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Abstract Understanding the oral microbiome in health and disease is essential as it will give further directions to explore the functional and metabolic alterations associated with the diseased states, and to identify molecular signatures for drug development and targeted therapies which will ultimately help in rendering personalized and precision medicine. In this article we explore the development of the oral microbiome, ask what might constitute a ‘healthy’ oral microbiome, and question what still needs to be done in terms of research in order to fully understand the link between the oral microbiome, oral health, and systemic health. The Oral Microbiome The oral microbiome is thought to have the third highest diversity of any microbiome niche, and given its ease of collection has become one of the most well-studied (Dewhirst et al. 2010). Previously, studying the microbiome was limited to the conventional culture-dependent techniques, but the abundant microflora present in the oral cavity could not be cultured. Hence, studying the microbiome was difficult. The emergence of new genomic technologies including next-generation sequencing and bioinformatics has revealed the complexities of the oral microbiome, and has provided a powerful means of studying it. The oral microbiome comprises a complex and diverse community of microorganisms living within the oral cavity. It is understood to be the third most diverse and largest after the gut and skin microbiota with over 700 species of bacteria alone (excluding fungi, protozoa and viruses). The microbiome is crucial to the oral health of humans as it is formed of an abundance of bacteria that live on multiple different surfaces: teeth, soft tissues, and mucosa. It is also the first point of digestion and is therefore thought to be crucial in maintaining oral and systemic health (Deo & Deshmukh, 2019). Development of the Oral Microbiome Despite the womb being considered as sterile, recent studies have found colonization by oral microorganisms within the intrauterine environment in as many as 70% of pregnant women, namely Streptococcus spp. and Fusobacterium nucleatum. The development of the oral microbiota is understood to begin after birth, and grows as an infant is exposed to varying microorganisms from its environment. This happens as soon as a baby’s first weeks of life. At birth, a newborn acquires all the necessary species of microbes to keep it healthy, namely Streptococcus salivarius. Within the first year, an infant will go on to develop a more diverse microbiome with Lactobacillus, Actinomycetes and Neisseria (Deo, Deshmukh, 2019). The increase of microorganisms in the oral cavity is the result of a variety of factors including oral hygiene practices, diet, and environmental factors. As children grow and their teeth begin to emerge, the complexity of the microbiome increases, and the microbial community shifts to reflect changes in the oral environment. What is a ‘Healthy’ Oral Microbiome? According to Berg et al. (2020), the term "microbiome" pertains to the collective microbial population residing in a specific environment with unique characteristics. It encompasses not only the microorganisms co-existing in that environment but also their interactions with each other. It is generally accepted that for the microbiome to be healthy it needs to be balanced. The concept of a "core microbiome" in oral microbial communities refers to the presence of similar bacterial communities in the mouths of healthy individuals who are not related to each other, regardless of their age or ethnicity. This means that there are certain types of bacteria that tend to be present in the oral cavity of healthy people, regardless of their individual differences. A healthy microbiome is a barrier to external pathogens and possible exterior aggression. It must be balanced. The balance between bacteria is different between each individual because it depends on multiple factors. However, the species found in individuals overlap (Zaura, et al, 2009). To maintain this balance, oral hygiene with products targeting the microbiome is recommended, meaning the use of products that do not upset the balance of the microbiome. Pre and probiotics can also be interesting ingredients in oral health products for a balanced microbiome (Nanavati et al, 2021). An unbalanced oral microbiome can allow the overgrowth of pathogenic bacteria and lead to an oral infection locally in the mouth, for example Filifactor alocis, Porphyromonas, Synergistetes, and Peptostreptococcaceae are genera known to be a causal agent for periodontal disease (Lovegrove, 2004). Amazingly, pathogenic bacteria in the mouth might contribute to systemic diseases, for example, an increase in Fusobacterium and other bacterial species has been found in oral cancer patients and diabetics, reinforcing the importance of a balanced oral microbiome (Matsha, et al, 2020). Ectopic colonization of oral bacteria in other tissues or organs such as the stomach, heart, brain, placenta or even tumors could influence these diseases through an inflammatory response. Some recent studies also point to the possible usefulness of the oral microbiome as a treatment for infections of different organs of the body. For example, it has been shown that the use of oral firmicutes spores could help treat C.difficile infections. (Feuerstadt, et al, 2022) Next steps for research The link between the oral microbiome and systemic health is still an evolving area of research, thanks to the emergence of sequencing and bioinformatics we are closer to understanding this link. Further research on the correlation between systemic diseases and the oral microbiome is needed in order to gather such consistent and reliable results required to fully understand the important role of oral cavity bacteria. To date, we have conducted numerous oral microbiome studies. If you are interested in carrying out any research with us and testing your oral care products, you can reach us at team@sequential.bio. Lexicon: Oral Microbiome: All genomes of microorganisms in the oral cavity (Deo, Deshmukh,2019) Systemic disease: Disease that impact the whole body C. difficile infections: Clostridium difficile, also called C. difficile, is a type of bacteria that can cause a bowel infection Fusobacterium: Bacteria normally present in the mouth, but can cause infections when  unbalanced Prebiotics: ingredients that promote the balance of the microbiome Probiotics: Microorganisms that have health benefits References: Deo, P.N. and Deshmukh, R. (2019) “Oral microbiome: Unveiling the fundamentals.,” Journal of Oral and Maxillofacial Pathology, 23(1), pp. 122–128. Available at: https://doi.org/10.4103/jomfp.jomfp_304_18. Feuerstadt, P. et al. (2022) “SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection,” New England Journal of Medicine, 386(3), pp. 220–229. Available at: https://doi.org/10.1056/nejmoa2106516. Lovegrove JM. Dental plaque revisited: bacteria associated with periodontal disease. J N Z Soc Periodontol. 2004;(87):7-21. PMID: 15143484. Marsh, P.D. (2000) “Role of the Oral Microflora in Health,” Microbial Ecology in Health and Disease, 12(3), pp. 130–137. Available at: https://doi.org/10.1080/089106000750051800. Matsha, T.E. et al. (2020) “Oral Microbiome Signatures in Diabetes Mellitus and Periodontal Disease,” Journal of Dental Research, 99(6), pp. 658–665. Available at: https://doi.org/10.1177/0022034520913818. Nanavati, G., Prasanth, T., Kosala, M., Bhandari, S.K. and Banotra, P., 2021. Effect of probiotics and prebiotics on oral health. Dental Journal of Advance Studies, 9(01), pp.01-06. Zaura, E. et al. (2009) “Defining the healthy ‘core microbiome’ of oral microbial communities,” BMC Microbiology, 9(1), p. 259. Available at: https://doi.org/10.1186/1471-2180-9-259.

