Regulatory T cells help tolerate commensal bacteria on the skin during first few weeks of life

The human skin is the body’s first line of defense against pathogens that your body comes in contact with. Just like the gut and mouth, the skin lives in communion with bacteria. One important unanswered question that many scientists have is why commensal bacteria do not trigger an inflammatory immune response when they come in contact with the skin. An article published by Cell Press explores exactly this question, looking specifically at regulatory T cells (treg, a type of white blood cell that plays a major role in establishing homeostasis of the immune system).

Researchers engineered the genes of Staphylococcus epidermidis to produce a specific protein antigen that can be fluorescently viewed. To test whether the immune system plays a role in tolerance of skin commensal bacteria the researchers colonized the skin of 6-week-old mice with this fluorescent protein. Three weeks later the mice were compared to a group of control mice and it was found that pre-colonization with the protein was not enough to establish immune tolerance of the bacterial antigens. 

The researchers were curious as to what affect this bacterial antigen on the skin of infant mice had, so the same experiment was done with 7-day-old mice. After 3-4 weeks, when the mice were adult, a significantly diminished immune response to the commensal bacteria could be seen. This shows that exposure during the neonatal period promotes tolerance to commensal bacteria.

After examining adult vs. neonatal skin, this study concludes that there is a difference between the two in terms of immune response and windows of tolerance build-up. Specifically, the period of neonatal skin development seems to be essential in mice for the immune tolerance of commensal bacteria. The implications of this study are important for understanding of the human immune system and bacteria tolerance. Because the skin is our body’s first defense system, it is important to have an understanding as to what mediates its immune response.           

Understanding the nasal microbiome

Electron micrography of Staphylococcus aureus.

The nasal microbiome remains largely unstudied despite its potential importance to many diseases, such as rhinosinusitis, allergies, and staph infection (incuding MRSA).  Staphylococcus aureus is probably the most well-known nasal resident, but simple questions, such as which species of bacteria are most prevalent in the nose, are still not answered.  Understanding all the residents of the nasal microbiome, the influence of our genetics and the environment on defining their populations, and the influence each one has on others may be critically important to preventing diseases such as staph infection, and more research is needed.  Fortunately, a new study out of Johns Hopkins that investigated sets of twins shed light on many of these questions, and was published in Science Advances last week.

The scientists sequenced the nasal microbiomes of 46 identical and 43 fraternal pairs of twins.  First, thy learned that these people’s nasal microbiomes could be classified into 7 different phenotypes or community state types (CST) which broadly described their nasal microbiomes.  These 7 types are defined by their most abundant bacteria, and are as follows: CST1 – S. aureus, CST2 - Escherichia spp., Proteus spp., and Klebsiella spp., CST3 - Staphylococcus epidermidis, CST4 - Propionibacterium spp., CST5 - Corynebacterium spp., CST6 - Moraxella spp., and CST7 - Dolosigranulum spp.   The most common CTS was CTS4 with 29% of the sampled population having that CTS, whereas CTS4 was the least popular, coming in at 6% of the individuals tested.  The researchers noted that many of these bacteria, such as Proteus, were not considered to be important to the nasal microbiome at all, so their dominance in some noses was surprising.  The scientists learned that genetics plays nearly no role in the microbiome community composition, but does influence the overall microbiome population.  In addition, gender influenced the overall population, with women having about half as many total bacteria in their noses as men.

With regards to S. aureus, while it existed in 56% of the individuals studied, it was associated with other bacterial.   For example, the researchers discovered that Dolosigranulum, and Propionibacterium granulosum were negatively correlated to the existence of S. aureus, whereas S. epidermidis was positively correlated with S. aureus abundance.  This lends itself to the idea that specific bacteria can create colonization resistance against S. aureus, and thus could be used to prevent the disease.  The researchers suggest a probiotic should be tested for its therapeutic value in preventing S. aureus colonization, and hopefully they move forward with those trials.

The oral microbiome of children, and its relation to dental caries

The oral microbiome is a popular area of exploration because bacteria are a prominent part of dental health, and because it is one of the most heavily colonized and easily accessible niches in the body. Many studies have been discussed on this blog concerning adult oral microbiomes, and its relations to bodily issues such as cystic fibrosis and periodontitis. It is also very useful to investigate children and the ways that their bacterial communities first inhabit and develop. A study done in Sweden at the Umeå University, and published by Plos One, takes a look at the maturation of the oral microbiome from infants at 3 months old to children at 3 years old.

The Swedish researchers performed a longitudinal study that followed children from 3 months to 3 years of age, looking for microbial characteristics of children with dental caries (i.e. cavities) compared to those without. There were 207 original participating 3 month olds that were consented by their parents to be in the study. The parents provided information on mode of feeding, mode of delivery, use of antibiotics or probiotics, health issues like allergies, and presence of teeth. At 3 months and later at 3 years samples were taken from the buccal mucosa, tongue, and alveolar ridges. Teeth were also scraped for plaque and saliva was collected. Of the original 207 participants, 155 returned for sampling at 3 years of age, and 13 of those children had dental caries.

