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Background on Malassezia The skin surface micro-environment is colonised by a wide range of microorganisms, including bacteria, archaea, viruses, and fungi. Collectively this is referred to as the skin microbial community or microbiome. Malassezia  was discovered in the 19th century by Malassez and Sabaouraud. Malassezia  is the major component of the fungal skin microbiota, is present on all humans (and warm-blooded animals), and is most abundant on sebaceous (oily) body sites. It is a lipid dependent microbe, which is quite unusual. As shown below, in different areas of the body, even if it is oily, moist or dry, Malassezia  is the only resident fungi found on all skin. The only skin area with a higher diversity is the toes and the feet, where there is a rich diversity of skin fungi. For example, there are a variety of different fungi related to athlete's foot and nail fungus. Of course, our feet are our connection to the outside environment so this makes sense, as evolutionarily speaking feet would have a higher diversity of fungi because they (without wearing shoes) are exposed to more microbes than other areas of the skin. https://www.science.org/doi/10.1126/science.1260144 Recent Studies Professor Thomas Dawson is a major player in skin microbiota and has spent his career understanding this specific microbe called Malassezia . His work has been aimed at uncovering whether Malassezia  is commensal, pathogenic, or protective (mutualistic), and this work is what we will focus on here. A literature review paper ‘Cutaneous Malassezia : Commensal, Pathogenic, or Protector?’ (Chandra et al 2021) in which Tom Dawson is the lead author, is a significant article and one to which we would like to draw attention. The study had two main objectives; firstly, to advance our understanding of Malassezia  in the context of pathogenicity, commensalism, and mutualism, and secondly to share what we know about microbe-microbe and host-microbe interactions. The skin fungal population is almost always overlooked, as over the last decade the focus has been primarily on 16S rRNA sequencing specific to bacteria. However, fungi are increasingly found to be important for human health and disease. Consequently, work to uncover the importance of this microbe is extremely important and valuable.   What we know Commonly published articles reference that skin is occupied by 90-95% bacteria. However, this misrepresents the proportion of the microbial community, as it counts the number of genomes. As Malassezia  are huge compared to bacteria, Malassezia  have 200-500 times the cellular biomass per genome relative to Staphylococcus epidermidis , a representative and common skin bacterium. Hence, they have similar biomass to bacteria on the sebaceous areas, for example places like the forehead where there is a lot of oil and lipids. Moreover, Malassezia  have haploid genomes of 8-9Mb, emphasizing how well adapted they are to their specific environment and which makes them have among the smallest genomes for free-living fungi. Malassezia  genomes encode lipases, phospholipases, and acid sphingomyelinases for utilisation of lipids, and proteases for utilisation of proteins. Thus, they are equipped with everything they need to be able to survive on our skin. Lipases secreted by Malassezia  decompose the human skin sebum-derived lipids, such as mono-, di-, and triglycerides, into saturated and unsaturated fatty acids. The saturated fatty acids, which are healthy for skin, are consumed by Malassezia  for survival, whereas the unsaturated fatty acids accumulate on the stratum corneum. One theory is that this accumulation might interfere with the permeability of the skin barrier thereby leading to various skin disorders. One such example of this is scalp dandruff. In this article the Malassezia  clade is subdivided into three major groups; Group A, Group B, and Group C. Group A are considered M. furfur -like, are more robust in culture, less frequent inhabitants of human skin, and more often linked to skin or septic disease. Group B are common on healthy human skin, with M. restricta  and M. globosa  by far the most common and found on the skin of all humans, followed by M. sympodialis, then distantly by the other Group B members. The Group B exception is M. pachydermatis , which can cause human septic infections but is only normally found on animal skin.  Group C are divergent Malassezia, found specifically on animal species such as rabbit ears and bats.  Phylogenetic tree for Malassezia species, taken from Chandra et al 2021. Malassezia  in Ageing Skin The amount of Malassezia  on skin changes throughout a person's lifetime. At birth, neonatal sebaceous glands are turned on by hormones present in the maternal circulation and therefore produce lipids supporting initial Malassezia  colonization and growth until around 3 months. Malassezia  then decrease in number as the sebaceous glands shut down from lack of stimulatory androgens. Upon puberty androgen secretion increases, sebaceous glands turn back on, and the Malassezia  population again takes over. This sebaceous activity is slowly lost with the decline of androgen stimulation during adulthood, where skin is typically drier. This effect is particularly apparent during menopause.   A depiction on the amount of Malassezia present on the skin over a lifetime, Sequential. As Malassezia  are among the major commensal fungi in neonates, it is hypothesised that they may also induce and establish specific immune tolerance pathways, involving regulatory T cells (Tregs), in essence “training” our immune systems as to what is “self” and what is not (Dhariwala et al 2021). So, early exposure to Malassezia  is critical in training our immune system to be familiar with Malassezia , as we need Malassezia  as a commensal or protective mutualist on our skin. Importantly, this happens regardless of whether birth is vaginal or via caesarean. Malassezia  in Skin Disease Differently from the gut and the gut microbiome, healthy skin has a low microbial diversity dominated by a very few species: Malassezia , C acnes , and healthy Staphylococcus . Keratinocytes sense microbial populations through recognition of microbial pathogen-associated molecular pattern (PAMP) motifs via their pattern recognition receptors (PRRs), leucine rich repeat (LRRs) containing receptors, and Toll-like receptors (TLRs). These initiate a cascade of inflammation, signalling to the immune system to secrete antimicrobial peptides that can rapidly inactivate any pathogenic microorganisms. Malassezia  is associated with multiple different skin diseases, with conditions either being caused or exacerbated by alterations by Malassezia  in changing skin. One possible mechanism of Malassezia  mediated skin disease is host genetic susceptibility. In this hypothesis, an underlying genetic difference in individuals causes the same Malassezia  or their metabolites to be toxic to some people, but not others. For example, a defect in skin barrier properties might mean a toxin could penetrate and cause trouble in people with susceptibility but not in others. In this case the same Malassezia  and metabolites could be present on both individuals, but only one be affected. This is common in many fungal mediated diseases and has been clearly demonstrated in dandruff (DeAngelis et al 2005).    When there are even mild barrier defects, Malassezia  can cause the common skin condition pityriasis versicolor, this is most commonly associated with M. furfur, M. globosa  and M. sympodialis . There is increasing evidence about the role of Malassezia  in inflammatory skin conditions, such as atopic dermatitis and psoriasis. Malassezia metabolites trigger a scalp inflammatory response causing dandruff, and in severe situations seborrheic dermatitis, and can invade and inflame hair follicles to cause folliculitis. Moreover, infantile seborrheic dermatitis associated with M. furfur  shows a scaling scalp, ‘cradle cap’, which may be improved by an antifungal shampoo (although this is not a particularly targeted approach). Outside of the skin field, the contribution of Malassezia  has now been found in conditions like Crohn’s disease (Limon et al 2019), and cancers such as pancreatic cancer (Aykut et al 2019), demonstrating the importance of this microbe in the fine balance of human health.   Future Directions  Looking towards the future, an improved understanding of the host- Malassezia  relationship offers potential for the development of treatments to improve skin health outcomes. In a more cosmetic context, there is also opportunity to develop and introduce prebiotic or post-biotic metabolites to restore healthy skin microbiome, to normalize skin microbiome diversity, and restore functional attributes such as barrier, dryness, inflammation, and reverse dysbiosis. Thus, giving the healthy microbes which already live on our skin the right environment and the right nutrients may be used to improve skin health. However, there are still question marks and issues with using probiotics on the skin, and we are still yet to see the engineering of a beneficial probiotic in the context of Malassezia , bearing in mind here that it was only in the 2000s that Malassezia  was first genetically engineered because it was indeed so difficult to do so. Ultimately, we conclude that more research is needed to address the mechanistic processes in fungal-fungal, and microbe-host for skin health and disease, but are hopefully awaiting future developments in this fast-moving arena.    