Quarterly Review: skin microbiome research in 2022

A few years ago, scientific questions were limited to understanding which microorganisms can be found on the skin and how accurately compositional changes can be detected.

In the future, the focus will be on what the presence of a specific microorganism means, and the central interactions of the skin with its guests as well as the interactions among the microorganisms.

In this regard, Dr Samantha Samaras from Unilever stated: “The first misconception is that the microbiome is static and that there are ‘bad bugs’ and ‘good bugs’, and that you just need to go in and kill the bad bugs and everything will be OK, when actually they’re incredibly complex living environments”.

Metabolomic and other omics technologies are the new buzzwords that will help us better understand these interactions and the resulting metabolic changes. These approaches will create vast amounts of data that can only be interpreted by trained data scientists. Although wrong conclusions based on inadequate data management will be a major challenge in the coming years, we will be able to show correlations and better understand various skin disorders such as sensitive skin and acne.

This article offers a non-exhaustive compilation of relevant publications in the skin microbiome field, providing key insights into the current state of research with a focus on the personal care industry.

Skin microbiome of atopic dermatitis

Li Fang Koh, Ruo Yan Ong and John E. Common

This comprehensive review summarizes the current understanding on how the human skin microbiome impacts atopic dermatitis (AD) − a frequent inflammatory skin barrier disorder.

Several interesting topics and open questions are covered, such as:

  • How are microbes connected to AD? Several skin-resident microbes, such as Staphylococcus aureus and fungal Malassezia species aggravate skin barrier dysfunction and drive AD pathogenesis.
  • How do different skin microbial species interact with each other, and how do these interactions impact skin health? Several fungal and bacterial skin microbes have been shown to secrete products (metabolites) that inhibit colonization of skin by S. aureus, and as such reduce AD severity.
  • Can microbes regulate the skin immune system? In fact, commensal microbiota can trigger an appropriate immune response and consequently have a protective function in early life. Indeed, reduced exposure to microbes increases susceptibility to AD in early childhood. This means that early life could be a critical time to initiate microbiome interventions.
  • Could next-generation microbiome-based biotherapies help treat AD? Several promising directions are currently being investigated, such as repopulating AD skin lesions with commensal microbes. Without doubt, microbiome-based therapies have diverse treatment possibilities for AD, and it will be interesting to see what future investigations will reveal.

These findings are also important for the work of Louis Danoux, which examined C. acnes ribotype in subjects with acne (phylotype I increased and II decreased i.e. those with the least amount of antioxidant enzymes). Importantly, Danoux and team found that the effects of antimicrobial peptides were greater on IA-1 strains.

Sabrina Leoty-Okombi from chemical company BASF studied the microbiome in wrinkles of Caucasian skin. Increases in alpha diversity were observed in the aged group, with reduced C. acnes and higher levels of Corynebacterium kroppenstedtii and Veillonella parvula. Decreased levels of lactic acid bacteria such as Lactobacillus crispatus were observed in wrinkled areas. Lipid analysis showed decreased sterols, docosanol and octadecanoic acid that may be related to these changes. These findings emphasize the potential importance of Lactobacillus bacteria on aged skin, and that their metabolites may be beneficial. L-lactic acid is a well-known anti-aging ingredient.

Host–microbe interaction on the skin and its role in the pathogenesis and treatment of atopic dermatitis

Danuta Nowicka, Karolina Chilicka and Iwona Dzie´ndziora-Urbinska

The skin microbiome and its interaction with the human host clearly seems to impact the development and course of skin disorders, in particular AD, which is reflected by this great literature review. The review attempts to identify factors that are involved in the pathogenesis of AD-related bacterial and fungal skin colonization.

