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The Development of New Therapies in Skin Microbiome: The Ultimate Reward

We spoke to Lindsay Kalan, from the University of Wisconsin-Madison about wound healing, the similarities between gut and skin microbiome and what the future holds for the development of new therapies.

Could you tell us a little bit more about your research?

My lab is interested in many different aspects of the skin microbiome. The first is in the context of wound healing, so we’re particularly interested in how the microbiome influences tissue repair processes and we tend to look at this using high-throughput DNA sequencing methods. A lot of my work has been in the context of chronic wounds, which don’t always follow a normal healing process.

Usually, when you are relatively healthy and you get a cut, the wound will heal according to a highly coordinated process. In around 10 to 12 days to the wound will be closed. But, in some individuals, those processes are impaired and wounds develop that just won’t heal.

Diabetics often get wounds on their feet and they turn into ulcers that can sometimes stay open for months, or even years in some cases, and it’s debilitating. There’s an understanding now that a distinct microbiome exists within these wounds and it’s thought that this contributes to that stalled healing process.

What we’re trying to understand is how these microbes are contributing to impaired tissue repair processes for two reasons:

  1. We want to understand if we can somehow interrupt that and promote healing
  2. Can we use the microbiome as a biomarker of sorts? For example, can we use the microbiome to predict when the wound is going to heal or not. This is really important for developing new therapies for some of these therapeutics of wounds and ulcers.

We are also really interested in understanding how a healthy microbiome is maintained and the requirements to keep it stable and to promote health. We’re particularly interested in microbial metabolism and the different metabolites that are produced by a healthy skin microbiome and how they’re interacting with each other to keep a healthy, stable community but also to interact with the immune system.

There are also a lot of factors that are associated with diabetes that interrupt the healing pathways. The wound could be hypoxic, for example, meaning there is less oxygen and a delayed inflammatory response that creates environments to allow the colonisation of many different types of microbes.

What comparisons can be drawn between the gut and the skin microbiome?

A lot of people may not realise that at a high level, they’re not so different. The epithelial surface area of the gut and the skin are both extraordinarily large. This exposes both the gut and the skin to vast amounts of microbes – the gut through everything we eat, and the skin through everything we touch. Although the total density of microbes in the gut is higher, our skin is interacting with microbes just as much as the gut, if not more. Both environments are also protective in a way. We can get infection through our gut or through our skin, but we also have a robust immune response in both places that are interacting with the microbiomes.

In what way does a healthy skin educate the immune system?

Research in the past few years from many labs has shown that certain skin commensals are able to promote an immune response that protects against pathogens. For example, some skin commensals will elicit a response that will protect against infection such as fungal pathogens, such as Candida albicans.

A healthy skin microbiome is important from young to old age. There is evidence to show that colonisation by a microbiome on the skin is very important for educating and developing resident immune cells in neonates and in early life.

Could you tell us a little bit more about the wet-lab experiments or systems that you’ve been using to show the balance between beneficial and foreign microbes?

We use a few different systems. Our lab receives human samples from collaborators that collect skin or wound samples. We can extract and sequence the DNA or RNA from those and then, using a computational bioinformatics approach, analyse the connections between the microbiome and subject.

We’re also interested in looking at microbial interactions in the lab. To do that, we have a few different systems we use. We can do that in vitro and look at what happens when skin microbes are exposed to keratinocytes, the main type of cell in the skin, for example. But we’re also working with a diabetic mouse model, which is a model of impaired wound healing for diabetes. This model allows us to look at different microbial communities and how they impact wound healing. The third system that we work with is ex vivo skin. We get skin that is removed during surgery, keep it alive in the lab, and then inoculate the skin with microbes, simulating microbial colonisation. We can further look at the interactions with different microbes on the surface.

What other types of individuals are more susceptible to wound infections?

There’s a number of different types of chronic wounds. Diabetic foot ulcers are one unique type. Individuals who have poor circulation can often get wounds in their legs. But another susceptible group is burn patients. If a person is burned and the burn is deep enough, they’re susceptible to infection because of an altered immune response and trauma. Skin grafting is often used to treat the wound and that requires harvesting skin from another part of the body. This means that that person now has two wounds to heal: the initial burn and the actual graft site. That’s concerning because if you graft someone and then the graft gets infected, it can be costly and painful. In that case, it’s important to that antimicrobials are used to ensure no infection develops.

Why is the extent of microbial influences on tissue regeneration a controversial topic?

I don’t know if ‘controversial’ is the best word, but there is a lot of back and forth in the field because sometimes, in a chronic wound for example, it doesn’t appear clinically infected. Even though the patient isn’t showing the normal signs of infection, we can sample the wound and know that there is a diverse polymicrobial community within that tissue.

The question is: “we know there are microbes there, but are they actually doing anything? Are they benign and just hanging out and it’s okay? Are they influencing the tissue repair process in ways that we just don’t understand yet?” If it’s hard to visualise, we can use sequencing to identify the organisms that are there, but it’s difficult to take a sample and look in the wound and understand if they are forming a biofilm.

It’s believed that the biofilm is the cause of persistent, nonhealing wounds. These are difficult to detect in tissue without highly advanced microscopy techniques and, even then, it can still be challenging.

How much progress do you think we’ve made in understanding skin microbiome?

We’ve made a lot of progress in the last 5 to 10 years and I see more and more skin microbiome papers published every week. There’s still a lot that we don’t understand though, but this is a rapidly expanding field. In the next 5-10 years, we’re going to know a lot more and make important medical advances. The ultimate reward is if our research can lead to the development of new therapies.

 

Lindsay Kalan will give her presentation “Cutaneous Microbiome Interactions in Health and Disease” at the Microbiome R&D & Business Collaboration Forum: USA.

 

The Skin Microbiome & Cosmeceuticals Congress: Europe will take place in Rotterdam in May. Download the agenda to find out more.

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