References Aykut, B., Pushalkar, S., Chen, R. et al. (2019). The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL. Nature 574, 264–267. https://doi.org/10.1038/s41586-019-1608-2   Dhariwala, M., and T Scharschmidt (2021) Baby’s skin bacteria: first impressions are long-lasting. Trends Immunol., https://doi.org/10.1016/j.it.2021.10.005 Limon JJ, Tang J, Li D, Wolf AJ, Michelsen KS, Funari V, Gargus M, Nguyen C, Sharma P, Maymi VI, Iliev ID, Skalski JH, Brown J, Landers C, Borneman J, Braun J, Targan SR, McGovern DPB, Underhill DM. (2019). Malassezia Is Associated with Crohn's Disease and Exacerbates Colitis in Mouse Models. Cell Host Microbe. 2019 Mar 13;25(3):377-388.e6. doi: 10.1016/j.chom.2019.01.007. Epub Mar 5. Vijaya Chandra, S. H., Srinivas, R., Dawson, T. L., Jr, & Common, J. E. (2021). Cutaneous Malassezia: Commensal, Pathogen, or Protector?. Frontiers in cellular and infection microbiology, 10, 614446. https://doi.org/10.3389/fcimb.2020.614446 Yvonne M. DeAngelis, Christina M. Gemmer, Joseph R. Kaczvinsky, Dianna C. Kenneally, James R. Schwartz, Thomas L. Dawson. (2005). Three Etiologic Facets of Dandruff and Seborrheic Dermatitis: Malassezia Fungi, Sebaceous Lipids, and Individual Sensitivity. Journal of Investigative Dermatology Symposium Proceedings. https://doi.org/10.1111/j.1087-0024.2005.10119.x . ( https://www.sciencedirect.com/science/article/pii/S0022202X15526146 )

The skin microbiome is influenced by various environmental factors, with ultraviolet (UV) exposure being a significant one. Current research is exploring the impact of UV rays on the skin microbiome and developing innovative solutions to prevent sun damage while preserving the microbiome's delicate balance. What We Know: Certain bacteria and fungi have been observed to respond to UV exposure by producing melanin as a protective measure. These include species such as Cladosporium spp., Sporothrix Schenckii and Cryptococcus neoformans (Woo et al., 2022). A study recruited 21 participants who spent at least 7 days in a sunny holiday destination and compared their skin microbiome samples taken before the trip and up to 84 days after their return. The dominant bacterial phyla at all time points were Actinobacteria, Proteobacteria and  Firmicutes . However, by day 28 post-holiday, all participants exhibited significant changes in microbial beta diversity (Willmott et al., 2023). Participants identified as “sun-seekers" showed an immediate reduction in Proteobacteria  just one day after their holiday, though these levels gradually recovered over time. These results, among others, suggest that sun exposure can alter the diversity and composition of the skin microbiome, which may have downstream effects on skin health (Willmott et al., 2023). Lactobacillus crispatus  possesses UV-protective properties. However, because of the variable response of skin microbes to UV exposure, sunscreen can reduce skin microbiome diversity. One study showed that the application of SPF 20 sunscreen was correlated with a decrease in Cutibacterium acnes  levels following UV exposure (Schuetz et al., 2024). Industry Impact and Potential: Beame is soon to introduce their upcoming "Something You Mist SPF 30 Face Mist," the world’s first SPF product with stress-reducing benefits. This breakthrough formula features neurophroline, a natural active ingredient derived from the seeds of the wild indigo plant (Tephrosia purpurea) , which helps balance cortisol levels, protecting against stress-induced ageing while boosting skin brightness. Products like Beame's align with emerging skincare trends such as psychodermatology, which integrates mental wellness into skincare by treating skin conditions while also addressing their psychological impact, and neurocosmetics, which utilise active ingredients to harness the connection between the skin, nervous system and brain, aiming to enhance both skin quality and mood (Rizzi et al., 2021). Our Solution: Sequential offers a comprehensive, end-to-end microbiome product testing solution, enhanced by specialised product development and formulation services. Leveraging our deep expertise, we help businesses create innovative skin products, including topical sunscreens and photoprotective solutions, that safeguard microbiome integrity while promoting overall skin health.  References: Rizzi, V., Gubitosa, J., Fini, P. & Cosma, P. (2021) Neurocosmetics in Skincare—The Fascinating World of Skin–Brain Connection: A Review to Explore Ingredients, Commercial Products for Skin Aging, and Cosmetic Regulation. Cosmetics. 8 (3), 66. doi:10.3390/cosmetics8030066. Schuetz, R., Claypool, J., Sfriso, R. & Vollhardt, J.H. (2024) Sunscreens can preserve human skin microbiome upon erythemal UV exposure. International Journal of Cosmetic Science. 46 (1), 71–84. doi:10.1111/ics.12910. Willmott, T., Campbell, P.M., Griffiths, C.E.M., O’Connor, C., Bell, M., Watson, R.E.B., McBain, A.J. & Langton, A.K. (2023) Behaviour and sun exposure in holidaymakers alters skin microbiota composition and diversity. Frontiers in Aging. 4. doi:10.3389/fragi.2023.1217635. Woo, Y.R., Cho, S.H., Lee, J.D. & Kim, H.S. (2022) The Human Microbiota and Skin Cancer. International Journal of Molecular Sciences. 23 (3), 1813. doi:10.3390/ijms23031813.

Vaginal microbiome transplantation (VMT) is an emerging treatment that aims to restore the natural balance of the vaginal microbiome, offering a promising alternative to traditional therapies for vaginal disorders. Recent studies highlight its potential to treat conditions like bacterial vaginosis, recurrent yeast infections, sexually transmitted infections (STIs) and preterm birth. What We Know: The vaginal microbiome is typically acidic (pH < 4.5) due to the presence of lactic acid-producing Lactobacilli . This acidity creates a protective barrier with microbicidal and virucidal properties, preventing infections and reducing the risk of issues such as STIs, infertility and pregnancy complications (Turner et al., 2023). Therefore, disruption of this microbial balance, whether by a shift in resident bacteria or the introduction of pathogens, can lead to discomfort and inflammation (Meng, Sun & Zhang, 2024). Due to the parallels between the gut and vaginal microbiomes - both maintaining health through a balanced microbial environment and experiencing infections when disrupted - research has explored similar therapeutic approaches. Just as faecal microbiota transplantation (FMT) has been effective for gut disorders, VMT shows promise in restoring microbial balance and improving health outcomes in women with vaginal microbiome dysbiosis (Meng, Sun & Zhang, 2024). Industry Impact and Potential: Research links reduced Lactobacillus  dominance and increased vaginal microbiome diversity to precancerous lesions and cervical cancer. The microbiota associated with HPV, dysplasia or cancer includes bacteria from bacterial vaginosis and other dysbiosis. These findings suggest that VMT might aid cervical cancer treatment by restoring healthier vaginal microbiota and addressing HPV-related factors (Łaniewski, Ilhan & Herbst-Kralovetz, 2020) . Freya BioSciences has successfully completed a Phase I clinical trial of FB101, a microbiome treatment derived from healthy donors designed to boost Lactobacillus levels and address vaginal dysbiosis in women undergoing IVF. The treatment demonstrated lasting effects for over 8 weeks and improved inflammatory markers, showing promise for enhancing infertility outcomes, as dysbiotic vaginal microbiomes are linked to lower IVF pregnancy rates. Phase II trials are expected to conclude by 2025 (Smith, 2023).  Our Solution: Sequential leads the way in microbiome research, providing comprehensive services that extend beyond vaginal microbiome analysis. We also design and support studies focused on the skin, scalp and oral microbiomes while assisting your company in formulating products that protect microbiome health. Our team of experts is dedicated to helping your business develop thorough and effective studies - such as those aimed at nurturing and enhancing the vaginal microbiome - ultimately promoting women's health and well-being. References: Łaniewski, P., Ilhan, Z.E. & Herbst-Kralovetz, M.M. (2020) The microbiome and gynaecological cancer development, prevention and therapy. Nature Reviews. Urology. 17 (4), 232–250. doi:10.1038/s41585-020-0286-z. Meng, Y., Sun, J. & Zhang, G. (2024) Vaginal microbiota transplantation is a truly opulent and promising edge: fully grasp its potential. Frontiers in Cellular and Infection Microbiology. 14. doi:10.3389/fcimb.2024.1280636. Turner, F., Drury, J., Hapangama, D.K. & Tempest, N. (2023) Menstrual Tampons Are Reliable and Acceptable Tools to Self-Collect Vaginal Microbiome Samples. International Journal of Molecular Sciences . 24 (18), 14121. doi:10.3390/ijms241814121.