Abstract When it comes to the personal care industry for intimate female care products, there is still a lot to be explored and infinitely more that we do not know. For this reason, it is crucial to shed light on current and past research so that we can learn from it and make efforts to widen the literature to bring more effective formulations to the industry. The Intimate Care Industry The intimate care industry for female products is projected to reach USD $69,853 million by 2030 (Acumen Research and Consulting, 2022). For years there has been a stigma linked to women’s intimate care and a lack of willingness to discuss such topics. However, we are seeing a shift towards one that favours openness and education. Women’s intimate care products account for approximately 17% of the personal care market, with popularity rising for hygiene products the likes of intimate washes (FMI, 2019). As companies begin to formulate their own products for the needs of this niche of the market, the interesting question arises of what one should look for within these formulations. As we have seen in recent years, the skincare industry is seeing a drastic turn towards science-backed products with an increase in demand for microbiome-friendly formulas. However, what do we truly know about the vaginal and vulvar microbiome? Vaginal Microbiome The microbiome refers to the microbial population that occupies a habitat with distinct properties. It doesn’t just refer to the microorganisms that live together, but how they interact with one another (Berg et al., 2020). The vaginal microbiome consists of about 9% of the total human microbiome. Ordinarily, we find that the microbiome is at its healthiest when the population of bacteria is diverse. This is the case for the skin as well as the gut microbiome. However, research informs that the vaginal and vulvar microbiome act in the opposite way. When there is a high diversity in the vulvar and vaginal microbiome, it draws attention to an underlying problem that needs addressing (Saraf et al., 2021). In females of reproductive age, it is noted that the Lactobacillus species is a key characteristic of a healthy vaginal microbiome. These include: L. iners, L. crispatus, L. gasseri, and L. jensenii (Saraf et al., 2021). We also find that the same can be said about Bifidobacterium, which suggests protective characteristics as well (Freitas and Hill, 2017). If we look on the opposite side of the spectrum, we note that species such as Prevotella, Atopobium, Gardnerella, Megasphaera, and Mobiluncus are associated with an unhealthy or abnormal vaginal microbiota (Ravel et al., 2011). Diving Deeper into Vaginal Lactobacillus species Lactobacillus is characterized as a Gram-positive bacteria with a rod shape. These bacteria are known to produce lactic acid and make the vagina's pH more acidic (<4). According to current research, an acidic environment can restrict the growth of non-indigenous bacteria, which can foster a healthier environment. As a general rule, the lactobacillus species converts sugar into pyruvate which in turn converts it to lactic acid. They can make two types of lactic acid known as D-Lactic acid and L-Lactic acid (Saraf et al., 2021). Characterizing the Vaginal Microbiome In 2011 the concept of Community State Types (CSTs) was introduced with the aim of categorizing the vaginal microbiome communities (Ravel et al., 2011). This categorization was introduced after sampling women of asymptomatic ages through to reproductive women with 16S rRNA Sequencing. As a result, 5 CSTs were found, namely: I (L. crispatus): Type 1 is understood to be the healthiest, with research showing that this type can even prevent infections such as STIs, BV, and UTIs. II (L. gasseri): Type 2 is also linked to a healthy vaginal microbiome, with Lactobacillus gasseri dominating the population of bacteria. III (L. iners): Type 3 is neutral meaning it could be disruptive or protective to the vaginal community and is dominated by a species of Lactobacillus known as Lactobacillus iners. IV (Diversity group): Type 4 is understood to be an unhealthy vaginal environment with a high diversity of bacteria and low population of lactobacilli. V (L. jensenii): Type 5 is another state type acknowledged as healthy with a dominance of Lactobacillus jensenii. It is interesting to note that within this research females of different ethnic backgrounds fell under different community types. It is crucial to acknowledge that ethnicity plays a key role in the vaginal microbiome and further research is necessitated to understand how it varies from female to female (Ravel et al., 2011). This image has been pulled out from “Vaginal microbiome of reproductive-age women” (Ravel et al., 2011) In a paper published in 2020, it is disputed that CSTs needs to go a step further to help classify the vaginal microbiome. That’s where Valencia comes in (or VAginaL community state typE Nearest CentroId clAssifier). It is a centroid-based tool for measuring vaginal microbial communities based on composition (France et al, 2020).  The aim is to classify samples based purely on similarities against a reference that has been defined from 13,160 taxonomic profiles from 1,975 women within the United States. This large dataset allows for a more comprehensive process of identifying, characterizing and defining CSTs. Vaginal Microbiota Through the Female Lifespan Just as with any element of the human body, the vaginal microbiome alters throughout a female’s lifespan, particularly during the menstruating period and after menopause. This is due to the structural and hormonal features of the vaginal tissue (epithelium), which results in a changing environment. It is still not entirely clear what specific changes we can expect to see in each of these stages, as there are many factors at play, including lifestyle, environment and yes, even ethnicity. In order to uncover more about the vaginal and vulvar microbiome, it is crucial to conduct further studies and test products made for feminine intimate care with the correct methodologies and quantitative analysis to understand their true effect on the microbiome. Sequential is a testing company with years of expertise in the field of skin microbiome and genetics. We utilise deep molecular analysis and next-generation sequencing (NGS) technology to understand the impact on an individual’s microbiome from products they use, and the effect from their environment. All of our testing is carried out in-vivo and with the utmost care for unearthing the secrets that lie on the surface of the skin.  If you are interested in carrying out any research with us and testing products, you can reach us at team@sequential.bio. Lexicon Community State Types (CSTs): introduced with the aim of categorizing the vaginal microbiome communities (Ravel et al., 2011). Microbiome: The microbiome is a characteristic microbial community occupying a reasonably well-defined habitat which has distinct physio-chemical properties. The microbiome not only refers to the microorganisms involved but also encompasses their theater of activity, which results in the formation of specific ecological niches. This includes their genetic material, and also structural molecules, like enzymes, membrane lipids or polysaccharides. (Definition based on Berg et al., 2020) Skin microbiome: is present on the whole skin surface, including oral cavity and mucosal surfaces of the external genital organs. The composition of the skin microbiome is dynamic, site-specific but also differs from individual to individual. (Definition based on Byrd et al., 2018) Valencia: is a centroid-based tool for measuring vaginal microbial communities based on composition (France et al, 2020). References Acumen Research and Consulting. (2021). Feminine hygiene products market size worth around $38.5 billion by 2028. Acumen Research and Consulting. https://www.acumenresearchandconsulting.com/feminine-hygiene-products-market#:~:text=The%20Global%20Feminine%20Hygiene%20Products,have%20grown%20over%20the%20years. France MT, Ma B, Gajer P, Brown S, Humphrys MS, Holm JB, Waetjen LE, Brotman RM, Ravel J. VALENCIA: a nearest centroid classification method for vaginal microbial communities based on composition. Microbiome. 