Generally, scientists agree that structural and functional defects of the epidermal skin barrier, a dysbiotic skin microbiome (including over-colonization by S. aureus), a disturbed immunity and environmental and genetic factors contribute to development of AD. The roles of several factors are discussed systematically, including:

  • The role of the epidermal barrier. An altered skin barrier function seems to trigger inflammatory responses in the skin of AD patients, as well as facilitating colonization by microorganisms such as S. aureus. For example, the skin of AD patients is characterized by an altered lipid composition, which in turn has been shown to increase retention and thus colonization by pathogenic microorganisms.
  • The microbiome and its role in atopic skin inflammation. A well-functioning skin microbiome is characterized by diversity. Indeed, the microbiome of the skin of AD patients is significantly less diverse than that of healthy individuals. The skin microbiome even changes during the different phases of the disease. During periodic exacerbations of AD, S. aureus and Staphylococcus epidermidis are dominant, whereas during remission, Streptococcus, Propionibacterium and Corynebacterium become dominant.
  • The microbiome and its role in immune disease. Besides the well-described potential roles of the skin microbiome in AD development, dysbiosis of the gut microbiome seems to affect the immune system and lead to immune diseases, including dermatological diseases.
  • The role of probiotics in AD. Plenty of studies have reported positive impacts of orally consumed probiotic bacteria from the genera Lactobacillus and Bifidobacterius for the treatment and prevention of skin disorders, including AD. Interestingly, this review does not mention the potential of skin microbial probiotics as a therapeutic approach to treat skin disorders. However, the review by Fangg Kon et al. comprehensively covers this topic.

A better understanding of host–microbe interactions and the mechanisms involved in these interspecies communications will help to develop probiotics that can manipulate the host microbiome, and consequently have a positive effect on the reduction of symptoms associated with AD.

Advances in microbiome-derived solutions and methodologies are founding a new era in skin health and care

Audrey Gueniche, Olivier Perin, Amina Bouslimani, Leslie Landemaine, Namita Misra, Sylvie Cupferman, Luc Aguilar, Cécile Clavaud, Tarun Chopra and Ahmad Khodr

This review shares the current view regarding the interactions between the skin and its microbiome, and the impact on skin health and disease. For example, skin microbiome variability due to age and extrinsic factors (such as pollution and cosmetics) and in association with skin health and disorders are discussed.

The review also provides an overview of how the landscape of skin microbiome research has evolved. For example, methods in skin microbiome exploration, such as next-generation sequencing, metabolomics and data science for integration of multiple investigations are discussed. Metagenomics is of particular interest for the dermo-cosmetic industry. The naturally occurring skin microbes allow the discovery of new molecules as potential targets for disease diagnosis and treatment.

The review also addresses how microbiome research can be translated into products and concepts in the dermo-cosmetic field, highlighting that:

  • Intervening and finely modulating the microbiome by using pre-, pro- or post-biotics to correct skin conditions is a rising field of research.
  • Each human has their own ‘microbial fingerprint’ that is specific to their skin, and this specific microbiome may open the path to personalized microbiome-derived cosmetic solutions.

Microbiota and maintenance of skin barrier function

Tamia A. Harris-Tryon and and Elizabeth A. Grice

This review highlights the importance of the skin microbiome in maintaining skin barrier function. The review also discusses the prospect that manipulating skin–microbiome interactions could help to improve skin disease conditions and wound healing. Implications for disorders of distant organs, such as intestines and lungs, mediated by host–microbiome interactions are also discussed.

For example, the review highlights that:

  • The skin microbiota strengthens multiple levels of barrier function. The review discusses how skin microbes interact with microbial, chemical, innate and adaptive immune components of the skin barrier.
  • Pathological microbial–host interactions and skin disorders. Once the habitat of skin microbes is disturbed, which can occur in association with skin disorders, the microbial communities must adapt accordingly to the change. Independent of the uncertainty as to whether disruption of the niche causes the skin microbiome to change, or vice versa, unbalanced microbial compositions can mediate tissue damage and/or inflammation across a variety of skin disorders. Certain microbial species, such as S. aureus, secrete proteases and other metabolites, which further accelerate skin barrier damage and induce inflammatory responses of the skin. Interestingly, tryptophan metabolites, which are known to support the skin barrier defense systems, are depleted in the skin of AD patients. External application of these metabolites reduced inflammation in mouse models. Whether this finding can be translated to human skin remains to be investigated.
  • Systemic roles for the skin microbiome. There is increasing evidence that skin damage and sensitization can affect other barrier sites, such as the intestine and the lung. Emerging evidence suggests that crosstalk between skin and other distant organ systems is mediated by the skin microbiota. It was shown that allergic sensitization of skin, in combination with S. aureus infection, results in lung inflammation. Furthermore, skin injury in mouse models releases hyaluronan fragments, which drives gut inflammation. It was also observed that pore-forming toxins are released during the infection cycle of S. aureus that are implicated in mechanisms of pain generation.