Atopic Dermatitis (AD) is a chronic inflammatory skin condition marked by skin barrier dysfunction and immune dysregulation. Influenced by genetic, immunological and environmental factors, as well as the skin microbiome, AD often occurs alongside food allergies (FA). Research has investigated how the skin microbiome contributes to this. What We Know: The 'Dual Allergen Exposure Hypothesis' posits that dermal exposure to allergens during the early life period can lead to FA development, whereas early consumption of allergenic foods promotes tolerance (Lack et al., 2003) . During AD flare-ups, the skin microbiome composition changes: microbial diversity decreases as disease severity increases and generally the abundance of Staphylococcus aureus significantly rises. Approximately 70% of AD individuals are colonised with S. aureus  on lesional skin and 30%–40% in non-lesional skin. Staphylococcus epidermidis  communities are present in both flare and post-flare states (Totté et al., 2016) . Industry Impact and Potential: Mouse studies have shown that FA can develop through skin exposure to allergens due to compromised skin barriers in AD. This involves immune cell activation, increased allergen-specific antibodies and inflammation. Exposure to staphylococcal toxin (SEB) and allergens results in stronger allergic responses than exposure to allergens alone, suggesting that SEB may enhance food allergy development through AD-affected skin (Savinko et al., 2005) . AD children colonised by S. aureus  have a higher risk of FA compared to healthy controls. Infants aged 4-60 months colonised by S. aureus  have an increased risk of developing peanut and egg allergies within their first 5 years, regardless of AD severity (Jones, Curran-Everett & Leung, 2016; Tsilochristou et al., 2019) .  A deeper understanding of how the skin barrier and microbiome contribute to the development of AD and FA has sparked interest in skin-based interventions for allergy prevention. Several randomised controlled trials have examined prophylactic skin interventions from infancy to prevent AD, yielding mixed results. Future research should investigate how early-life shifts in skin microbiota affect AD and FA onset to refine intervention strategies and identify microbial biomarkers for high-risk infants. Although using skin microbes as biotherapeutics for AD shows promise, further investigation is needed to assess its potential for sustained clinical benefits  (Tham et al., 2024) . Our Solution: At Sequential, we specialise in comprehensive Microbiome Product Testing tailored to meet your specific goals in formulating products, such as AD and FD treatment and prevention strategies. Our customised services empower businesses to confidently develop topical solutions. We facilitate microbiome studies to ensure these products maintain microbiome integrity, promoting efficacy and compatibility for healthier skin.  References: Jones, A.L., Curran-Everett, D. & Leung, D.Y.M. (2016) Food allergy is associated with Staphylococcus aureus colonization in children with atopic dermatitis. Journal of Allergy and Clinical Immunology. 137 (4), 1247-1248.e3. doi:10.1016/j.jaci.2016.01.010. Lack, G., Fox, D., Northstone, K. & Golding, J. (2003) Factors Associated with the Development of Peanut Allergy in Childhood. New England Journal of Medicine. 348 (11), 977–985. doi:10.1056/NEJMoa013536. Savinko, T., Lauerma, A., Lehtimäki, S., Gombert, M., Majuri, M.-L., Fyhrquist-Vanni, N., Dieu-Nosjean, M.-C., Kemeny, L., Wolff, H., Homey, B. & Alenius, H. (2005) Topical Superantigen Exposure Induces Epidermal Accumulation of CD8+ T Cells, a Mixed Th1/Th2-Type Dermatitis and Vigorous Production of IgE Antibodies in the Murine Model of Atopic Dermatitis1. The Journal of Immunology. 175 (12), 8320–8326. doi:10.4049/jimmunol.175.12.8320. Tham, E.H., Chia, M., Riggioni, C., Nagarajan, N., Common, J.E.A. & Kong, H.H. (2024) The skin microbiome in pediatric atopic dermatitis and food allergy. Allergy. 79 (6), 1470–1484. doi:10.1111/all.16044. Totté, J.E.E., van der Feltz, W.T., Hennekam, M., van Belkum, A., van Zuuren, E.J. & Pasmans, S.G.M.A. (2016) Prevalence and odds of Staphylococcus aureus carriage in atopic dermatitis: a systematic review and meta‐analysis. British Journal of Dermatology. 175 (4), 687–695. doi:10.1111/bjd.14566. Tsilochristou, O., Toit, G. du, Sayre, P.H., Roberts, G., Lawson, K., et al. (2019) Association of Staphylococcus aureus colonization with food allergy occurs independently of eczema severity. Journal of Allergy and Clinical Immunology. 144 (2), 494–503. doi:10.1016/j.jaci.2019.04.025.

Introduction: What are nanoparticles? Nanoparticles (NPs) are particles with sizes ranging from 1 to 100 nanometers and can be categorized based on their properties, shapes, or sizes. Their nanoscale dimensions and large surface area make them possess unique physical and chemical characteristics. These attributes make NPs ideal for a wide range of applications, including enhancing catalysis, imaging, biomedical uses, energy research, and environmental technologies (Khan et al ., 2019). Examples of some naturally occurring nanoparticles are Silver (Ag), Gold (Au), Iron Oxide (Fe3O4), and Silica (SiO2). Ag can be found in aquatic environments and are used for their antimicrobial properties in products like plastics, paints, and cosmetics. Au are found in ore deposits and are utilized in tumor phototherapy, immunoassays, and biosensors. Fe3O4 are present in sediments and are employed in controlled drug release systems. SiO2, which can be released during volcanic eruptions or found naturally in rocks, sand, soil and water, are used as food additives, in cellular imaging, and as nanocarriers (Griffin et al ., 2017). NPs can be engineered to interact with biological systems at both the molecular and cellular levels. This precise interaction makes them highly promising tools for influencing and modulating the microbiome.  Nanocarriers Nanocarriers (NCs) are nanoengineered, biocompatible materials or devices designed to work in combination with bioactive compounds. They play a crucial role in pharmaceutical and also in cosmetic sciences by enhancing the delivery and efficacy of therapeutic agents (Rout et al ., 2018). For instance, NCs enhance drug delivery by ensuring that antifungal medications are more effectively targeted to the infection site, improving their therapeutic impact. Their small size allows for better skin penetration as well as a controlled and sustained release of drugs, which maintains therapeutic levels longer and reduces the frequency of application. Additionally, nanocarriers improve the bioavailability of poorly soluble drugs and minimize systemic side effects by focusing the drug action more precisely on the infected areas (Keshwania et al ., 2023). Bioconjugated nanoparticulate systems are now being employed in the treatment of a range of severe and previously incurable infectious diseases, including tuberculosis, as well as chronic conditions like diabetes and various types of cancers (Rout et al ., 2018). Challenges in modulating the skin microbiome Rising Antimicrobial Resistance A significant challenge in skin microbiome management is the development of antimicrobial resistance. For instance, many Cutibacterium acnes  strains, a common skin bacterium associated with acne, have developed resistance to major antibiotics such as erythromycin, clindamycin, doxycycline, trimethoprim/sulfamethoxazole, and tetracycline (Alkhawaja et al ., 2020). Stability and Competition of Applied Microbiota Stabilizing applied bacteria on the skin is challenging. Despite initial topical disinfection, it is difficult to eliminate the existing subcutaneous microbiota. Consequently, new microbiota applied to the skin surface must compete with the microbiota residing in deeper skin layers, which can undermine their effectiveness (Callewaert et al ., 2021). Technical Difficulties in Probiotic Delivery Delivering probiotics effectively presents its own set of challenges: limited concentrations, low viability in harsh environments, susceptibility to oxidative damage, challenging preservation and distribution, etc. Encapsulation technology offers a solution by enabling precise and controlled release of probiotics at varying concentrations. This method protects probiotics from harsh conditions and environmental factors such as oxygen, temperature, and light, enhancing their survival and functionality (Pandey  et al ., 2024). Advances of nanotechnology in biomedical applications To address these challenges nanotechnology has been advancing rapidly, particularly in the development of innovative drug delivery systems. Innovations in nanocarrier systems, such as nanoparticles and liposomes (Figure 1), are now engineered to specifically target pathogens or infected tissues (Zong et al ., 2022). Liposomes can carry both water-soluble (Figure 1a) and fat-soluble (Figure 1b) drugs in one structure. They are biocompatible, biodegradable, low in toxicity, and cause minimal immune response. Different types of liposomes can be made positively charged, negatively charged, or neutral (Figure 