2020 Nov 23;8(1):166. doi: 10.1186/s40168-020-00934-6. PMID: 33228810; PMCID: PMC7684964. Freitas, A. C., and Hill, J. E. (2017). Quantification, isolation and characterization of Bifidobacterium from the vaginal microbiomes of reproductive aged women. Anaerobe 47, 145–156. doi: 10.1016/j.anaerobe.2017.05.012 Ravel, J., Gajer, P., Abdo, Z., Schneider, G. M., Koenig, S. S. K., McCulle, S. L., … Forney, L. J. (2010). Vaginal microbiome of reproductive-age women. Proceedings of the National Academy of Sciences, 108(Supplement_1), 4680–4687. doi:10.1073/pnas.1002611107 Future Market Insights. (2019). Women intimate care market: Global industry analysis 2013-2017 and opportunity assessment 2018-2028. Future Market Insights. https://www.futuremarketinsights.com/reports/women-intimate-care-market De Seta, F., Campisciano, G., Zanotta, N., Ricci, G., & Comar, M. (2019). The Vaginal Community State Types Microbiome-Immune Network as Key Factor for Bacterial Vaginosis and Aerobic Vaginitis. Frontiers in Microbiology, 10. doi:10.3389/fmicb.2019.02451 Saraf, V. S., Sheikh, S. A., Ahmad, A., Gillevet, P. M., Bokhari, H., & Javed, S. (2021). Vaginal microbiome: normalcy vs dysbiosis. Archives of Microbiology, 203(7), 3793–3802. doi:10.1007/s00203-021-02414-3

Abstract: Understanding the Baby Microbiome How important is it to understand the baby's microbiome? This post will explore what we know so far about the baby microbiome, and concludes by highlighting that in order to keep the very sensitive skin of infants as healthy as possible finding out more about the composition of the baby microbiome is crucial. What Do We Know About the Baby Microbiome The skin is the human body’s largest organ. The skin microbiome is made up of an organic ecosystem of trillions of bacteria that sit on the surface of the skin. It acts as a barrier against the threats and infections posed by the outside world, and works in a team to keep your skin healthy by fighting infection, supporting the immune system, healing wounds and controlling inflammation. Therefore, the microbiome needs to remain dynamic and responsive to the changing environments throughout the human life cycle. This is also true for the baby microbiome, and an infant’s exposure to environmentally sourced microbes may vary across different settings. It is interesting to consider how differences in childcare practices across sociocultural contexts could play a part in differential microbial exposures, for example, those linked to hygiene practices, attending daycare, and physical contact with siblings (Manus et al, 2020). At Birth Fetal skin is colonized by surrounding microorganisms immediately after birth. There are a variety of factors at birth that can influence the skin microbiome. Firstly is the mode of delivery. In vaginally delivered newborns, the skin’s bacterial signature resembles the mother’s vaginal bacteria. Whereas newborns delivered by cesarean resemble the bacteria relating to the skin. Moreover, newborns delivered by cesarean were found to have reduced skin microbial diversity (Dominguez-Bello et al, 2010). A second factor is whether the newborn is carried to full term. Where a newborn is born prematurely, the overall variety of species of skin bacteria and the relative abundance of the community are likely to be lower than babies born full-term (Pammi et al, 2017). However, it is important to note that the regional differences between preterm and full-term infants disappear after the first month of life. Maturation of the Infant Microbiome Within the first 6 weeks of life, the significant re-organization of the infant microbiota is primarily driven by body site, rather than by the mode of delivery (Chu et al, 2017). More significant differences have been discovered between the infant and maternal stool. Amazingly, it has been found that the baby microbiota becomes very similar to that of the adult by just the fourth week of life (Gaitanis et al, 2019). The Benefits of Understanding the Baby Microbiome Baby’s skin is known to be especially sensitive, highly prone to inflammatory conditions like eczema and dermatitis, and susceptible to infections such as candidiasis. The key benefit of understanding the composition of the baby microbiome is that strategies, for example, specific prebiotics and probiotics targeting the skin, can be developed to prevent the excessive growth of opportunistic pathogens and help us to ensure the baby's skin is kept healthy. Sequential Bio is a testing company with years of expertise in the field of skin microbiome and genetics. We utilise deep molecular analysis and next-generation sequencing (NGS) technology to understand the impact on an individual’s microbiome from products they use, and the effect from their environment. Having previously carried out skin microbiome testing on infants down to as little as 4 months, we have the knowledge and technology to help companies better understand the infant microbiota as they go about formulating their targeted products. All of our testing is carried out in-vivo and with the utmost care for unearthing the secrets that lie on the surface of the skin.  If you are interested in carrying out any research with us and testing products, you can reach us at team@sequential.bio. Lexicon Microbiome: The microbiome is a characteristic microbial community occupying a reasonably well-defined habitat which has distinct physio-chemical properties. The microbiome not only refers to the microorganisms involved but also encompasses their theatre of activity, which results in the formation of specific ecological niches. This includes their genetic material, and also structural molecules, like enzymes, membrane lipids or polysaccharides. (Definition based on Berg et al., 2020) Skin microbiome: is present on the whole skin surface, including the oral cavity and mucosal surfaces of the external genital organs. The composition of the skin microbiome is dynamic, and site-specific but also differs from individual to individual. (Definition based on Byrd et al., 2018) Probiotics: Live microorganisms that are intended to have health benefits when consumed or applied to the body. They can be found in yoghurt and other fermented foods, dietary supplements, and beauty products. Prebiotics: Non-living ingredients that are used to support the balance of both good and bad bacteria on your skin throughout your skin and within your body. References Chu DM, Ma J, Prince AL, Antony KM, Seferovic MD, Aagaard KM. Maturation of the infant microbiome community structure and function across multiple body sites and in relation to mode of delivery. Nat Med. 2017 Mar;23(3):314-326. doi: 10.1038/nm.4272. Epub 2017 Jan 23. PMID: 28112736; PMCID: PMC5345907. Capone KA, Dowd SE, Stamatas GN, Nikolovski J. Diversity of the human skin microbiome early in life. J Invest Dermatol. 2011 Oct;131(10):2026-32. doi: 10.1038/jid.2011.168. Epub 2011 Jun 23. PMID: 21697884; PMCID: PMC3182836. Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci USA. 2010;107(26):11971–11975. doi: 10.1073/pnas.1002601107. Gaitanis G, Tsiouri G, Spyridonos P, Stefos T, Stamatas GN, Velegraki A, et al. Variation of cultured skin microbiota in mothers and their infants during the first year postpartum. Pediatr Dermatol. 2019;36(4):460–465. Manus MB, Kuthyar S, Perroni-Marañón AG, Núñez-de la Mora A, Amato KR. Infant Skin Bacterial Communities Vary by Skin Site and Infant Age across Populations in Mexico and the United States. mSystems. 2020 Nov 3;5(6):e00834-20. doi: 10.1128/mSystems.00834-20. PMID: 33144313; PMCID: PMC7646528. Pammi M, O'Brien JL, Ajami NJ, Wong MC, Versalovic J, Petrosino JF. Development of the cutaneous microbiome in the preterm infant: a prospective longitudinal study. PLoS One. 2017;12(4):e0176669. doi: 10.1371/journal.pone.0176669.

