens the skin.
Practical prebiotics Other ingredient makers aren’t yet ready to go as far as introducing microbes to the skin or even
tech firm, is offering Algaktiv BioSKN, a prebiotic derived from microalgae. Joan Tarraga, who heads business development for the firm, describes BioSKN as a carbohydrate derived from microalgae cell membranes. The skin is subject to a variety of assaults, including “sun radiation, urban pollution, weather, and chemicals in the environment,” Tarraga argues. As a result, the epidermis thins “and our microbiome is altered, leading to inflammation,” he says. Incorporated into a cosmetic formulation, BioSKN helps beneficial bacteria grow and reduces the proliferation of harmful bacteria that can cause inflammation, he claims. Skin research consultant Dayan says she expects that scientists and cosmetic ingredient formulators will over time look more deeply into the “cross talk between the microbiome and human cells.” Understanding the complex community of microbes resident on the skin—and comprehending how those microbes can vary from individual to individual—can lead to the next steps in skin product development, she suggests. It’s uncharted territory for the personal care business. For years people have been taught to fear bacteria and knew of only the infections and illnesses they could cause. Time will tell whether the public is now ready to accept skin care products full of bacteria and turn microbiome-inspired cosmetics into the next big thing. ◾