1c). Liposomes interact with cells mainly through endocytosis (Figure 1d) or fusion (Figure 1e). Additionally, they can easily be modified with surface appendages allowing them to target molecules like antibodies, proteins, or enzymes to direct drugs to infection sites (Figure 1f) (Zong et al ., 2022). NP as Transdermal drug delivery systems (TDDS) The transdermal drug delivery system is a technique that allows drugs to be absorbed through the skin. Nevertheless, the great hydrophobicity and physiology of the skin layers prevent the passive permeation of drug molecules over 500kDA, thus limiting transdermal drug diffusion. Nanoparticles have the ability to improve drug bioavailability, drug penetration and physical stability alongside providing precise dose control and targeted delivery, ensuring that drugs are released in a controlled manner and directed specifically to desired tissues or skin layers. This improved targeting helps in overcoming the skin barrier, thus enhancing treatment efficacy and reducing side effects (Palmer & DeLouise., 2016). Drugs can penetrate the stratum corneum (SC) through two primary pathways: the transepidermal route and the transappendageal route (Figure 2). Transepidermal route In the transepidermal route, drugs can penetrate the skin via two pathways: the transcellular route , which is a direct path through corneocytes and lipid layers, and the intercellular route , which involves diffusing through the lipid matrix around corneocytes. Hydrophilic drugs typically use the transcellular route, while lipophilic  drugs prefer the intercellular route (Barnes et al ., 2021).  While lipophilic and amphiphilic molecules favour the intercellular route, the architecture of the epidermis presents a difficult path to follow causing limited permissibility. However, skin penetration enhancers (e.g. DMSO, glycols, laurocapram, etc.) can enhance drug permeation. The transcellular pathway on the other hand would be unfavorable for most drugs as they would be required to alternate hydrophilic and lipophilic regions.    Transappendagel route The transappendageal route involves drug transport through sweat glands and hair follicles, creating channels across the SC. While these appendages cover only about 0.1% of the skin's surface and contribute minimally to drug absorption, they are crucial for ions and large polar molecules. Sweat ducts and sebaceous glands can limit drug permeation due to their hydrophilic and lipid-rich environments (Barnes et al ., 2021). Notwithstanding, they benefit from accelerated transport through the skin and can serve as a reservoir for the drugs for an improved and sustained controlled localised release into skin in addition to a great proximity to the capillary vessels, facilitating systemic delivery. How can nanoparticles be used to modulate the microbiome? Nanocarriers as delivery systems Delivery of antimicrobial agents NPs can be engineered to carry antimicrobial agents like antibiotics, antimicrobial peptides, or essential oils, delivering them directly to targeted areas of the skin to combat harmful microbes. For instance, silver nanoparticles are known for their broad-spectrum antimicrobial properties, effectively inhibiting the growth of various bacteria and fungi. This makes them valuable in treating skin infections, as they can disrupt microbial cell membranes, inhibit enzyme activity, and generate reactive oxygen species (ROS) that lead to microbial death (Yin et al ., 2020). Assisting probiotic delivery Encapsulating probiotics within protective nanocarriers acts as a physical barrier that shields them from harsh environments, such as stomach acid and bile, ensuring higher survival rates upon consumption. This encapsulation also protects probiotics from external factors like temperature and light during storage, enhancing their stability and shelf life. Additionally, nanocarriers enable the precise and controlled release of probiotics at targeted sites, maximizing their therapeutic potential. Co-encapsulation is also an option, where probiotics and other bioactive compounds are delivered together, potentially enhancing overall health benefits through synergistic effects (Pandey et al ., 2024). Targeted drug delivery NPs can be engineered for specific cell, tissue, or location targeting by modifying their surface with ligands or antibodies, allowing for precise delivery of therapeutic agents directly to the intended site. This targeted approach significantly limits off-target effects, reducing damage to healthy cells and minimizing bystander effects. Additionally, the enhanced targeting and delivery efficiency provided by NPs enable a reduction in the required dose of the therapeutic compound, improving safety, and conserving biocompounds (Afzal et al ., 2021). Hussain et al. (2018) accomplished this by conjugating a 9 amino acid oligopeptide to a porous silicon NP loaded with antibiotic targeting specifically S. aureus  infected tissues.  Disruption of biofilms A biofilm is a collection of microbial cells attached to a surface, encased in a matrix of extracellular polymeric substances (Donlan et al ., 2002).  Following are few metal NPs that are known to have strong defence mechanism to combat biofilm formation;  Immunomodulation There are four types of immunomodulatory nanosystems: organic , inorganic , biomimetic , and naturally derived . Organic nanosystems, such as liposomes and polymeric nanoparticles, are known for their biocompatibility and controlled release capabilities. Inorganic nanosystems, including metal and silica nanoparticles, offer stability and can directly interact with immune cells. Biomimetic nanosystems mimic natural biological structures, enhancing cellular uptake and immune response. Naturally derived nanosystems use compounds from natural sources, like plant extracts or microbial products, providing inherent biocompatibility and immunomodulatory properties (Khatun et al ., 2023). Case study: Probiotic-based nanoparticles for targeted microbiota modulation and immune restoration in bacterial pneumonia (Fu et al ., 2022) Fu et al. designed probiotic-based nanoparticles called OASCLR by coating chitosan (CS), hyaluronic acid (HA), and ononin onto living Lactobacillus rhamnosus (LR). This probiotic was chosen by virtue of its microbial competitiveness, its ability to modulate the immune response in hyperactive immunocompetent and immunocompromised hosts and its role as a modulator of the microbiome composition. To ensure the viability of LR in the lungs, the probiotic was first encapsulated in CS, known for its unique mucoadhesive properties and great biocompatibility. HA was then added as it can regulate the immune system by specifically targeting pro-inflammatory M1 macrophages via CD44 receptors. To alleviate the oxidative damage rising from the harsh conditions in the lungs, the isoflavone Ononin was added to the coating. Through ROS-scavenging, anti-inflammatory and anti-oxidant properties, ononin could enhance OASCLR’s resistance against ROS-mediated cytotoxicity and hyaluronidase degradation while also promoting the growth of LR and inhibiting pathogens. Considering the low bioactivity of LR in the ROS environment, the designed CS/HA–ononin shell could prevent LR from oxygen damage and allow OASCLR nanoparticles targeting pro-inflammatory macrophages by the interaction of HA with CD44.  These nanoparticles demonstrated over 99.97% antibacterial efficiency against common clinical pathogens. Notably, OASCLR modulated lung microbiota by reducing pathogens and enhancing the richness and diversity of probiotic and commensal bacteria. They also targeted inflammatory macrophages via CD44, alleviating excessive immune responses in hyperactive pneumonia. Additionally, OASCLR improved macrophage phagocytic function in immunocompromised pneumonia, increasing phagocytic ability from 2.61% to 12.3%. This work suggests a promising strategy for treating both hyperactive and immunocompromised bacterial pneumonia (Figure 3) (Fu et al ., 2022). Method To determine whether the lung microbiome was altered following OASCLR treatment, the study established a primary pneumonia model in mice using Staphylococcus aureus  (SA). The experimental design involved infecting mice with SA via nasal intubation on Day -3. The mice were then treated with either PBS as a negative control or OASCLR through non-invasive aerosol inhalation on Day 0. Blood tests were conducted on Days 1 and 7, and 16S ribosomal RNA gene sequencing was performed on Day 2 to analyze changes in the lung microbiome (Figure 4) (Fu et al ., 2022). Results: Modulation of lung microbiome by OASCLR OASCLR group exhibited a higher Chao richness index, indicating greater bacterial species richness (Figure 5D). Further analysis showed a shift in microbiota composition, with increased Firmicutes and decreased Proteobacteria  and Bacteroidota  (Figure 5E). Additionally, OASCLR reduced pathogenic bacteria like Staphylococcus  while boosting probiotic and commensal bacteria such as Lactobacillus  and Bifidobacterium , suggesting that OASCLR effectively promotes a healthier lung microbiota (Figure 5F) (Fu et al ., 