Abstract Topical Steroid Withdrawal (TSW) can affect the quality of life of individuals, and the fact that there is currently no cure means that this is a particularly important area of research to consider. The role of the microbiome in TSW is not yet fully understood. Although some studies have begun looking at different types of therapy as a possible new treatment for TSW, this article explores the condition and where we are we research. What is Topical Steroid Withdrawal? Topical Steroid Withdrawal (TSW) describes the appearance of symptoms occurring after putting an end to long-term topical steroid use. TSW can happen after immediate use of treatment, but can also happen after misuse of treatment, decreasing the strength of treatment, and applying the treatment less frequently or to fewer parts of the body. Side effects are typically placed into two different categories; local and systemic. Local side effects describe symptoms which generally occur with prolonged treatment, and are conditional on the strength of the topical steroid, its vehicle and area of application. Most common examples of local side effects include skin atrophy, rosacea, perioral dermatitis, acne, and purpura. The other category of side effects, systemic adverse effects, are seen when very strong topical steroids are used for prolonged periods on the skin. What is important to highlight about TSW is that there is not currently any medication that provides a cure, patients can only attempt to manage the symptom. Treatments aimed at controlling and suppressing symptoms usually include cool compresses on the skin, antibiotics for inflammation, and over-the-counter antihistamine treatment to reduce redness and itching. Topical Steroid Withdrawal and the Skin Microbiome The skin microbiome is made up of an organic ecosystem of trillions of bacteria that sit on the surface of the skin. It acts as a first-line of defense against the outside world, and works in a team to keep your skin healthy by fighting infection, supporting the immune system, healing wounds and controlling inflammation. In order for the skin microbiome to work together efficiently with the human host, it needs to be balanced with a diversity of bacteria populating the skin. As the skin microbiome performs such a crucial function in keeping the skin healthy, understanding the role of the skin microbiome within the context of TSW may be essential to making progress in controlling the associated symptoms. Next Steps For Research The role of the microbiome in TSW is not fully explained. Considering little to know research exists on the impact of TSW on the skin microbiome, it is clear that further research should be conducted with a sufficient sample size to evaluate if a pre-/pro-/post-biotic treatment could improve the symptoms of TSW. Moreover, in order to find out whether the changes in symptoms are linked to the alterations in the microbiome community and changes in diversity, further work is required. Sequential is a testing company with years of expertise in the field of skin microbiome and genetics. We utilise deep molecular analysis and next-generation sequencing (NGS) technology to understand the impact on an individual’s microbiome from products they use, and the effect from their environment. All of our testing is carried out in-vivo and with the utmost care for unearthing the secrets that lie on the surface of the skin. If you are interested in carrying out any research with us and testing products, you can reach us at team@sequential.bio. Lexicon Microbiome: The microbiome is a characteristic microbial community occupying a reasonably well-defined habitat which has distinct physio-chemical properties. The microbiome not only refers to the microorganisms involved but also encompasses their theatre of activity, which results in the formation of specific ecological niches. This includes their genetic material, and also structural molecules, like enzymes, membrane lipids or polysaccharides. (Definition based on Berg et al., 2020) Skin microbiome: is present on the whole skin surface, including oral cavity and mucosal surfaces of the external genital organs. The composition of the skin microbiome is dynamic, site-specific but also differs from individual to individual. (Definition based on Byrd et al., 2018) Probiotics: Viable (active or dormant) microorganisms added to a cosmetic product with an intended cosmetic benefit to the host at the application site, either directly or via an effect on the host microbiome, when utilized in adequate amounts. Reference List Moreno-Indias, I. et al. Neonatal Androgen Exposure Causes Persistent Gut Microbiota Dysbiosis Related to Metabolic Disease in Adult Female Rats. Endocrinology 157, 4888-4898, doi:10.1210/en.2016-1317 (2016). Yurkovetskiy, L. et al. Gender bias in autoimmunity is influenced by microbiota. Immunity 39, 400-412, doi:10.1016/j.immuni.2013.08.013 (2013)

Abstract Retinoids refer to a variety of topical vitamin A-based products used on the skin, they are used to treat mild acne and as a preventative measure to reduce signs of ageing. Despite widespread usage and prescription by doctors, the full effects on the skin microbiome are unclear. Since the skin microbiome has an essential function in the health of the skin, understanding this further is critical. In this article, we will explore the evidence defining the relationship between retinoids and the skin microbiome. In summary, we find that studies suggest that Vitamin A and its metabolite may aid the self-regulatory process of the skin microbiome. However, we also need to be aware of the limitations of these studies, and consequently the need to conduct further studies in order to explore the questions which are still left unanswered. What are Retinoids? “Retinoids” is an umbrella term referring to a variety of vitamin A-based products used on the skin. Retinoids are available over-the-counter in weaker strengths in the form of creams, gels and serums to be applied directly on the skin, and are generally used to treat mild acne and used as a preventative measure to reduce signs of ageing. Prescription-strength treatments are also available, usually to treat moderate to chronic skin conditions. How are Retinoids Used? A lack of Vitamin A is associated with increased susceptibility to skin infection and inflammation (Chen et al, 2019), particularly as a result of an increase in the population of bacteria such as Staphylococcus aureus which become dominant within the skin (Wiedermann et al, 1996). Therefore, retinoids could have the potential to be beneficial for skin health by ensuring the skin barrier and microbiome are in check. Retinoids work by increasing blood flow and boosting skin cell turnover, therefore accelerating the cell renewal process and preventing dead skin cells from clogging pores, which may ultimately help the skin to repair itself quicker and reduce inflammation. However, retinoids are also known to potentially cause an initial ‘skin purging’ period (Leyden et al, 2017), where irritation may occur within the first few weeks but then later subsides, which can be an alarming and uncomfortable experience. Retinoids are well known for their benefits in reducing the signs of ageing by targeting fine lines, wrinkles, and pigmentation. Retinoids are advised to be used by individuals in their mid-twenties as a preventative measure, aimed at slowing down the natural ageing process by increasing the production of collagen and stimulating the production of new blood vessels in the skin. Yet it is important to highlight that retinoids are not typically considered a “quick fix” solution, as optimal results generally require a certain level of consistency and patience. In general, improvements are expected to begin to become visible within 3-6 months of regular use, while the best results are expected to take closer to 12 months. Skin Microbiome and Retinoids The skin microbiome is made up of an organic ecosystem of trillions of bacteria that sit on the surface of the skin. It acts as the first line of defence against the outside world and works in a team to keep your skin healthy by fighting infection, supporting the immune system, healing wounds and controlling inflammation. In order for the skin microbiome to be at its healthiest, it needs to be balanced with a high diversity of bacteria populating the skin. Retinoids are generally acknowledged to be quite harsh treatments, and so it is necessary that the potential effects their use may have on the skin microbiome are explored to ensure overall skin health is not compromised. Current Studies Linked to Retinoids Studies have suggested that Vitamin A and its metabolite can maintain the homeostasis of the skin microbiome, by regulating the innate immune system in a number of ways (Silvestre, Sato, & Reis, 2018). The key elements of the innate immune system in the skin are Toll-like receptors (TLRs), these TLRs act as a guard by recognising and fighting off pathogenic bacteria. In the skin, Vitamin A deficiency means that certain TLRs (specifically TLR2 and TLR3) are unable to function normally and cannot recognise any potentially bad bacteria growing on the pores or hair follicles. Additionally, sometimes TLRs do not activate until there is a certain number of pathogens reached (Roche & Harris-Tryon, 2021). Studies have suggested this could indicate a potential link between Vitamin A deficiency and skin conditions such as psoriasis and atopic