Aging-associated changes in the adult human skin microbiome and the host factors that affect skin microbiome composition

Brian Howard, Charles C. Bascom, Ping Hu, Robert L. Binder, Gina Fadayel, Tom G. Huggins, Bradley B. Jarrold, Rosemarie Osborne, Heather L. Rocchetta, Dionne Swift, Jay P. Tiesman, Yuli Song, Yu Wang, Kenneth Wehmeyer, Alexa B. Kimball and Robert J. Isfort

This paper addresses a key question that has been of great interest since microbiome research first gained attention: how does aging affect our microbiome, and can the skin microbiome affect the skin-aging process? The main goal of this project was to provide better understanding towards the changes in the skin microbiome and its relationship to host skin factors during aging.

The main findings were:

  • Skin bacterial diversity increases with age, and relative abundances of Lactobacillus and Cutibacterium genera decrease with age (as found in previous publications).
  • A significant decrease in the size of the facial sebaceous gland area (and consequently sebum production) with age was also observed. Skin oiliness was positively correlated with the presence of Cutibacterium and Streptococcus, and negatively correlated with Acinetobacter, Enhydrobacter and Corynebacterium.
  • Natural moisturizing factors (NMFs) in the skin stratum corneum showed a significant age-related increase. The presence of Cutibacterium and Staphylococcus was negatively correlated with NMF levels, whereas the presence of Corynebacterium, Micrococcus, Streptococcus, Anaerococcus, Finegoldia, Methylobacterium-Methylorubrum, Acinetobacter, Enhydrobacter and Leptospira was positively correlated with overall levels of NMFs. Of note is that NMFs are known to increase bacteria proliferation and adherence in the skin.
  • Gene expression of antimicrobial peptides (AMPs) in the epidermis showed that lysozyme and RNAse7 significantly increased with age.

The review concludes that age-related decreases in sebocyte area and increases in NMFs, AMPs and skin lipids are correlated with changes in specific bacterial genera. Changes in the skin microbiome composition may be the result of aging-related alterations in host skin components, such as those used as microbial food sources and antimicrobial defense.

Selective targeting of skin pathobionts and inflammation with topically applied lactobacilli

Sarah Lebeer, Eline F. M. Oerlemans, Ingmar Claes, Tim Henkens, Lize Delanghe, Sander Wuyts, Irina Spacova, Marianne F. L. van den Broek, Ines Tuyaerts, Stijn Wittouck, Ilke De Boeck, Camille N. Allonsius, Filip Kiekens and Julien Lambert

Per definition, “probiotics are live micro-organisms that, when administered in adequate amounts, confer a health effect on the host”. Probiotics have been long known in the food industry and are becoming increasingly interesting for dermal applications. Advances in DNA sequencing techniques have also allowed the design of tailored skin microbiome modulation approaches – these, however, remain highly challenging and have not yet been widely considered for direct application on the skin.

This paper elegantly discloses a stepwise study execution, from rationalizing the in vitro selection of Lactobacillus strains to the design of viable probiotic formulation in cream, skin microbiome modulation with live lactobacilli and, finally, lactobacilli-mediated improvement of acne symptoms:

  • Even though lactobacilli are underestimated members of the skin microbiota, specific strains of lactobacilli were selected for their functional applicability to the skin and their capacity to inhibit the growth of skin pathobionts and the associated inflammation.
  • Lactobacilli are not considered to be classic skin commensals. Indeed, they do not generally occur as the most abundant taxa on the skin. However, some volunteers showed a relatively high abundance of lactobacilli taxa. This finding led the authors to postulate that lactobacilli could play a role as keystone microbes, which are defined as “taxa exerting a considerable influence on microbiome structure and functioning irrespective of their abundance across space and time”.
  • The carefully selected lactobacilli strains were formulated as microcapsules for topical formulations and tested in patients with mild-to-moderate acne.
  • Although lactobacilli have a long history of safe use in the food industry, it was not certain whether lactobacilli could also be used as a bioactive ingredient in a skin cream.
  • The selected lactobacilli were shown to reduce inflammation, associated with a temporary modulation of the microbiome, including a reduction in relative abundance of Staphylococci and Cutibacterium acnes.
  • Physicians often prescribe antibiotics to treat acne. Because of the rising problems of antibiotic resistance, alternative therapies, such as the described “active pharmaceutical” or “pharmabiotic”, are of urgent need.
  • Encouragingly, the reduction in inflammatory lesions was still apparent 4 weeks after treatment with lactobacilli, indicating a possible additional immunomodulatory effect.

Alteration of barrier properties, stratum corneum ceramides and microbiome composition in response to lotion application on cosmetic dry skin

Barry Murphy, SallyGrimshaw, Michael Hoptrof, Sarah Paterson, DavidArnold, Andrew Cawley, Suzanne E. Adams, Francesco Falciani, Tony Dadd, Richard Eccles, Alex Mitchell, William F. Lathrop, Diana Marrero, GalinaYarova, AnaVilla, John S. Bajor, Lin Feng, Dawn Mihalov and Andrew E. Mayes

What happens to skin and specifically the skin microbiome after application of cosmetic products? This paper provides new insight into this topic.

Dry skin (xerosis) is usually associated with low levels of ceramides. Treatment of xerosis regularly includes the use of ingredients that restore barrier integrity and improve the hydration of the skin, which in turn should establish a health-associated microbiome. Much research has been done to understand how the skin microbiome differs between healthy skin and skin disease states (such as acne and AD). However, almost no work exists that examines the cosmetic dry skin microbiome and its response to treatment.

This paper now investigates the impact of commercially available body lotion on both skin condition and the skin microbiome:

  • Analysis of multiple skin biomarkers showed consistent improvement after the body lotion usage period. For example, skin dryness showed significant improvements for the study participants. Other significant increases were seen in the level of ceramides, free fatty acids and cholesterol following body lotion application, which provides further evidence for the critical role of lipids in maintaining good skin hydration and barrier function.
  • In addition to improvements in skin condition and composition, changes in the skin microbiome were also examined. Microbiome assessment of skin before and after body lotion use showed limited differences between the groups. No differences were seen in skin microbiome alpha diversity (differences in species richness within one group) and beta diversity (differences between two groups).
  • Using traditional qPCR (quantitative PCR), a significant increase was seen for S. epidermidis post intervention. S. epidermidis is one of the most important members of the microbiome for maintenance of skin health. Indeed, recent activities have examined the beneficial impact of the application of S. epidermidis to the skin of clinical subjects, leading to an increase in lipid content of the skin, suppression of water evaporation and better maintenance of the skin’s acidic pH.
  • Finally, predictive functional analysis showed that pathways involved in microbial production of skin-relevant fatty acids are potentially upregulated after body lotion application.

This is the first demonstration of such an effect on cosmetically dry skin as a result of moisturizer application, with the findings suggesting that improvements in skin barrier function may be, in part, mediated by alterations in the skin microbiome composition, function and connectivity.

Anatomy promotes neutral coexistence of strains in the human skin microbiome

Arolyn Conwill, Anne C. Kuan, Ravalika Damerla, Alexandra J. Poret, Jacob S. Baker, A. Delphine Tripp, Eric J. Alm and Tami D. Lieberman

What enables strains of the same species to coexist in a microbiome? So far, the anatomy as a factor that impacts co-residence of microbes and thus skin microbiome activity has not been discussed intensively. The paper addresses this topic using Cutibacterium acnes, the most abundant species on human skin, as example.