2022). Results: Decreased inflammation Immunofluorescence analysis revealed that OASCLR treatment reduced CD45 and TNF-α expression while slightly increasing IL-10, indicating a decrease in pro-inflammatory responses. RT-PCR analysis also showed a decreased TNF-α to IL-10 ratio in the OASCLR group compared to PBS (Figure 6). These results suggest that OASCLR effectively modulates excessive inflammation in primary bacterial pneumonia (Fu et al ., 2022). Results: Macrophage polarization OASCLR treatment altered the immune landscape by reducing pro-inflammatory markers such as TNF-α and increasing anti-inflammatory IL-10. It also lowered the expression of CD80, a marker associated with M1 macrophages, which are typically involved in pro-inflammatory responses and tissue damage. They suggested that (This indicates that)  OASCLR promotes a shift towards M2 macrophages, which are known for their anti-inflammatory properties, enhanced phagocytosis, and role in tissue repair and regeneration. This change in macrophage polarisation suggests that OASCLR helps reduce inflammation and supports tissue healing (Fu et al ., 2022). Results: Biocompatibility The mice treated with OASCLR showed no significant tissue damage or adverse effects. Blood tests and H&E staining confirmed that OASCLR nanoparticles did not affect liver or kidney function and were safe for major organs. These findings suggest OASCLR has strong therapeutic potential for treating hyperactive immunocompetent primary pneumonia while complying to biocompatibility requirements (Fu et al ., 2022). Conclusion of the case study OASCLR nanoparticles were reported to restore host immunity, regulate lung inflammation, and enhance macrophage phagocytosis in bacterial pneumonia. The ononin shell allows immune evasion and safe clearance, supporting clinical use. Combining probiotics with biomaterials boosts their function, making OASCLR nanoparticles a potential treatment for various diseases beyond pneumonia (Fu et al ., 2022). Consideration of NPs for microbiome modulation Challenges in using NPs for microbiome modulation include meeting strict regulatory standards, achieving precise targeting to avoid off-target effects, and ensuring NPs stability during storage and administration. It is also important to understand the NPs degradation to ensure timely and effective drug release. These factors are critical for advancing NP-based therapies in clinical settings (Wang et al ., 2017). Conclusion: Small entities for a big future NPs have a potential to significantly impact antimicrobial therapy and microbiome modulation despite their tiny size. NPs' unique properties, such as their ability to target specific pathogens and modulate biological systems, position them as powerful tools for advancing medical treatments. This perspective underscores the transformative possibilities of NPs in addressing current challenges in healthcare, including antibiotic resistance and precise drug delivery (Wang et al ., 2017). References Afzal Shah, Saima Aftab, Jan Nisar, Muhammad Naeem Ashiq, Faiza Jan Iftikhar,  Nanocarriers for targeted drug delivery, Journal of Drug Delivery Science and Technology, Volume 62, 2021, 102426, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2021.102426 . ( https://www.sciencedirect.com/science/article/pii/S1773224721001064 ) Ali SG, Ansari MA, Alzohairy MA, Alomary MN, AlYahya S, Jalal M, Khan HM, Asiri SMM,  Ahmad W, Mahdi AA, El-Sherbeeny AM, El-Meligy MA. Biogenic Gold Nanoparticles as Potent Antibacterial and Antibiofilm Nano-Antibiotics against Pseudomonas aeruginosa . Antibiotics (Basel). 2020 Feb 27;9(3):100. doi: 10.3390/antibiotics9030100. PMID: 32120845; PMCID: PMC7148532. Alkhawaja E, Hammadi S, Abdelmalek M, Mahasneh N, Alkhawaja B, Abdelmalek SM.  Antibiotic resistant Cutibacterium acnes among acne patients in Jordan: a cross sectional study. BMC Dermatol. 2020 Nov 17;20(1):17. doi: 10.1186/s12895-020-00108-9. PMID: 33203374; PMCID: PMC7673087. Barnes TM, Mijaljica D, Townley JP, Spada F, Harrison IP. Vehicles for Drug Delivery and  Cosmetic Moisturizers: Review and Comparison. Pharmaceutics. 2021 Nov 26;13(12):2012. doi: 10.3390/pharmaceutics13122012. PMID: 34959294; PMCID: PMC8703425. Callewaert C, Knödlseder N, Karoglan A, Güell M, Paetzold B. Skin microbiome  transplantation and manipulation: Current state of the art. Comput Struct Biotechnol J. 2021 Jan 4;19:624-631. doi: 10.1016/j.csbj.2021.01.001. PMID: 33510866; PMCID: PMC7806958. Donlan RM. Biofilms: microbial life on surfaces. Emerg Infect Dis. 2002 Sep;8(9):881-90. doi:  10.3201/eid0809.020063. PMID: 12194761; PMCID: PMC2732559. Fu J, Liu X, Cui Z, Zheng Y, Jiang H, Zhang Y, Li Z, Liang Y, Zhu S, Chu PK, Yeung KWK,  Wu S. Probiotic-based nanoparticles for targeted microbiota modulation and immune restoration in bacterial pneumonia. Natl Sci Rev. 2022 Oct 16;10(2):nwac221. doi: 10.1093/nsr/nwac221. PMID: 36817841; PMCID: PMC9935993. Griffin S, Masood MI, Nasim MJ, Sarfraz M, Ebokaiwe AP, Schäfer KH, Keck CM, Jacob C.  Natural Nanoparticles: A Particular Matter Inspired by Nature. Antioxidants (Basel). 2017 Dec 29;7(1):3. doi: 10.3390/antiox7010003. PMID: 29286304; PMCID: PMC5789313. Hussain, S., Joo, J., Kang, J., Kim, B., Braun, G.B., She, Z.-G., Kim, D., Mann, A.P., Mölder, T., Teesalu, T., Carnazza, S., Guglielmino, S., Sailor, M.J., Ruoslahti, E., 2018.  Antibiotic-loaded nanoparticles targeted to the site of infection enhance antibacterial efficacy. Nat Biomed Eng 2, 95–103. https://doi.org/10.1038/s41551-017-0187-5 Ingle AP, Duran N, Rai M. Bioactivity, mechanism of action, and cytotoxicity of copper-based  nanoparticles: a review. Appl Microbiol Biotechnol. 2014 Feb;98(3):1001-9. doi: 10.1007/s00253-013-5422-8. Epub 2013 Dec 5. PMID: 24305741. Jardeleza C, Rao S, Thierry B, Gajjar P, Vreugde S, Prestidge CA, Wormald PJ.  Liposome-encapsulated ISMN: a novel nitric oxide-based therapeutic agent against Staphylococcus aureus biofilms. PLoS One. 2014 Mar 21;9(3):e92117. doi: 10.1371/journal.pone.0092117. PMID: 24658315; PMCID: PMC3962386. Keshwania P, Kaur N, Chauhan J, Sharma G, Afzal O, Alfawaz Altamimi AS, Almalki WH.  Superficial Dermatophytosis across the World's Populations: Potential Benefits from Nanocarrier-Based Therapies and Rising Challenges. ACS Omega. 2023 Aug 22;8(35):31575-31599. doi: 10.1021/acsomega.3c01988. PMID: 37692246; PMCID: PMC10483660. Khan, Ibrahim & Saeed, Khalid & Khan, Idrees. (2019). Nanoparticles: Properties,  Applications and Toxicities. Arabian Journal of Chemistry. 12. 908-931. 10.1016/j.arabjc.2017.05.011.  Khatun S, Putta CL, Hak A, Rengan AK. Immunomodulatory nanosystems: An emerging  strategy to combat viral infections. Biomater Biosyst. 2023 Jan 30;9:100073. doi: 10.1016/j.bbiosy.2023.100073. PMID: 36967725; PMCID: PMC10036237. Palmer BC, DeLouise LA. Nanoparticle-Enabled Transdermal Drug Delivery Systems for  Enhanced Dose Control and Tissue Targeting. Molecules. 2016 Dec 15;21(12):1719. doi: 10.3390/molecules21121719. PMID: 27983701; PMCID: PMC5639878. Pandey, R.P., Gunjan, Himanshu et al.  Nanocarrier-mediated probiotic delivery: a systematic  meta-analysis assessing the biological effects. Sci Rep  14, 631 (2024). https://doi.org/10.1038/s41598-023-50972-x Rout GK, Shin HS, Gouda S, Sahoo S, Das G, Fraceto LF, Patra JK. Current advances in  nanocarriers for biomedical research and their applications. Artif Cells Nanomed Biotechnol. 2018;46(sup2):1053-1062. doi: 10.1080/21691401.2018.1478843. Epub 2018 Jun 7. PMID: 29879850. Trivedi R, Upadhyay TK, Kausar MA, Saeed A, Sharangi AB, Almatroudi A, Alabdallah NM,  Saeed M, Aqil F. 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In the UK, around 120,000 people visit A&E annually due to burn injuries, with 72% resulting in hypertrophic scarring, a type of raised scar that forms within the boundaries of the original wound due to excessive collagen production during healing. While traditional wound dressings effectively promote healing, there’s growing interest in innovative approaches that address post-burn scarring more effectively.  What We Know: Traditional dressings help close and heal wounds by providing hydration and antimicrobial protection, but they aren’t designed to prevent or treat post-burn scarring. Burns disrupt the skin’s microbial balance, favouring heat-loving microbes like Aeribacillus, Caldalkalibacillus  and Nesterenkonia  while reducing beneficial bacteria such as Cutibacterium, Staphylococci and Corynebacteria . Increased levels of Corynebacterium  are linked to higher infection risks, whereas Staphylococci and Cutibacterium  are associated with lower infection rates post-burn (Yang et al., 2024).  