dermatitis (Chen et al,2019). Topical retinoids can activate these TLRs so that they are able to function effectively, and therefore the use of retinoids may have therapeutic benefits in skin and hair regeneration (Kim et al, 2019). Next Steps for Research While we know that retinoids alter the skin microbiome and the potential benefits are clear, current research does not explore the specific strains of microbes that derive benefits from retinoid use and the impact this has on microbial diversity. In order to have a clearer and fuller understanding of the effects of retinoids on the skin microbiome, more focused studies are clearly necessary. Sequential is a testing company with years of expertise in the field of skin microbiome and genetics. We utilise deep molecular analysis and next-generation sequencing (NGS) technology to understand the impact on an individual’s microbiome from products they use, and the effect from their environment. All of our testing is carried out in-vivo and with the utmost care for unearthing the secrets that lie on the surface of the skin. If you are interested in carrying out any research with us and testing products, you can reach us at team@sequential.bio. Lexicon Skin Microbiome: refers to the collection of genomes from all the microorganisms in the environment (on your skin). Retinoids: a catch-all for an array of vitamin A-based products used on the skin, used to treat mild acne and reduce fine lines and wrinkles. Bacteria: bacteria are single-cell organisms that live everywhere on earth, including on the surface of the skin. Homeostasis: the self-regulating process by which biological systems maintain stability while adjusting to changing external conditions. Staphylococcus aureus (S.aureus): S. aureus is a key bacterium, typically considered to be harmful because it can cause skin infection as well as inflammation in the outer skin barrier. Reference List Chen, W., Zhao, S., Zhu, W., Wu, L. & Chen, X. Retinoids as an Immunity-modulator in Dermatology Disorders. Arch Immunol Ther Exp (Warsz) 67, 355-365, doi:10.1007/s00005-019-00562-5 (2019). Eichner, R. Epidermal effects of retinoids: in vitro studies. J Am Acad Dermatol 15, 789-797, doi:10.1016/s0190-9622(86)70235-1 (1986). Harris, T. A. et al. Resistin-like Molecule alpha Provides Vitamin-A-Dependent Antimicrobial Protection in the Skin. Cell Host Microbe 25, 777-788 e778, doi:10.1016/j.chom.2019.04.004 (2019). Idres, N., Marill, J., Flexor, M. A. & Chabot, G. G. Activation of retinoic acid receptor-dependent transcription by all-trans-retinoic acid metabolites and isomers. J Biol Chem 277, 31491-31498, doi:10.1074/jbc.M205016200 (2002). Kim, D. et al. Noncoding dsRNA induces retinoic acid synthesis to stimulate hair follicle regeneration via TLR3. Nat Commun 10, 2811, doi:10.1038/s41467-019-10811-y (2019). Leyden, J., Stein-Gold, L. and Weiss, J. Why topical retinoids are mainstay of therapy for acne. Dermatology and therapy, 7(3). 296-297, doi:https://doi.org/10.1007/s13555-017-0185-2 (2017). Leyden J, Stein-Gold L, Weiss J. Why Topical Retinoids Are Mainstay of Therapy for Acne. Dermatol Ther (Heidelb). 2017 Sep;7(3):293-304. doi: 10.1007/s13555-017-0185-2. Epub 2017 Jun 5. PMID: 28585191; PMCID: PMC5574737. Piipponen, M., Li, D. & Landen, N. X. The Immune Functions of Keratinocytes in Skin Wound Healing. Int J Mol Sci 21, doi:10.3390/ijms21228790 (2020). Rittie, L., Varani, J., Kang, S., Voorhees, J. J. & Fisher, G. J. Retinoid-induced epidermal hyperplasia is mediated by epidermal growth factor receptor activation via specific induction of its ligands heparin-binding EGF and amphiregulin in human skin in vivo. J Invest Dermatol 126, 732-739, doi:10.1038/sj.jid.5700202 (2006). Roche FC, Harris-Tryon TA. Illuminating the Role of Vitamin A in Skin Innate Immunity and the Skin Microbiome: A Narrative Review. Nutrients. 2021 Jan 21;13(2):302. doi: 10.3390/nu13020302. PMID: 33494277; PMCID: PMC7909803. Silvestre, M. C., Sato, M. N. & Reis, V. Innate immunity and effector and regulatory mechanisms involved in allergic contact dermatitis. An Bras Dermatol 93, 242-250, doi:10.1590/abd1806-4841.20186340 (2018). Schroeder, M. & Zouboulis, C. C. All-trans-retinoic acid and 13-cis-retinoic acid: pharmacokinetics and biological activity in different cell culture models of human keratinocytes. Horm Metab Res 39, 136-140, doi:10.1055/s-2007-961813 (2007). Wiedermann, U. et al. Vitamin A deficiency predisposes to Staphylococcus aureus infection. Infect Immun 64, 209-214, doi:10.1128/iai.64.1.209-214.1996 (1996).

Abstract Benzoyl peroxide (BPO) is well known to be used for people that have acne. Although the effect of this drug in reducing acne is clear, the effect on the skin microbiome is less known which may have a role to play in the long-term effects and symptoms of BPO usage. In this post, we will discuss what is known, and how the skin microbiome might be affected. What is Benzoyl Peroxide and How Is It Used? Benzoyl Peroxide (BPO) is a drug that is commonly used in the treatment of mild to moderate acne. It is often formulated with active ingredients, antibiotics, or retinoids and infused into topical skincare products such as gels, face washes, and spot treatments. Since BPO can be quite strong, each formulation will typically contain a maximum of 5% of the drug. BPO products are generally recommended in controlled amounts, therefore are most often sold as spot creams to be used only in targeted areas. Individuals are advised to gradually increase the number of applications up to a maximum of twice in one day. Common Side Effects of Benzoyl Peroxide The reason that BPO should be applied with caution and control is due to common side effects that include dry skin, peeling skin, and skin irritation. These are reported to occur in just over 10% of individuals, which can be alarming, especially for those who have sensitive skin. Excessive use of BPO has been reported to cause the skin to become very dry and flaky. In addition, the prolonged use of BPO products can also cause the skin to become over-dependant, which consequently risks the return or worsening of the acne when the treatment is stopped. What does this all mean in the context of the skin microbiome? Skin Microbiome and Benzoyl Peroxide The skin microbiome is made up of an organic ecosystem of trillions of bacteria that sit on the surface of the skin and acts as a first-line defence against external factors. For the skin microbiome to be at its healthiest, it needs to be balanced with a high diversity of bacteria populating the skin. Now when looking at it through the context of BPO, we are left with quite an interesting situation. BPO claims to fight acne and potentially prevent new breakouts by working as an antiseptic to attack and reduce the bacteria on the surface of the skin. It also removes dead skin in order to unclog and minimize the appearance of pores. As far as attacking and reducing bacteria is concerned, scientists are left with a crucial question to answer. How does BPO affect the skin microbiome and the diversity of bacteria on the skin? Current Studies Linked to Benzoyl Peroxide Research on this subject is mixed, with some academic papers reporting that BPO may have a link to reduced microbial diversity (as well as acne), however, other research fails to show any statistical change. A recent study published (Zhou et al, 2022) compared skin microbiome changes in people who suffer from acne before and after the use of BPO, but found that among the top 20 bacteria species two of them (Staphylococcus, Acinetobacter) increase in abundance whilst one decreased Corynebacterium. Another research study (Ahluwalia et al., 2019) found that although there weren’t statistically significant changes in the diversity of the skin microbiome, the use of BPO resulted in a statistically significant increase in Streptococcus mitis (S.mitis) population. Taking a different look at things, it was found that after the use of BPO S.epidermidis increased, which could potentially inhibit the growth of harmful bacteria such as Cutibacterium acnes (C.acnes), certain strains of which are a known culprit in individuals with acne (Wang et al., 2014). However, the argument arose that even if Staphylococcus epidermidis (S. epidermidis) rose to help stave off C.acnes, could the benefits outweigh the ill effects of using BPO in general? Next Steps for Research To be able to answer questions like this in more depth, there is a strong need to conduct further research in a controlled environment, with the aim of decoding the impacts of BPO on the skin microbiome and the diversity of not just the most common bacteria, but also the obscure ones that one might not think to be significant. Other questions might be, does the skin microbiome significantly change if the use of BPO becomes chronic? And does this have lasting effects and long-term ill effects on the skin? Sequential is a testing company with years of expertise in the field of skin microbiome and genetics. We utilise deep molecular analysis and next-generation sequencing (NGS) technology to understand the impact on an individual’s microbiome from products they use, and the effect from their environment. All of our testing is carried out in-vivo and with the utmost care for unearthing the secrets that lie on the surface of the skin. If you are interested in carrying out any research with us and testing products, you can reach us at