Urolithin A – from the MUW lab into the world of drugs and cosmetics
What is urolithin A and where can we find it?
Professor Jakub Piwowarski: Urolithin A is a post-biotic metabolite, i.e. it belongs to the group of compounds produced as a result of the metabolic activity of our gut microbiota. Gut microbiota produces urolithin A by interacting with tannins, found in food such as coffee, tea, legumes, fruit, nuts, or dark chocolate. Our team has been working on urolithin A for over a dozen years. This compound has very interesting biological properties, mostly related to inhibiting inflammation. We have demonstrated this anti-inflammatory property in our research. Many projects and publications have been created around that molecule since, and we have obtained a number of patents.
Does everyone produce urolithin A in the same amount?
Professor Sebastian Granica: No. People can produce more or less of urolithin A. Some do not produce it at all. This depends on the composition, condition, and metabolic activity of gut microbiota, and most importantly, on the supply of products rich in tannins from the group of ellagitannins. Because they are essential for the production of urolithin A. They serve as substrates for the microbiota, which biotransforms this group of compounds into urolithin A.
Does this mean that if we consume tannin-rich products, their anti-inflammatory action will be guaranteed?
Professor Jakub Piwowarski: In theory, yes. However, in the United States there are dietary supplements with urolithin A, and their only confirmed clinical action is in muscle regeneration after exercise. Their mechanism of action relies on activating mitophagy, i.e. the removal of dead mitochondria. But our focus is on anti-inflammatory action, not demonstrated by those supplements. Why? Apparently, once absorbed in the gut, urolithin A gets deactivated. When it crosses the gut barrier, it interacts with the glucuronic acid and loses its anti-inflammatory properties. We have observed this in our research as well. So we have a molecule with interesting biological properties, but we are unable to take advantage of them when administering it orally. What can we do about this? Both Professor Granica and I like challenges, so we decided to find some sort of workaround for this problem. We came up with three concepts how to do that.
What were they?
Professor Jakub Piwowarski: The first one is based on the hypothesis of activation in the area of the inflammation. This concept assumes that an inactive form of urolithin A is absorbed and distributed around the body, and then activated specifically in the area affected by inflammation. We have been able to confirm this in in vitro (lab) conditions; before we confirmed this in vivo (in a living organism), however, another team from Spain had already done that.
The second strategy was to obtain urolithin A derivatives with nonsteroidal anti-inflammatory drugs, which would inhibit the process of its deactivation. For that project, we obtained financing from the PRELUDIUM BIS program from the National Science Centre. The research was carried out by Maciej Korczak, PhD. And it turned out that with such a modification, we can improve the unavailability parameters of free urolithin.
And finally, the third option was research into urolithin A used to inhibit skin inflammation. We managed to get this project to a fairly advanced stage.
Professor Sebastian Granica: We decided to apply the molecule externally, in skin inflammations. This concept was developed by the two of us along with Professor Marek Naruszewicz, in cooperation with Professor Mariusz Sacharczuk. We conducted tests on laboratory animals. We managed to confirm the anti-inflammatory activity of urolithin A in rats, in which we had generated an inflammation of the skin. The effects were comparable to the application of a standard steroid-based drug, i.e. hydrocortisone. Except that there were no adverse effects caused by that steroid.
Why does urolithin A not cause adverse effects, even if it has anti-inflammatory properties just like the steroid?
Professor Sebastian Granica: Urolithin A has a different mechanism of action, it uses a different pathway to modulate the inflammation.
What does this mean exactly?
Professor Jakub Piwowarski: Glucocorticoids act at the nuclear level, at a very early stage in the transmission of the inflammatory signal. They do not interfere with one specific pathway responsible for the inflammation, but with many pathways at the same time. Urolithin A, on the other hand, inhibits the transfer of a specific subunit (called the NFkB) to the nucleus. So it inhibits one very specific process responsible for the development of inflammation. That is why it does not cause adverse effects in the way glucocorticoids do. So far, we have only tested this on animals. We have not reached trials involving humans yet. It is worth noting, however, that any molecule that is pharmacologically active may cause some adverse effects. This could also be true for urolithin A. What could they be? We do not know yet. What we do know is that severe adverse effects such as skin atrophy or chromogenic anemia do not occur.
Professor Sebastian Granica: If we see any adverse effects, they are unlikely to be severe, because urolithin A is produced in our body. So the body, the biochemical pathways, and the cells are in a way used to the presence of this substance and to the contact with it.
How did you obtain the urolithin A used in your research?
Professor Jakub Piwowarski: The research that gave rise to the patent had been conducted several years ago. Like any technology, it was subsequently developed further. As part of the LIDER project, financed by the National Centre for Research and Development, we developed a method to synthesize urolithin A at scale. This allowed us to produce it in amounts sufficient for preclinical or clinical trials.
We have also developed a formulation for topical administration on the skin. It is stable and meets all the requirements for formulations used in clinical trials. That was the formulation tested on the skin of laboratory animals.
At present, we have been working on the results of those tests, and we also have additional research in progress using molecular biology techniques. We want to specify the mechanism of action of urolithin A with even greater precision, and to discover its potential adverse effects.
When will trials involving humans be conducted?
Professor Sebastian Granica: The patents registered for the anti-inflammatory application of urolithin A have already been commercialized, i.e. purchased from the university by a company that aims at marketing a product containing urolithin A either as a drug for topical administration, a cosmetic formulation, or a medical device. A specific cosmetic formulation has also been purchased, and it is ready for marketing.
What could be the applications of such a cosmetic with urolithin A?
Professor Sebastian Granica: At low concentrations, urolithin A as a cosmetic formulation may be used to prevent chronic inflammation of the skin. And according to the latest theories, it is the chronic, low-grade inflammation of the skin that causes its ageing. This means that urolithin A may be used in anti-ageing cosmetics.
Professor Jakub Piwowarski: It is important that we have managed to register urolithin A as a new cosmetic ingredient, a new cosmetic raw material.
Professor Sebastian Granica: It is registered in the INCI database, which means that it can be used in the European Union as a cosmetic ingredient. Whether and when such cosmetics will appear depends on whether the company that holds the patent applications finds an investor that will take the product to the market. Remember that the cosmetics market is tough, because it mainly relies on promises. So it is very aggressive and highly competitive.
And when can we see urolithin A as a medicine? What conditions will it be used for?
Professor Sebastian Granica: In this case, clinical trials are needed to confirm its efficacy in humans. This requires huge financial resources. When it comes to the uses, the formulation is patented with a broad range of applications: for topical administration in any types of skin and mucosa inflammation. So not just in atopic dermatitis, but also in psoriasis and many other conditions.
Is there a group of people who will especially benefit from treatment with urolithin A?
Professor Jakub Piwowarski: Children with atopic dermatitis, for sure. AD most commonly affects children, even very young ones, and on large areas of the skin. For them, using urolithin A, which is not an aggressive molecule, is a good alternative for steroid treatment, which comes with severe adverse effects.
Professor Sebastian Granica: Another group that will definitely benefit from urolithin A treatment are patients with chronic skin inflammation. Such people have to use medicines on a long-term basis. Urolithin A may be a good third option in such situations, besides glucocorticoids and calcineurin inhibitors. Those last two groups of medicines come with many adverse effects. Urolithin A may allow us to avoid them. And finally, urolithin will be a solution for the group of patients with inflammatory diseases of the skin who cannot take glucocorticoids or calcineurin inhibitors.