Despite reduced bacterial richness at the genus level, burn patients exhibit increased microbial community diversity and evenness. This altered microbial landscape, marked by a lower overall bacterial burden and an overgrowth of Staphylococcus  species, highlights a persistent dysbiotic state in the skin microbiota during the subacute phase of wound healing (Liu et al., 2018) . Industry Impact and Potential: @Healome Therapeutics has developed a groundbreaking bioactive skin dressing technology, recently cleared by the @Medicines and Healthcare products Regulatory Agency (MHRA) for a phase I trial aimed at reducing scarring. The trial, conducted at Queen Elizabeth Hospital in Birmingham, UK, involves 25 patients with burns covering 3-20% of their body surface. Healome’s innovative dressing is a clear film that not only offers the benefits of traditional wound dressings but also incorporates synthetic human-derived decorin protein, which plays a critical role in wound healing. This protein reduces the inflammatory response and regulates the wound’s microenvironment. Early research suggests that this approach may reduce fibrosis and promote tissue regeneration, offering new hope for scar management in burn patients. Products like Healome’s dressing showcase the exciting potential of using the microbiome and skin environment to enhance wound healing, paving the way for future innovations in burn care. Our Solution: At Sequential, we offer comprehensive services for evaluating product impacts and formulations, supported by a vast database of over 20,000 microbiome samples and 4,000 ingredients, along with a global network of more than 10,000 testing participants. Our customizable microbiome studies simulate real-world testing scenarios, ensuring that your products preserve biome integrity while delivering optimal results. References: Liu, S.-H., Huang, Y.-C., Chen, L.Y., Yu, S.-C., Yu, H.-Y. & Chuang, S.-S. (2018) The skin microbiome of wound scars and unaffected skin in patients with moderate to severe burns in the subacute phase. Wound Repair and Regeneration: Official Publication of the Wound Healing Society [and] the European Tissue Repair Society. 26 (2), 182–191. doi:10.1111/wrr.12632. Yang, Y., Huang, J., Zeng, A., Long, X., Yu, N. & Wang, X. (2024) The role of the skin microbiome in wound healing. Burns & Trauma. 12, tkad059. doi:10.1093/burnst/tkad059.

Swimming is a widely enjoyed physical activity that provides various health benefits, such as improved cardiovascular fitness, enhanced muscle strength, and reduced stress levels. Nevertheless, swimming also involves exposure to different water environments, including chlorinated pools, seawater, and freshwater lakes. Each of these environments possesses distinct chemical and microbial properties that can uniquely affect the skin microbiome. Consequently, comprehending the significance of the skin microbiome in swimming is essential. What we know: Studies have found that exposure to chlorinated pool water reduces microbial diversity on the skin, as it acts as a disinfectant, killing both harmful and beneficial bacteria, which can lead to an imbalance in the skin microbiome. This imbalance may increase the risk of skin conditions like dermatitis and infections (Puce et al ., 2022). Ocean water contains a diverse range of marine bacteria, thereby enhancing the diversity of the skin microbiome. The ocean water simultaneously removes resident skin bacteria while depositing ocean-borne bacteria onto the skin (Nielsen et al ., 2019). The predominating phyla Actinobacteria , Firmicutes , and Proteobacteria on the skin changed after swimming when compared to before swimming tends to decrease, whereas Bacteroidetes  tends to increase. As time passed, the bacterial community composition trended towards baseline (Nielsen et al ., 2019). The quantity of Vibrio spp.  found on human skin was over ten times higher than that in the ocean water sample (which was only 0.032%), indicating that Vibrio spp.  has a particular affinity for adhering to human skin (Nielsen et al ., 2019). Industry impact & potential: Research shows that males are more prone to acquiring infections from Vibrio vulnificus and Aeromonas spp.  following water exposure. Future research could provide valuable insights into the factors contributing to these infections and explore potential differences in the skin microbiome between males and females after such exposure (Nielsen et al ., 2019). Formulations such as post and pre-swim cleansers and moisturizers should be designed to aid in microbiome recovery while also protecting the skin from chlorine and salt damage. Our solution: Sequential, is a company focusing on microbiome studies. We carry out various services from clinical testing to helping with formulations. We have at home testing kits that will allow you to discover the state of your skin microbiome. Through our Skin Health Tracker app, we can give you tips on how you can improve your skin and the microbiome.  Reference: Nielsen MC, Jiang SC. Alterations of the human skin microbiome after ocean water  exposure. Mar Pollut Bull. 2019 Aug;145:595-603. doi: 10.1016/j.marpolbul.2019.06.047. Epub 2019 Jul 2. PMID: 31590829; PMCID: PMC8061468. Puce L, Hampton-Marcell J, Trabelsi K, Ammar A, Chtourou H, Boulares A, Marinelli L, Mori  L, Cotellessa F, Currà A, Trompetto C, Bragazzi NL. Swimming and the human microbiome at the intersection of sports, clinical, and environmental sciences: A scoping review of the literature. Front Microbiol. 2022 Aug 3;13:984867. doi: 10.3389/fmicb.2022.984867. PMID: 35992695; PMCID: PMC9382026.

The scalp microbiome plays a crucial yet often overlooked role in the development and treatment of alopecia. Studies have shed light on how rebalancing these microbes can significantly enhance the efficacy of treatments for hair loss, offering new hope for patients. What We Know: Cutibacterium spp.  and Staphylococcus spp . constitute about 90% of healthy scalp microbiomes, with Corynebacterium spp., Streptococcus spp., Acinetobacter spp . and Prevotella spp . making up the remaining 10% (Jo et al., 2022) . Alopecia patients’ scalp microbiomes exhibit increased C. acnes , Stenotrophomonas geniculata, Wallemia  and Eurotium , as well as reduced Malassezia, when compared to healthy individuals. Therefore, it is likely that an imbalance in scalp microbiota may contribute to alopecia (Zhang et al., 2024) . Industry Impact and Potential: Platelet-rich plasma (PRP) has proven effective in treating alopecia, but its impact on the scalp microbiome was previously unexplored. A recent study revealed that PRP treatment rebalances the scalp microbiome, specifically increasing Cutibacterium  levels while decreasing Staphylococcus  and Lawsonella  levels (Zhang et al., 2024) . Cutibacterium  plays a vital role in maintaining skin homeostasis and is crucial for lipid regulation, follicular niche competition, immune regulation and mitigating oxidative stress. Furthermore, the balance between Cutibacterium and Staphylococcus  is important for regulating immune response. Reduction in Lawsonella  suggests decreased scalp sebum production following treatment. This is relevant to alopecia treatment, as imbalances in sebum production can exacerbate hair loss by contributing to inflammation and follicle damage (Zhang et al., 2024) .  Lactic acid bacteria (LAB), Limosilactobacillus fermentum  LM1020 and its heat-treated version HT-LM1020, can help promote hair growth on human scalp tissue and dermal papilla cells. These bacteria work with other ingredients to fight hair loss by boosting cell growth and regulating the expression of proteins important for cell division (Bae et al., 2024) . AMOREPACIFIC patented a composition that uses extracellular follicles derived from LAB to prevent hair loss, stimulate hair growth and support overall hair health. These extracellular follicles (cellular components or secretions released by the bacteria) represent a promising advancement in alopecia treatment, offering potential benefits for both hair and scalp health. Our Solution: With a database of over 20,000 microbiome samples and 4,000 ingredients, and a global network of more than 10,000 testing participants, Sequential offers comprehensive services to evaluate product impacts and formulations. Our customisable microbiome studies provide real-life context testing, and our formulation support ensures products maintain biome integrity, making us the ideal partner for your product development and efficacy needs. References: Bae, W.-Y., Jung, W.-H., Shin, S.L., Kim, T.-R., Sohn, M., Suk, J., Jung, I., Lee, Y.I. & Lee, J.H. (2024) Heat-treated Limosilactobacillus fermentum LM1020 with menthol, salicylic acid, and panthenol promotes hair growth and regulates hair scalp microbiome balance in androgenetic alopecia: A double-blind, randomized and placebo-controlled clinical trial. Journal of Cosmetic Dermatology . n/a (n/a). doi:10.1111/jocd.16357. Jo, H., Kim, S.Y., Kang, B.H., Baek, C., Kwon, J.E., Jeang, J.W., Heo, Y.M., Kim, H.-B., Heo, C.Y., Kang, S.M., Shin, B.H., Nam, D.Y., Lee, Y.-G., Kang, S.C. & Lee, D.-G. (2022) Staphylococcus epidermidis Cicaria, a Novel Strain Derived from the Human Microbiome, and Its Efficacy as a Treatment for Hair Loss. Molecules . 27 (16). doi:10.3390/molecules27165136. Zhang, Q., Wang, Y., Ran, C., Zhou, Y., Zhao, Z., Xu, T., Hou, H. & Lu, Y. (2024) Characterization of distinct microbiota associated with androgenetic alopecia patients treated and untreated with platelet‐rich plasma (PRP). Animal Models and Experimental Medicine . 7 (2), 106–113. doi:10.1002/ame2.12414.