team@sequential.bio. —-------------------------------------------------------------------------------------------------------------- Lexicon Skin Microbiome: refers to the collection of genomes from all the microorganisms in the environment (on your skin). Skin Microbiota: refers to microorganisms that are found within a specific environment. Microbiota can refer to all the microorganisms found in an environment, including bacteria, viruses, and fungi. Bacteria: bacteria are single-cell organisms that live everywhere on earth, including on the surface of the skin. Benzoyl Peroxide: Benzoyl Peroxide (BPO) is a drug that is commonly used in the treatment of mild to moderate acne. Streptococcus mitis (S.mitis): S.mitis is a gram-positive bacteria found mainly in the mouth but low in the skin and is usually opportunistic/pathogenic in Adults. In fact, several anti-bacterial lipids have been tested against this bacteria. On the other hand, the pre-adolescent microbiome might have more S.mitis and very little C.acne because sebaceous glands have not developed fully yet. Only after puberty do we start to see C.acne increasing and other bacteria such as S.mitis decreasing. Cutibacterium acnes (C.acnes): is a highly prevalent bacterium that inhabits pores where sebum/natural oils are formed. it is linked to skin conditions such as acne, but only with some strains. Staphylococcus epidermidis (S.epidermidis): is one of more than forty species of bacteria that belongs to the Staphylococcus family and is part of the organisms that normally inhabit humans, specifically the skin. Reference List Ahluwalia, J., Borok, J., Haddock, E. S., Ahluwalia, R. S., Schwartz, E. W., Hosseini, D., Amini, S., & Eichenfield, L. F. (2019, Mar). The microbiome in preadolescent acne: Assessment and prospective analysis of the influence of benzoyl peroxide. Pediatr Dermatol, 36(2), 200-206. https://doi.org/10.1111/pde.13741 Coughlin, C. C., Swink, S. M., Horwinski, J., Sfyroera, G., Bugayev, J., Grice, E. A., & Yan, A. C. (2017, Nov). The preadolescent acne microbiome: A prospective, randomized, pilot study investigating characterization and effects of acne therapy. Pediatr Dermatol, 34(6), 661-664. https://doi.org/10.1111/pde.13261 Karoglan et al, 2019 https://pubmed.ncbi.nlm.nih.gov/31573666/ Oh, J., Conlan, S., Polley, E. C., Segre, J. A., & Kong, H. H. (2012). Shifts in human skin and nares microbiota of healthy children and adults. Genome Med, 4(10), 77. https://doi.org/10.1186/gm378 Wang, Y., Kuo, S., Shu, M., Yu, J., Huang, S., Dai, A., Two, A., Gallo, R. L., & Huang, C. M. (2014, Jan). Staphylococcus epidermidis in the human skin microbiome mediates fermentation to inhibit the growth of Propionibacterium acnes: implications of probiotics in acne vulgaris. Appl Microbiol Biotechnol, 98(1), 411-424. https://doi.org/10.1007/s00253-013-5394-8 Zhou, L., Chen, L., Liu, X., Huang, Y., Xu, Y., Xiong, X., & Deng, Y. (2022, Mar). The influence of benzoyl peroxide on skin microbiota and the epidermal barrier for acne vulgaris. Dermatol Ther, 35(3), e15288. https://doi.org/10.1111/dth.15288

Often colloquially termed "fungal acne," Malassezia folliculitis (MF) is an infection of the hair follicle triggered by yeasts belonging to the Malassezia genus (formerly known as Pityrosporum). While these lipophilic yeasts are typically part of the natural skin microbiome, under specific conditions, they can become pathogenic causing acne-like symptoms. What We Know: Following birth, Malassezia typically establishes residence on the skin and is usually well-tolerated by the immune system. However, its pathogenic capabilities emerge when it infiltrates the stratum corneum under conducive conditions, such as hot and humid climates, engaging directly with the host immune system and via chemical mediators (Saunte, Gaitanis & Hay, 2020). Essentially, the transformation of Malassezia from commensal to pathogenic is driven by a complex interaction between the host and the fungus, resulting in the production of virulence factors such as indoles, reactive oxygen species, azelaic acid, hyphae formation and biofilm formation (Kurniadi, Hendra Wijaya & Timotius, 2022). The primary species linked to MF include M. furfur, M. globosa, M. restricta, M. sympodialis and M. pachydermatis (Henning et al., 2023). These species penetrate the pilo-sebaceous unit, resulting in follicular dilation and the accumulation of Malassezia cells. If follicular walls rupture, it triggers an inflammatory response. This can be misdiagnosed as acne, steroid acne, bacterial folliculitis, eosinophilic folliculitis, pustular drug eruptions or lymphomatoid papulosis (Saunte, Gaitanis & Hay, 2020). Industry Impact and Potential: While systemic antifungal monotherapy typically yields better results, topical therapy is useful in conjunction and is beneficial in situations where systemic treatment is not feasible. Topical antifungals, tretinoin, benzoyl peroxide azoles, selenium sulphide, and propylene glycol are viable topical options for managing MF (Saunte, Gaitanis & Hay, 2020). Currently, there is no internationally approved treatment guideline for managing MF. This presents an exciting opportunity to explore microbiome-focused treatment approaches, tailoring therapies to restore microbial balance and target Malassezia overgrowth effectively (Saunte, Gaitanis & Hay, 2020). Our Solution: With a vast database of over 20,000 microbiome samples and 4,000 ingredients, Sequential offers comprehensive services to tackle issues like MF. Our customisable microbiome studies and product formulation support ensure effective product development. References: Henning, M. a. S., Hay, R., Rodriguez-Cerdeira, C., Szepietowski, J.C., Piraccini, B.M., et al. (2023) Position statement: Recommendations on the diagnosis and treatment of Malassezia folliculitis. Journal of the European Academy of Dermatology and Venereology. 37 (7), 1268–1275. doi:10.1111/jdv.18982. Kurniadi, I., Hendra Wijaya, W. & Timotius, K.H. (2022) Malassezia virulence factors and their role in dermatological disorders. Acta Dermatovenerologica Alpina, Pannonica, Et Adriatica. 31 (2), 65–70. Saunte, D.M.L., Gaitanis, G. & Hay, R.J. (2020) Malassezia-Associated Skin Diseases, the Use of Diagnostics and Treatment. Frontiers in Cellular and Infection Microbiology. 10, 112. doi:10.3389/fcimb.2020.00112.

While our understanding of the microbial composition of the vulva is still evolving, it holds the potential to maintain overall genital health. Investigating how feminine hygiene products affect the vulvar microbiome is crucial for understanding and improving women's health and intimate care practices. What We Know: The vulvar microbiome displays significant diversity both within individuals and among different women, with current research having found no single species universally present (Graziottin, 2024). While opinions vary among professionals regarding the necessity of feminine care products, in instances where they are deemed beneficial, certain ingredients can offer greater advantages to the vulvar microbiome than others. Thymol, a component of thyme oil, has gained attention in feminine hygiene products for its antimicrobial and antifungal properties, effectively maintaining the beneficial microbiota. It inhibits the growth of pathogenic microbes like Candida albicans and Gardnerella vaginalis, while also possessing anti-inflammatory properties (Braga et al., 2008). The inclusion of lactic acid in feminine hygiene products helps to support the vulvar microbiome by maintaining an acidic pH (Graziottin, 2024). To manage odours, feminine washes may contain ketoglutaric acid, which is an antioxidant. These properties have the potential to oxidise amines linked to malodor, thereby providing anti-odour benefits (Graziottin, 2024). Industry Impact & Potential: Researchers have developed a cleansing wash containing thymol and an acidic pH, along with glycerin, ketoglutaric acid, and lactic acid, which has shown promise in reducing pH levels and discomfort in pregnant and postpartum women with vulvar and vaginal issues. Compared to alternative lactic acid-based washes, it better preserves skin hydration (Murina et al., 2020). Despite advancements like this, the market remains underexplored, offering opportunities for the exploration and development of microbiome-friendly products in the realm of feminine hygiene. Our Solution: In addition to vulvar microbiome analysis, we at Sequential provide services for assessing skin, scalp and oral microbiomes, and have established our company as a leader in facilitating the development of microbiome-friendly products. Our team of experts is well-equipped to support your company in formulating innovative products suitable for maintaining and improving the vulvar microbiome to support women’s health. Reference List: Braga, P.C., Culici, M., Alfieri, M. & Dal Sasso, M. (2008) Thymol inhibits Candida albicans biofilm formation and mature biofilm. International Journal of Antimicrobial Agents. 31 (5), 472–477. doi:10.1016/j.ijantimicag.2007.12.013. Graziottin, A. (2024) Maintaining vulvar, vaginal and perineal health: Clinical considerations. Women’s Health (London, England). 20, 17455057231223716. doi:10.1177/17455057231223716. Murina, F., Caimi, C., Felice, R., Di Francesco, S. & Cetin, I. (2020) Characterization of female intimate hygiene practices and vulvar health: A randomized double-blind controlled trial. Journal of Cosmetic Dermatology. 19 (10), 2721–2726. doi:10.1111/jocd.13402.