Highlights include:

  • Individual people typically harbor multiple lineages of C. acnes. Each adult has a unique mix of C. acnes strains, which are found at substantially higher abundance within follicles of pilosebaceous units (skin pores) compared with the skin surface.
  • C. acnes lineages coexist across an individual’s skin but not within the same pore. The anatomy and physiology of human skin promotes substantial intraspecies diversity − in part by segregating the C. acnes population across disconnected pores. Strikingly, the authors find that each skin pore is dominated by a single C. acnes lineage, despite the coexistence of multiple lineages within the immediate vicinity. However, these patterns do not seem to hold for S. epidermidis and related species, which are thought to grow primarily at the top of pores and on the skin surface.
  • The authors hypothesize that the physical structure of skin pores may create an environment in which luck and location − rather than genomically encoded fitness − predict colonization success. Therefore, the adaptive potential of C. acnes on individual people is limited. This mechanism, termed ‘bottlenecking’, suppresses selective forces by reducing competition between microbial cells with different genotypes and introducing randomness in which cells get to proliferate. These proposed mechanisms emphasize how host anatomy has the potential to suppress selective forces and raise an interesting question of whether these physical skin pore structures have evolved because limiting commensal evolution is beneficial to the host.
  • Understanding how host anatomy and physiology influence strain-level composition in microbiomes is critical to the design of precision microbiome therapeutics. In particular, these results suggest that the ability of a probiotic strain to engraft on sebaceous skin may hinge less on the probiotic strain’s competitive fitness, and more on the efficient removal or destabilization of the existing community prior to treatment.

Small molecules enhance the potency of natural antimicrobial peptides

Valeria Losasso, Khushbu Agarwal, Morris Waskar, Amitabha Majumdar, Jason Crain, Martyn Winn and Michael Hoptroff

Niacinamide is often present in cosmetic skincare products and promotes better skin health. This paper addresses the question of what potential mechanisms are responsible this beneficial effect, and how this small molecule impacts the skin microbiome.

The human body has developed several defense mechanisms to modulate the skin-associated microbiome, including endogenously produced AMPs, which are secreted by sweat and sebaceous glands. Keratinocytes, which are the main living constituents of the epidermis, produce and secrete several AMPs, including the cathelicidin LL-37 – the production of which is stimulated in presence of undesirable Gram-positive and -negative bacteria, including viruses.

Discovering how AMPs exert their antimicrobial effect and translating this insight into consumer products that work in partnership with natural defense peptides is important when identifying innovative and sustainable technologies for consumers. Interestingly, several AMPs have different target specificity – that is, they target microorganisms with different cell membrane compositions − suggesting that modulating the lipid membrane structures rather than redesigning AMPs may increase AMP potency. Indeed, the bacterial membrane composition distinguishes itself from mammalian cells in that it contains anionic lipids, thus explaining the selective toxicity of AMPs against bacteria while sparing mammalian cells.

The small molecule niacinamide, a form of vitamin B3, has been reported to boost the expression level of AMPs in human tissues. This paper addresses the question of whether niacinamide can amplify the antimicrobial potency of AMPs, specifically LL-37, through mechanisms of physical interactions.

The investigation involved complex in vitro experiments using simplified model membrane substrates, and in silico experiments using adaptively biased molecular dynamics computer simulations, leading to the following insights:

  • Niacinamide has a synergistic effect with the human AMP LL-37 and enhances protection against the pathogenic bacterium S. aureus, which is closely associated with AD.
  • Niacinamide is predicted to partition into the headgroup region of an anionic bilayer, a characteristic for bacterial membranes, with little effect on zwitterionic bilayers that mimic a mammalian membrane.
  • Authors conclude that niacinamide enhances the activity of AMPs by modulating the physical properties of the bacterial membrane, and to a lesser extent through direct interactions with the peptide.

In summary, this paper describes a model that may explain how a small molecule such as niacinamide, which is not inherently antimicrobial, enhances skin health benefits by potentiating the body’s natural defenses. This is done by: (1) boosting the number of AMPs; and (2) by potentiating their activity against pathogens.

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