Diabetes mellitus is a chronic condition marked by elevated blood glucose levels due to abnormal insulin production or insulin resistance, leading to complications of the heart, kidneys, eyes, blood vessels and nerves. Type 2 diabetes specifically is associated with skin issues like chronic foot ulcers and increased infections, potentially due to disruptions in the skin microbiome. What We Know: In 2021, the global prevalence of diabetes among adults was estimated at 537 million and is projected to rise to 783 million by 2045 (International Diabetes Federation, 2021).  Diabetic foot ulcers (DFUs) are defined as “Ulcers in the foot of individuals with diabetes, often accompanied by lower limb neuropathy and/or peripheral arterial disease.” DFU can also be defined as a chronic skin disease linked to altered bacterial diversity and instability in wound microbiota (Zhang et al., 2023).  The total lifetime risk of DFU complications for patients with diabetes (type 1 or 2) is 25%. These wounds are slow to heal, difficult to treat and vulnerable to infection (Gardiner et al., 2017; Packer, Ali & Manna, 2024). Bacterial infection is the most common cause of delayed healing in DFUs and the lack of appropriate diagnostic tools makes it difficult to determine if the bacteria in the DFU are due to changes in the original colonised bacteria or an external infection. Few studies have investigated the transition of bacterial flora from healthy skin to diabetic skin to DFU skin (Zhang et al., 2023).  Industry Impact and Potential: While some bacterial species can hinder wound healing and lead to chronic wounds, others can accelerate healing and prevent pathogen colonisation. Significant differences in skin microbial composition exist between diabetic and non-diabetic patients, with diabetic wounds showing increased levels of Staphylococcus, Aerococcus, Porphyromonadaceae  and Proteobacteria , and decreased levels of Streptococcus, Lachnospiraceae  and Acinetobacter  (Zhang et al., 2023).  There are changes in the bacterial colony structure of DFU skin compared to healthy or diabetic skin without ulcers. In DFU skin, Staphylococcus , Enhydrobacter  and Corynebacterium_1  are significantly reduced, while Escherichia coli  and Pseudomonas  are increased (Zhang et al., 2023).  Thus, the difference between healthy skin and diabetic skin with or without ulcers lies in the balance between normal and pathogenic microbiota. Subsequently, altering the microbiota composition of wounds may help the treatment of DFU (Zhang et al., 2023).  Our Solution: Sequential offers customisable end-to-end Microbiome Testing for your research needs, like investigating the influence of the skin microbiome on diabetic skin and wound healing. Sequential offers real-world testing scenarios, and additionally formulation support to develop products that maintain microbiome stability for the skin, as well as for the oral, scalp and vaginal microbiomes.  References: Gardiner, M., Vicaretti, M., Sparks, J., Bansal, S., Bush, S., Liu, M., Darling, A., Harry, E. & Burke, C.M. (2017) A longitudinal study of the diabetic skin and wound microbiome. PeerJ. 5, e3543. doi:10.7717/peerj.3543. International Diabetes Federation (2021) IDF Diabetes Atlas. 2021. IDF Diabetes Atlas. https://diabetesatlas.org/ [Accessed: 5 July 2024]. Packer, C.F., Ali, S.A. & Manna, B. (2024) Diabetic Ulcer. In: StatPearls. Treasure Island (FL), StatPearls Publishing. p. http://www.ncbi.nlm.nih.gov/books/NBK499887/ . Zhang, X.-N., Wu, C.-Y., Wu, Z.-W., Xu, L.-X., Jiang, F.-T. & Chen, H.-W. (2023) Association Between the Diabetic Foot Ulcer and the Bacterial Colony of the Skin Based on 16S rRNA Gene Sequencing: An Observational Study. Clinical, Cosmetic and Investigational Dermatology. 16, 2801–2812. doi:10.2147/CCID.S425922.

Micro-Botox is a specialised technique involving the injecting of diluted botulinum toxin into the skin. It is a frequently performed procedure to improve facial skin tone, texture, fine wrinkles, and enlarged pores. Unlike traditional Botox, which targets deeper facial muscles, Micro-Botox is administered more superficially and in a more diluted form. This allows for a more uniform and subtle rejuvenation effect without significantly affecting facial expressions.  What we know: ▫️Botulinum toxin type A (BoNT-A) is widely recognized for its use as a neuromodulator in treating facial lines, correcting facial asymmetry, and creating a lifting effect in the lower face by administering via multiple injections into the superficial fibres of facial muscles ( Fabi , et al., 2023). ▫️Micro-botox has demonstrated effectiveness in enhancing the skin's sheen and texture, reducing sweat and sebum production, and minimising enlarged pores. It works by shrinking sebaceous glands, which in turn tightens the skin envelope (Salem et al., 2023).  ▫️Sebum provides a nutrient-rich environment for Cutibacterium acnes. By reducing sebum production, Micro-botox can decrease the availability of nutrients for Cutibacterium acnes bacteria, potentially reducing their population (Rho et al., 2021). ▫️The combined use of Micro-Botox and hyaluronic acid has been found to enhance skin hydration and improve the dermal barrier function ( Kim , 2021).  ▫️Micro-Botox is effective for facial rejuvenation, lifting the mid to lower face, and reducing fine wrinkles in the forehead and cheek areas, particularly in younger individuals. It also works for neck rejuvenation, especially in older individuals ( Iranmanesh  et al., 2022).  Industry impact & potential: ▫️The demand for Micro-Botox procedures continues to increase, driven by its effectiveness in addressing various skin concerns. ▫️There's potential for combining Micro-Botox with other skincare to enhance overall skin health and appearance. ▫️There is very little research that has been done on Micro-Botox and its impact on the skin microbiome. Hence, further research is needed to understand how Micro-Botox procedures impact the skin microbiome. Our solution: Sequential, specialises in microbiome analysis and we use advanced testing technologies and longitudinal study designs, to analyse changes in microbial diversity and composition pre and post treatments. By correlating these microbiome shifts with clinical outcomes such as improvements in skin texture or pore size, we aim to uncover new insights into the cosmetic procedure's impact on skin health at a microbial level. Reference: Fabi SG, Park JY, Goldie K, Wu W. Microtoxin for Improving Pore Size, Skin Laxity, Sebum  Control, and Scars: A Roundtable on Integrating Intradermal Botulinum Toxin Type A Microdoses Into Clinical Practice. Aesthet Surg J. 2023 Aug 17;43(9):1015-1024. doi: 10.1093/asj/sjad044. PMID: 36857534; PMCID: PMC10481112. Iranmanesh B, Khalili M, Mohammadi S, Amiri R, Aflatoonian M. Employing microbotox  technique for facial rejuvenation and face-lift. J Cosmet Dermatol. 2022 Oct;21(10):4160-4170. doi: 10.1111/jocd.14768. Epub 2022 Jan 22. PMID: 35064633. Kim JS. Fine Wrinkle Treatment and Hydration on the Facial Dermis Using HydroToxin  Mixture of MicroBotox and MicroHyaluronic Acid. Aesthet Surg J. 2021 May 18;41(6):NP538-NP549. doi: 10.1093/asj/sjaa231. PMID: 32779694; PMCID: PMC8240748. Rho NK, Gil YC. Botulinum Neurotoxin Type A in the Treatment of Facial Seborrhea and  Acne: Evidence and a Proposed Mechanism. Toxins (Basel). 2021 Nov 19;13(11):817. doi: 10.3390/toxins13110817. PMID: 34822601; PMCID: PMC8626011. Salem RM, Salah SAE, Ibrahim SE. Microbotox injection versus its topical application  following microneedling in the treatment of wide facial pores: A split face comparative study. J Cosmet Dermatol. 2023 Apr;22(4):1249-1255. doi: 10.1111/jocd.15590. Epub 2023 Jan 6. PMID: 36606384.