Rosacea, a chronic inflammatory skin condition, involves complex interactions between the skin microbiota and host conditions. While the exact pathophysiology is not clearly understood, research has implicated various microorganisms. What We Know: Demodex mites (generally found at the base of eyelashes) have been associated with rosacea, with higher densities found in affected individuals. Although typically harmless in small numbers, D. folliculorum and D. brevis may stimulate inflammatory pathways and compromise the skin barrier, contributing to the condition. While their exact role in rosacea remains unclear, treatments targeting Demodex have shown potential (Sánchez-Pellicer et al., 2024). Bacillus oleronius (Heyndrickxia oleronia), a bacterium originally isolated from Demodex, has been shown to exacerbate inflammation in rosacea patients. Furthermore, elevated skin temperature characteristic of rosacea patients altered the growth and protein profile of B. oleronius, resulting in increased production of its immunoreactive proteins. However, studies on rosacea have shown its presence in affected skin samples to be inconsistent (Maher, Staunton & Kavanagh, 2018). Corynebacterium kroppenstedtii, found in mutualistic symbiosis with D. folliculorumhas, has been linked to rosacea, particularly in subjects between 40 and 49 years of age. Research suggests that effective antibiotic treatment against this bacterium could potentially improve rosacea symptom management (Rainer et al., 2020). Staphylococcus epidermidis, a typically beneficial bacterium, may exhibit virulence factors in rosacea patients, contributing to the disease's pathogenesis (Sánchez-Pellicer et al., 2024). Industry Impact & Potential: Systemic antibiotics have been effective in managing rosacea. However, their specific impact on the cutaneous microbiota and bacteria related to rosacea pathophysiology requires further study (Sánchez-Pellicer et al., 2024). In addition, while the microbiological aspects of rosacea provide insights into its pathogenesis, further research is needed to elucidate the exact roles of various microorganisms and develop targeted treatments (Sánchez-Pellicer et al., 2024). Studies suggest that topical probiotics can positively impact skin health by influencing the skin microbiota and immune response. While their effectiveness for rosacea is not fully understood, probiotics may enhance skin barrier function, reduce inflammation and restore balance to the skin microbiome, making them a promising avenue for symptom management and potential treatment (Sánchez-Pellicer et al., 2024). Our Solution: Sequential offers a unique end-to-end Microbiome Testing solution that may be applied to the case of rosacea. Get in touch to collaborate with our experts to investigate topical microbiome-focused approaches to treating skin concerns and conditions, like rosacea. Reference List: Maher, A., Staunton, K. & Kavanagh, K. (2018) Analysis of the effect of temperature on protein abundance in Demodex-associated Bacillus oleronius. Pathogens and Disease. 76 (4), fty032. doi:10.1093/femspd/fty032. Rainer, B.M., Thompson, K.G., Antonescu, C., Florea, L., Mongodin, E.F., Bui, J., Fischer, A.H., Pasieka, H.B., Garza, L.A., Kang, S. & Chien, A.L. (2020) Characterization and Analysis of the Skin Microbiota in Rosacea: A Case–Control Study. American Journal of Clinical Dermatology. 21 (1), 139–147. doi:10.1007/s40257-019-00471-5. Sánchez-Pellicer, P., Eguren-Michelena, C., García-Gavín, J., Llamas-Velasco, M., Navarro-Moratalla, L., Núñez-Delegido, E., Agüera-Santos, J. & Navarro-López, V. (2024) Rosacea, microbiome and probiotics: the gut-skin axis. Frontiers in Microbiology. 14. doi:10.3389/fmicb.2023.1323644.

Many consumers use skincare products with the intention of achieving various aesthetic goals, without realising their potential impact on the skin's microbiome. Factors like ingredients and formulations can disrupt this balance, highlighting the importance of understanding how skin care choices affect skin health What We Know: Cosmetic skincare products can influence the composition and diversity of the skin's microbial community. Ingredients like carbohydrates, proteins and lipids can promote the growth of specific skin bacteria. For example, the lipid components found in moisturisers can serve as nutrients, fostering the growth of lipophilic bacteria like Staphylococcus epidermidis and Cutibacterium acnes (Skowron et al., 2021). Furthermore, emulsifiers or preservatives, such as parabens, methylisothiazolinone have the potential to disturb microbial balance by suppressing the growth of beneficial bacteria like S. epidermidis, potentially leading to dysbiosis (Fournière et al., 2020). The impact of preservatives on the skin microbiome has been debated due to their necessity to prevent contamination, but simultaneous potentially negative effects on microbiome diversity. However, more recent research established that their impact depends on factors like concentration, exposure duration and individual skin resilience (Murphy et al., 2021). Industry Impact & Potential: Research into skin microbiota and ingredients optimising skin microbiota is essential for cosmetic companies creating new cosmetic products. Initiatives and certifications to ensure that cosmetic products are free from contaminants, harmless to specific bacteria and non-disruptive to the skin's natural microbiome equilibrium are becoming more prominent in the skincare industry (Han & Kim, 2024). Skincare brands have and continue to formulate products including microbiome beneficial ingredients, like pre- and postbiotics. These include Aveeno’s CALM+RESTORE® range (with oatmeal, which contains prebiotic carbohydrate beta-glucans), Lancome’s Genifique products (containing Bifida ferment lysate, Lactobacillus ferment, postbiotic yeast extract and prebiotic alpha glucan oligosaccharide) as well as Lactoclear’s postbiotic products (containing Enterococcus Faecalis ferment) among many others (Han & Kim, 2024). Our Solution: With an extensive database comprising over 20,000 microbiome samples and 4,000 ingredients, alongside a global network of more than 10,000 testing participants, Sequential delivers thorough services for assessing product impacts and formulations. Our customisable microbiome studies offer real-world testing scenarios, while our formulation support guarantees the preservation of biome integrity in products. Thus, we stand as the optimal partner to leverage our solutions for your product development and efficacy needs. Reference List: Fournière, M., Latire, T., Souak, D., Feuilloley, M.G.J. & Bedoux, G. (2020) Staphylococcus epidermidis and Cutibacterium acnes: Two Major Sentinels of Skin Microbiota and the Influence of Cosmetics. Microorganisms. 8 (11), 1752. doi:10.3390/microorganisms8111752. Han, J.H. & Kim, H.S. (2024) Skin Deep: The Potential of Microbiome Cosmetics. Journal of Microbiology (Seoul, Korea). doi:10.1007/s12275-024-00128-x. Murphy, B., Hoptroff, M., Arnold, D., Eccles, R. & Campbell-Lee, S. (2021) In-vivo impact of common cosmetic preservative systems in full formulation on the skin microbiome. PLOS ONE. 16 (7), e0254172. doi:10.1371/journal.pone.0254172. Skowron, K., Bauza-Kaszewska, J., Kraszewska, Z., Wiktorczyk-Kapischke, N., Grudlewska-Buda, K., Kwiecińska-Piróg, J., Wałecka-Zacharska, E., Radtke, L. & Gospodarek-Komkowska, E. (2021) Human Skin Microbiome: Impact of Intrinsic and Extrinsic Factors on Skin Microbiota. Microorganisms. 9 (3), 543. doi:10.3390/microorganisms9030543.