After sequencing the bacterial DNA samples, it was found that Escherichia coli, Staphylococcus epidermidis, and various Pseudomonas species were significantly more prevalent in 3 month olds. However, there were 23 genera that were more significantly prevalent at 3 years of age than at 3 months.

By comparing the children with and without caries, the scientists were able to make several conclusions.  The researchers identified seven taxa that appear to be associated with healthy teeth.  On the other hand, Streptococcus mutans seemed to be more prevalent in the children with caries, than in those without caries. Additionally, the colonization of this species was most prevalent in girls. This is possibly because girls develop faster, so earlier tooth eruption allows for a longer time for the colonization of these bacteria.

The results of this study show us that during the first three years of life, species richness and diversity seems to increase significantly in the mouth. While there is an increase in the type of the bacteria, there are also some taxa that are lost with age. The researchers also concluded that the oral microbial composition of the mouth at 3 months does not appear related to the development of dental caries. With this information, it might be smart to perform a related study that collects oral microbiome samples in children within the time frame of 3 months to 3 years, because it could show a clearer picture of the changes that take place in bacterial composition.

Using microbiome bacteria for cosmetics

Topical cosmetics are widely used for skin care, maintenance, and beauty.  There are entire industries dedicated to providing skin care products to a wide range of consumers, because for the most part, everyone desires healthy skin.  Scientifically speaking, skin is considered healthy if it effectively retains moisture, has a low surface acidity, and has good texture.  Many topical cosmetics act to augment or support these features.  Interestingly, researchers in Japan demonstrated that a microbiome bacterium can also provide these benefits to the skin, introducing the possibility of developing novel skin care therapy.

Staphylococcus epidermis has recently gained attention as a beneficial topical agent due its demonstrated skin care benefits.  Specifically, its metabolic products have been shown to enhance moisture retention and reduce surface acid levels.  Researchers investigated this by creating their own S. epidermidis topic gel and testing it on human subjects in a double-blind randomized study.  Skin was collected from the foreheads of 21 patients enrolled in this clinical trial.  Genetic analysis confirmed that S. epidermidis was removed from the skin.  Once isolated from other cells and bacteria, the S. epidermidis bacteria were cultured and lyophilized – or freeze dried – to preserve bacterial integrity.  The lyophilized S. epidermidis was then mixed in with a gel and continuously applied to patients’ faces in a double blind randomized clinical trial study that included a control population just receiving the gel, no bacteria. 

Patients who received the S. epidermidis had 1.4 times the amount of water in their skin after the trial was completed compared to before they started.  Additionally, a suppression of water evaporation on the skin surface was shown, concomitant to an increase in lipid content.  The increased lipid content was hypothesized to be a direct result of S. epidermidis metabolism, as the lipid metabolites provided an ample surface coat to keep moisture trapped on the skin surface.  Moreover, the S. epidermidis regiment also maintained a low acidic environment on the skin surface.

This study demonstrates S. epidermidis’s efficacy to support healthy skin.  Using certain microbiota as a topical agent is already being seen in practice, as Cambridge-based AOBiome are developing skin therapies using bacteria.  This unique approach has a lot of potential, and it will be interesting to see how bacteria can be used in this health arena.

Bacteria on the skin help shape immune response

The skin is the largest organ of the human body and the first line of defense against harmful microorganisms in the environment. However, it is also home to trillions of microbes that are beneficial to the host individual. In a study published in Nature, scientists found that specific bacteria on mammalian skin influence the host immune response.

To better understand this relationship, researchers chose Staphylococcus epidermidis, a bacterium commonly found on human skin, to see how the bacterium shaped the immune response. Using mice, the researchers found that the presence of S. epidermidis on mice skin caused an increase in CD8 β+ T cells, cells that are involved in immune response.  The application of other common skin bacteria to mice resulted in the increase of different T cell populations. The scientists next investigated how the skin cells detected the presence of S. epidermidis. The results suggested that a specific type of dendritic cell – located not on the exterior epidermal layer of skin cell, but within the dermal, second layer of the skin – is the cause of the unique CD8 β+ T cell response.

While mechanisms are still unclear, it is possible that S. epidermidis produce specific proteins that can trigger an immune response within the human skin when exposed to skin pathogens. What is clear from this study is that different bacteria living on the skin can elicit different immune responses. This suggests a commensal or possibly mutualistic relationship between skin cells and certain bacteria. Further investigation and knowledge of this relationship could lead to better understanding of the immune system and how the human microbiome participates in immunity as well as how this can be translated into therapy.