Summary & highlights Experts Meeting on Beyond-the-gut microbiome therapeutics & personal care

BaseClear held an Experts Meeting on “Beyond-the-Gut Microbiome Therapeutics & Personal Care” on Thursday April 29, 2021. This meeting focused on different skin environments. The meeting chairs were Dr Radhika Bongoni, Anais Guebey and Thaer Al Keilani from BaseClear. Both morning and afternoon sessions had over 40 participants in attendance, who were interested in how microbiome research in novel application areas such as the nose, vagina, eye and skin is being used to develop new therapeutics.

Presentations were given by the following speakers:

INTRODUCTION and PRESENTATION 1: The human microbiome beyond-the-gut – It is the little things that matter the most

Presented by Dr Radhika Bongoni

Our skin microbiome can be seen as a second skin: a biofilm of tiny organisms that form a barrier between the body and the outside world, and contribute to our health. The skin can be seen as its own ecosystem. This article from Nature by Eisenstein is named “The Second Skin” provides an up-to-date primer on the barrier function of the skin.

The skin is not ideal for bacterial growth, with generally low biomass compared to the gut. However, it contains a wide range of different ecological niches. Sebaceous sites on the chin and forehead are more densely populated with Cutibacteria and Corynebacteria, but with a low diversity. Moist sites such as the armpits have medium species diversity and moderate density, and tend to have more Staphylococcus and Corynebacteria. Dry sites like the back of the hand have the highest diversity and lowest density, featuring more Proteobacteria and Bacteroides. The foot is an additional skin ecosystem niche. Molecular techniques that are culture-independent are deepening our understanding of the skin microbiome, as described in seminal review from Grice and Segre.

Skin microbiome research is progressing in “little steps”. There is a cycle of discovery, development, testing, and further discovery, with each step bringing us closer to microbiome-based therapeutics for the skin. With this knowledge and information, the state-of-the-art microbiome therapeutics and applications are shaping the personalisation of cosmetic and hygiene products. In addition, other factors like host genotype, SNPs and environment play a dynamic role within the skin microbiome. Personalisation of personal care products is a growing trend.

Next generation sequencing such as shotgun metagenomics comes with challenges including host DNA from samples. Within our own R&D project, we noticed that the host DNA amount in a sample can vary considerably, from 5% in the cheek to 30% in the armpit. Some sites can contain more than 60% host DNA, such as burn sites, wounds, vaginal swabs, and biopsies.

Work on the “little things” in personal care and cosmetics to unravel the big picture and develop microbiome-based therapeutics.

PRESENTATION 2: Mycobiome and microbiome based understanding of dandruff

Presented by Dr Miriam Dormeyer

The body is like the Earth, and each area has its own niche environment for the growth of microbes. The scalp environment is relatively high in moisture and sebum. The yeast Malassezia has been widely studied for its role in dandruff. Malassezia are lipid dependent as they cannot synthesize fatty acids themselves, therefore the high-sebum environment of the scalp is ideal.

Dandruff has two main forms: dry and oily. Dry dandruff manifests itself as small, dry flakes in the scalp and is best treated with a mild, moisturizing shampoo that helps restore the scalp’s natural barrier function. Oily dandruff is recognized by the larger, yellow flakes and generally oily appearance of the dandruff. Certain strains of Malassezia are implicated in oily dandruff. A shampoo that contains a fungicide will work better for this type of dandruff. However, a fungicide will kill all fungi on the scalp including commensals, and can be drying. Can there be a gentler way to treat dandruff that is “microbiome friendly”?

Crinipan®PMC green is a synthetic compound that has been tested as a micro-activated anti-dandruff product. It can selectively remove Malassezia in oily dandruff thereby preserving microbial diversity on the scalp. The active ingredient is propanediol caprylate, which is broken down specifically by Malassezia to propanediol and caprylic acid. The caprylic acid has anti-microbial activity against Malassezia, and the propanediol acts as a moisturizer. The compound has shown to be effective against M. restricta and M. globosa and increased Cutibacterium on the scalp. There was a reduction in the relative abundance of Staphylococcus, though not significant.