Vitamin A and its derivatives have become essential components of mainstream skincare products, popular for their anti-aging and anti-acne benefits. Yet, as we probe further into their effects on skin well-being, their interplay with the skin microbiome emerges as an avenue for exploration, extending beyond their established properties and into new realms of understanding and application. What We Know: Vitamin A deficiency has been associated with skin infection. However, the mechanism of how vitamin A provides skin immunity is not yet well understood (Harris et al., 2019). Human skin cells naturally produce Resistin protein, while in mice, epidermal keratinocytes and sebocytes produce a similar molecule known as Resistin-like molecule α (RELMα). Research showed that when activated by the vitamin A analog isotretinoin, RELMα exhibited antimicrobial properties. This effectively prevented skin infections and may suggest a similar property of Resistin activated by vitamin A in humans (Harris et al., 2019). When administered as a 0.025% cream for topical acne treatment, retinoic acid, a potent derivative of vitamin A, demonstrated notable results for individuals with mild acne vulgaris. Following one month of use, it exhibited efficacy in reducing bacterial diversity, reshaping microbiota composition and notably decreasing Cutibacterium acnes while elevating Staphylococcus epidermidis relative abundance (Wongtada et al., 2023). Industry Impact & Potential: Vitamin A and its derivatives have immunomodulatory properties that offer protection against fungal infections caused by Candida albicans, Aspergillus spp. and Microsporum spp. This suggests that investigating vitamin A derivatives such as retinoids in clinical settings could offer a promising therapeutic approach for treating fungal infections (Joshi et al., 2023). Understanding the role of vitamin A and its derivatives on both the innate immune system and the skin microbiome is crucial for advancing translational skin biology research and devising effective therapeutic approaches (Roche & Harris, 2021). Specifically, this can provide insight on disease progression and treatment responses, particularly regarding therapies targeting innate immune signalling and antimicrobial peptide production (Roche & Harris, 2021). Our Solution: At Sequential, we specialise in comprehensive Microbiome Product Testing, which is customisable to align with your unique product development and formulation goals. With our expert guidance and tailored services, we empower businesses to pioneer innovative strategies for topical solutions, such as creating microbiome-friendly products containing vitamin A and its derivatives, ensuring efficacy and compatibility for healthier skin. Reference List: Harris, T.A., Gattu, S., Propheter, D.C., Kuang, Z., Bel, S., Ruhn, K.A., Chara, A.L., Edwards, M., Zhang, C., Jo, J.-H., Raj, P., Zouboulis, C.C., Kong, H.H., Segre, J.A. & Hooper, L.V. (2019) Resistin-like Molecule α Provides Vitamin-A-Dependent Antimicrobial Protection in the Skin. Cell Host & Microbe. 25 (6), 777-788.e8. doi:10.1016/j.chom.2019.04.004. Joshi, M., Hiremath, P., John, J., Ranadive, N., Nandakumar, K. & Mudgal, J. (2023) Modulatory role of vitamins A, B3, C, D, and E on skin health, immunity, microbiome, and diseases. Pharmacological Reports. 75 (5), 1096–1114. doi:10.1007/s43440-023-00520-1. Roche, F. & Harris, T. (2021) Illuminating the Role of Vitamin A in Skin Innate Immunity and the Skin Microbiome: A Narrative Review. Nutrients. 13 (2). doi:10.3390/nu13020302. Wongtada, C., Prombutara, P., Asawanonda, P., Noppakun, N., Kumtornrut, C. & Chatsuwan, T. (2023) Distinct skin microbiome modulation following different topical acne treatments in mild acne vulgaris patients: A randomized, investigator-blinded exploratory study. Experimental Dermatology. 32 (6), 906–914. doi:10.1111/exd.14779.

Multiple factors are responsible for the makeup of the skin microbiome of an individual, including host genetics, age, hygiene practices, diet, nutrition, lifestyle, topical treatments and the environment. Research suggests that where we live can profoundly influence the microbial composition and overall health of our microbiomes. What We Know: Facial skin is impacted by external factors like climate, temperature, humidity, UV exposure and pollution, as it is more exposed to the environment compared to other skin (Proksch, 2008). Research that investigated the facial microbiome and metabolome across different geographic regions concluded that there were significant alterations in the abundance of multiple microorganisms between individuals (Tao et al., 2024). In a study across various regions in China, those residing in the northwest (in high altitude and dry climate) exhibited lower levels of Malassezia and bacterial diversity, as well as reduced total lipid content. However, they showed elevated levels of ceramides and fatty acids compared to individuals in southern regions (warm and wet climates) (Tao et al., 2024). Skin bacteria thrive in warm temperatures (33.2–35.0°C) with lipid-dependent organisms like Malassezia and Cutibacterium flourishing in such environments due to increased sebum secretion (Grice & Segre, 2011). Research also demonstrated that subjects living in rural areas exhibited significantly greater intra group variation in microbial community structure compared to urban subjects (Ying et al., 2015). Variations in bacterial populations across regions may be influenced by factors like humidity, UV exposure and temperature fluctuations. Higher humidity levels support greater bacterial diversity, while UV exposure alters the skin microbiome (Tao et al., 2024) Industry Impact and Potential: By analysing these aspects across geography, we can uncover climate-related influences on skin disorders, enabling tailored skincare recommendations for diverse regions (Tao et al., 2024). Increasing urbanisation correlates with higher levels of potentially pathogenic  bacteria and fungi, which may explain the urban prevalence of skin diseases like acne and atopic dermatitis. This highlights the need for urban-specific skincare, creating opportunities for specialised products and research (McCall et al., 2020). However, further research is necessary to fully elucidate the effects of environmental factors on the microbiome (Tao et al., 2024) Our Solution: Exploring environmental influence on the microbiome is a promising avenue for personalised skincare tailored to the individual needs of people globally. With three testing centres in distinct climates (New York, London and Singapore) Sequential offers comprehensive Microbiome Testing and guidance in product development and formulation, providing a toolkit for your company to delve into personalised skincare that considers our uniqueness. References: Grice, E.A. & Segre, J.A. (2011) The skin microbiome. Nature Reviews Microbiology. 9 (4), 244–253. doi:10.1038/nrmicro2537. McCall, L.-I., Callewaert, C., Zhu, Q., Song, S.J., Bouslimani, A., et al. (2020) Home chemical and microbial transitions across urbanization. Nature Microbiology. 5 (1), 108–115. doi:10.1038/s41564-019-0593-4. Proksch, E. (2008) Protection Against Dryness of Facial Skin: A Rational Approach. Skin Pharmacology and Physiology. 22 (1), 3–7. doi:10.1159/000159771. Tao, R., Li, T., Wang, Y., Wang, R., Li, R., Bianchi, P., Duplan, H., Zhang, Y., Li, H. & Wang, R. (2024) The facial microbiome and metabolome across different geographic regions. Microbiology Spectrum. 12 (1), e03248-23. doi:10.1128/spectrum.03248-23. Ying, S., Zeng, D.-N., Chi, L., Tan, Y., Galzote, C., Cardona, C., Lax, S., Gilbert, J. & Quan, Z.-X. (2015) The Influence of Age and Gender on Skin-Associated Microbial Communities in Urban and Rural Human Populations. PLOS ONE. 10 (10), e0141842. doi:10.1371/journal.pone.0141842.