Snail mucin is the secretion produced by various species of snails, and it has recently gained attention for its potential benefits in skincare and cosmetic applications. Emerging studies indicate that its unique composition provides intense hydration and skin regeneration and positively influences the skin's microbiome, which is the delicate ecosystem of microorganisms on the skin's surface. What we know: Snail mucin is a complex mixture of proteins, glycoproteins, and other bioactive compounds such as allantoin, glycolic acid, and antibacterial peptides, providing benefits such as moisturizing, wound healing, and anti-inflammatory effects (Zhu et al ., 2024). Snail mucin contains natural antimicrobial peptides that selectively inhibits the growth of pathogenic bacteria while promoting the growth of beneficial bacteria, thereby maintaining a balanced skin microbiome (McDermott et al ., 2021).  Researchers have found that snail mucin demonstrates antibacterial effects against Pseudomonas aeruginosa and Staphylococcus aureus known to cause infections (Aflatooni et al ., 2023). Snail mucin is abundant in hyaluronic acid and glycolic acid, which improve skin hydration and barrier function (Yongeun et al ., 2022). A healthy skin barrier is essential for maintaining a stable microbiome, as it protects against external pathogens and prevents moisture loss. In-vitro studies had shown that Snail mucin had significantly improved the dermal density, skin elasticity, and wrinkles (Singh et al ., 2024). Cryptomphalus Aspersa  snail mucin boosts keratinocytes and fibroblasts proliferation, migration, and adhesion protein expression, potentially aiding scar healing, and thereby promoting a stable microbiome environment (Singh et at ., 2024). Industry impact & potential: The growing demand for snail mucin products and the need for research into its potential uses are driving an expanding economic market. The increasing demand for snail mucin creates pressure on collection methods, highlighting the critical need for ethical habitats for their collection (Singh et al ., 2024). As snail mucin is an animal-derived product it can lead to sustainability concerns. Therefore, more sustainable alternatives are much needed, such as synthetic or lab-grown mucin.    Our solution: Sequential, specializes in skin health solutions, features a state-of-the-art testing facility where we analyze the skin microbiome. We use advanced technology to test various skincare ingredients to better understand its impact on the skin microbiome. By conducting these tests, we aim to provide insights into the efficacy and sustainability of ingredients in skincare products.   Reference: Aflatooni S, Boby A, Natarelli N, Albers S. Snails and Skin: A Systematic Review on the  Effects of Snail-based Products on Skin Health. Journal of Integrative Dermatology . Published online October 31, 2023. McDermott M, Cerullo AR, Parziale J, Achrak E, Sultana S, Ferd J, Samad S, Deng W,  Braunschweig AB, Holford M. Advancing Discovery of Snail Mucins Function and Application. Front Bioeng Biotechnol. 2021 Oct 11;9:734023. doi: 10.3389/fbioe.2021.734023. PMID: 34708024; PMCID: PMC8542881. Singh N,  Brown AN,  Gold MH.  Snail extract for skin: A review of uses, projections, and  limitations. J Cosmet Dermatol .  2024; 23: 1113-1121. doi: 10.1111/jocd.16269 Yongeun Kim, Woo-Jin Sim, Jeong-seok Lee, Tae-Gyu Lim, Snail mucin is a functional food  ingredient for skin, Journal of Functional Foods, Volume 92, 2022, 105053, ISSN 1756-4646, https://doi.org/10.1016/j.jff.2022.105053 . Zhu K, Zhang Z, Li G, Sun J, Gu T, Ain NU, Zhang X, Li D. Extraction, structure,  pharmacological activities and applications of polysaccharides and proteins isolated from snail mucus. Int J Biol Macromol. 2024 Feb;258(Pt 1):128878. doi: 10.1016/j.ijbiomac.2023.128878. Epub 2023 Dec 21. PMID: 38141709.

While the harmful effects of smoking on overall health are widely recognised, its impact on the oral microbiome is still not fully understood, despite its significant health implications. This gap highlights the importance of delving deeper into the complex interplay between smoking and alterations in oral microbial communities.  What We Know: Smoking unleashes toxic compounds into the oral cavity, fostering unstable bacterial growth in biofilms, elevating saliva acidity, depleting oxygen levels, altering bacterial attachment, promoting antibiotic resistance, and compromising immune responses (Mohammed et al., 2024) . Smokers exhibit distinctive oral microbiome profiles, featuring reduced bacterial diversity and specific increases in inflammation and disease-associated bacteria. Notably, smokers display lower levels of Neisseria, Porphyromonas , and Capnocytophaga , while showing higher levels of Actinomyces, Veillonella, Streptococcus , and anaerobic bacteria (Wu et al., 2016) . Research comparing cigarette and smokeless tobacco users highlights a more diverse oral bacterial community among tobacco users, characterised by higher Firmicutes  and lower Proteobacteria  abundance. Notably, tobacco users may harbour opportunistic pathogens like Neisseria subflava, Bulleidia moorei , and Porphyromonas endodontalis   (Chattopadhyay et al., 2024) . Geographic and ethnic variations further underscore the complexity of smoking's impact on oral microbiomes. A study on an American smoking population showed reduced levels of Proteobacteria  and genera involved in carbohydrate, energy, and xenobiotic metabolism, supporting the hypothesis that smoking depletes oxygen levels in the oral cavity. Meanwhile, research on a Puerto Rican smoking group showed that Proteobacteria , associated with cardiovascular and metabolic conditions, were highly enriched in smokers, as did a study on a Qatari population (Mohammed et al., 2024) . Industry Impact and Potential: While smoking's detrimental effects are widely acknowledged, further investigation into its impact on the oral microbiome is essential. Comprehensive, age-specific studies are pivotal to elucidate smoking's influence on oral microbiota and its role in disease progression (Mohammed et al., 2024) .   Addressing these knowledge gaps is crucial to understanding smoking's intricate interplay with oral microbiome dysbiosis and chronic mouth diseases, laying the groundwork for more targeted prevention and treatment strategies. Preserving oral microbiome integrity is one clear path forward (Mohammed et al., 2024) . Our Solution: At Sequential, we specialise in oral microbiome analysis and product development, pioneering microbiome-friendly solutions. Leveraging our expertise, we stand poised to collaborate with your company in crafting innovative products that nurture a healthy oral microbiome and enhance microbiota diversity for consumers. References: Chattopadhyay, S., Malayil, L., Chopyk, J., Smyth, E., Kulkarni, P., Raspanti, G., Thomas, S.B., Sapkota, A., Mongodin, E.F. & Sapkota, A.R. (2024) Oral microbiome dysbiosis among cigarette smokers and smokeless tobacco users compared to non-users. Scientific Reports . 14 (1), 10394. doi:10.1038/s41598-024-60730-2. Mohammed, L.I., Zakaria, Z.Z., Benslimane, F.M. & Al-Asmakh, M. (2024) Exploring the role of oral microbiome dysbiosis in cardiometabolic syndrome and smoking. Experimental Lung Research . 50 (1), 65–84. doi:10.1080/01902148.2024.2331185. Wu, J., Peters, B.A., Dominianni, C., Zhang, Y., Pei, Z., Yang, L., Ma, Y., Purdue, M.P., Jacobs, E.J., Gapstur, S.M., Li, H., Alekseyenko, A.V., Hayes, R.B. & Ahn, J. (2016) Cigarette smoking and the oral microbiome in a large study of American adults. The ISME Journal . 10 (10), 2435–2446. doi:10.1038/ismej.2016.37.