Another product is a shampoo containing lactic acid bacteria in a heat-killed form (Symreboot™L19). The heat treatment is mild and preserves the outer membrane, retaining its properties as a bio-active. The molecules still present on the intact, killed lactic acid bacteria are effective against dry dandruff, without affecting the scalp microbiome. By not using a live probiotic, the product is easier to incorporate into cosmetic products. Both this product and Crinipan®PMC offer microbiome-friendly solutions to dry and oily dandruff.

Further research directions include investigating the balance of bacteria on the scalp. Xu and co-workers identified the relationship between Cutibacterium and Staphylococcus as important in dandruff prevention.

PRESENTATION 3: Dysbiosis in atopic dermatitis – chicken or egg?

Presented by Dr Tessa Niemeyer

Atopic dermatitis, otherwise known as eczema, is a relatively common chronic skin condition that tends to flare up in response to certain irritants or allergens. Symptoms include skin redness, swelling, itching, and the development of various kinds of skin lesions. The itching can be debilitating for patients.

Two theories describing the cause of atopic dermatitis exist. The outside-in theory is based on the idea of a defective skin barrier, which leads to water loss, dysbiosis, inflammation, itching and a vicious circle that ends in dermatitis. The inside-out theory is that allergens cause an excessive inflammatory response, leading to dysbiosis, itching and another vicious circle. Could reducing the inflammatory response by modifying the skin microbiome help via the inside-out theory?

There is a relationship between Staphylococcus aureus on the skin and atopic dermatitis. Atopic dermatitis sufferers tend to have higher overall S. aureus levels on the skin. During an atopic dermatitis flare-up, S. aureus levels increase. After treatment, which is currently a corticosteroid cream, S. aureus levels return to the (elevated) baseline. Some tests on preferentially reducing S. aureus levels on the skin were conducted to see whether rectifying dysbiosis could help resolve atopic dermatitis.

In an initial study, Niemeyer-van der Kolk et al. investigated the effect of an novel synthetic cationic peptide with antimicrobial properties against a range of gram positive and gram negative bacteria and fungi in vitro and in vivo. The peptide was administered to patients with mild to moderate atopic dermatitis. The peptide has selective activity against S. aureus. Patients applied the peptide as topical gel to atopic lesions once a day for 28 days. The peptide showed positive effects (symptom relief) on clinical end points such as dermatitis symptoms (local oSCORAD, %BSA), morning itch, evening itch, 5-D itch questionnaire and pharmacodynamics parameters like TEWL. Safety assessments (adverse events, laboratory blood tests, vital signs, ECGs) showed that the product was well tolerated and safe as used. The treatment reversed dysbiosis in terms of S. aureus abundance on the skin and in a target lesion. A second, larger study did not show resolution of symptoms although the dysbiosis was similarly reversed. The results do not support the theory that dysbiosis is a primary event in the pathophysiology of atopic dermatitis.

KEYNOTE PRESENTATION 4: Simplicity and diversity: the role of Lactobacillus crispatus in the vaginal ecology

Presented by Dr Rosanne Hertzberger

The vaginal microbiome has several unique qualities. It has a low taxonomic diversity with usually only one dominant species. This is often a Lactobacillus species, particularly L. crispatus, L. iners, L. gasseri or L. jenseii. The vaginal pH of humans is very low amongst primates, at around 3.5 compared to a neutral pH of 6-8 for the non-human primates. The low pH is due to the high lactate concentration in the human vagina. Vaginal dysbiosis occurs when the pH increases, with species such as Garderella Atopobium, Prevotella, Sneathia, Megashpaera becoming more prevalent. Vaginal dysbiosis is associated with vaginosis, which causes inflammation in the vagina and resulting itching and odour. Dysbiosis is also associated with increased susceptibility to sexually transmitted disease, preterm birth, and maternal and infant infections.

Vaginal microbiota diversity is associated with HIV transmission in high-risk populations, as summarized by Bayigga et al. A vaginal microbiome that was free of Lactobacillus was associated with a higher risk of acquiring a sexually transmitted disease. The lower secretion of pro-inflammatory cells such as IL-1α and TNF-α in high-L. crispatus women could be a factor.

Women with less L. crispatus were also less likely to experience miscarriage or preterm birth. The high lactate concentration in the human vagina is formed from the glycogen-rich vaginal epithelium. Alpha-glycosides are required to digest and transport glycogen. Most L. crispatus strains are able to utilize glycogen via cell-bound alpha-glycosidase, however it is unclear for women with most other dominant Lactobacillus species. The type 1-pullalanase present in Lactobacillus crispatus strains gives the ability to cleave the vaginal glycogen which in turn reduces the pH of the vaginal environment (see van der Veer et al.). Gardnerella vaginalis, associated with dysbiosis, uses a secreted amylase.

Can glycogen degradation be used as a way to shift the microbiome? Genomic analyses are able to show the genes involved in glycogen metabolism, and are present in common vaginal microbiome inhabitants, and could help in developing a therapeutic. Clearly, more research is needed in this area.

PRESENTATION 5: Nasal microbiome as a therapeutic target in consumer respiratory health

Presented by Dr Rob Howlin

Many diseases have a strong link to immune-inflammation dysregulation. As the microbiome can alter system inflammation, there is high interest from pharmaceutical companies in developing nasal microbiome-based products. Consumer awareness is also growing with regular news stories about the microbiome.

Adults breathe in 7000 litres of air each day, and there are 10,000 to 1,000,000 bacterial cells per cubic meter of air. Different parts of the nasal cavity shape the microbial communities found there. Local air conditions such as humidity, temperature, air pollution and oxygen levels can influence the nasal microbiome.

The nasal microbiome is colonized from birth following a particular pattern of succession. Mode of delivery and type of infant feeding affect the microbiome, and this is thought to explain why breast fed infants have a lower risk of respiratory infections. The nasal microbiome evolves and is dynamic along the growth period but also to the exposure to environment, shifting from predominance of Staphylococcus strains at birth to Dolosigranulum, Moraxella and Corynebacterium at the age of 2 years. Different events that affect the microbiome during the early years, such as infant feeding practices or use of antibiotics, are associated with the development of respiratory diseases such as asthma and allergies. The microbial footprint can thus be used as a biomarker to examine the link between health and risk of diseases.

The respiratory tract microbiome is considered a “gatekeeper to respiratory health”. There has been research interest in allergic rhinitis, a condition that affects 10-30% of adults and up to 40% of children. It is linked to poor sleep, lower work productivity, and reductions in general wellbeing. A microbiome link has been suggested with greater exposure to allergens during childhood associated with lower risk of allergic rhinitis. Particulate matter from air pollution tends to aggravate nasal rhinitis, and there are also changes in the nasal microbiome due to particulate matter in the air.

Potential interventions could include anti-inflammatory agents, hypertonic solutions to wash the nasal cavity, prebiotics, and probiotics. The effect has to be believable by the consumer, and care needs to be taken to distinguish disease claims from structure/function claims.

PRESENTATION 6: The ocular surface microbiome: scam or truth?

Presented by Dr Heleen Delbeke

The surface of the eye contains its own microbial ecosystem, and may affect ocular diseases related to infectious agents or the immune system. Improvements in genomic techniques allow a more refined analysis of the eye microbiome.

The microbiome may be behind why some patients have irritated eyes after surgery and others do not. Do the eye drops affect the microbiome? Also do they affect tolerance of contact lenses?

Geographic differences affect the microbiome found on the ocular surface. The most common species are Corynebacterium, Acinetobacter, Pseudomonas, Staphylococcus, and Propionibacterium. It is surprising that Pseudomonas is found so often on the healthy ocular surface as it is also a cause of ocular infections. Also, the contact lens microbiota is different to the ocular surface swab. Genomic techniques have allowed greater insights into the eye microbiome to be uncovered. A review article on the human eye microbiome can be found here.

A test was performed to see if eye drops used during surgery affect the microbiome, which could explain post-surgical infection or eye irritation. A topical anaesthetic was used. The results did not indicate that there was an effect of the anaesthetic on the microbiome, alpha and beta diversity or genus-level changes. Cutibacterium emerged as a potential biomarker.

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