Welcome to part two of the interview with Dr Amine Zorgani, a seasoned microbiome expert. If you missed part one, check it out here. Within this fascinating conversation, Kriben and Amine explore many interesting topics including optimising the skin microbiome for great skin, personalised microbiome medicine, and how to optimise gut neurotransmitters to improve mental health.

Skin Microbiome Health for Optimal Ageing

My time at a biotech was leading a team of civil scientists and at the time, the ideas to some people would have been a little wild. We were looking into the skin bacteria that we have and how we could use that to modulate some:

- Skin diseases: Acne, Psoriasis, or Atopic Dermatitis

- Skin conditions: Sensitivity and Aging

We were asking “How can you look into this skin microbiome?” When you look into the studies, they are just observational. When we looked into skin diseases, we found that there is one bacterium that is usually correlated adversely with the increase of the disease severity. This bacterium was named “propionibacterium acnes” and now is named “Cutibacterium acnes”. Many people will recognise the last name of this bacterium “acne” because it is the bacteria that causes acne. It is a little bit controversial because people say “How can you use Cutibacterium acnes to cure acne because doesn’t it cause acne in the first place?” But this bacterium represents 90% of the microbiota that lives on our face – and you can find it in most of the areas where we create sebum.

When you look at the increase in abundance of this bacteria, it correlates with the change in age. So when we are born, we have very little of it. Then it starts going up and up until it reaches the maximum at puberty and adulthood – then it starts to go down. It happens as well that not all Cutibacterium acne are the same. There are different clades (or families) of this same bacterium. So what we are trying to understand is if all of the Cutibacterium acnes are harmful and if not, can any of them reverse acne? We did find this to be true and that some Cutibacterium acnes would out-compete some food sources with the harmful Cutibacterium acnes, and block them from using that food source – which reduces acne.

Similarly, the same bacterium produces one of the most potent antioxidants, RoxP. This protein is ranked third among the most powerful antioxidants in the world – number one being dragon fruit. The scientist who first studied this protein in Sweden looked at the quantities of it in our skin. He found that we had higher quantities on the face and lower on other body parts, which also correlated with the presence of Cutibacterium acnes. It also correlates with the abundance of Cutibacterium acnes over time meaning if you were younger, you would have less RoxP and less Cutibacterium acnes.

Aging is also correlated with lower antioxidant potential of the skin itself. So if your skin has been exposed to solar rays or UV light – this affects the:

- Skin elasticity

- Skin moisture

- Skin humidity

- Skin barrier function (which is basically how the skin is reacting to all these pollutants that we come in contact with)

As you age, you have a reduction of RoxP, you start getting age spots, and wrinkles. This is why lowering your oxidative stress is important. Using the Cutibacterium acnes is important too because it is the only bacterium that we know of that produces RoxP.

How Do We Increase RoxP on Our Faces?

If you want to increase this antioxidant and do not want to put anything on your face, what you can do is start removing things. For example, use a more natural face wash. When you're born, you're colonised with some good bacteria that you get from your mother's skin. Many people do get some C acnes that are pro-inflammatory and that cause acne. This is where there are high amounts of it and it causes flares and inflammation – but there are different ways that you can fix this. One way that we can fix it is by isolating that specific strain that is known to reduce acne. In my previous company, we went through several clinical trials to see if a strain was validated and now they are using it in other trials. Once you have this specific strain, you can put it into a cream or an oil then you get a reduction in acne.

Other approaches have been used like a company in France just signed a big deal (several 100 million) for precision phage therapy. So they take some phages, using CRISPR-Cas9 with molecular scissors, to tweak those phages and to specifically target the C acnes that cause acne on the skin. They are not using antibiotics, they are just targeting specific strains on the face. It will still take a while for this to go to market but in the first iteration of it, it will go into cosmetic application where they isolate a few natural strains.

In the next two years, you might see a product on the market that produces RoxP as a protein. RoxP is quite a large protein, around 15 kilodaltons, which makes synthetic production extremely expensive. However, this protein is naturally overexpressed by the bacterium itself, so if you allow the bacterium to produce it, you'll get large quantities. On the skin, the amount of RoxP is significant—around 25 micromolars per square centimeter, if I remember correctly.

The bacteria produce RoxP in significant quantities, indicating that it plays an important role. From a technological standpoint, you can either use the bacterium itself, which is more effective, as it provides a continuous supply of the metabolite—this protein. However, this approach isn’t beneficial if the other part of the equation, your gut microbiome, is compromised. Many people who suffer from acne, especially during puberty, may not realise the connection between skin health and their diet. Puberty is a time when junk food and soda consumption tends to increase, which can negatively impact both the gut and skin microbiomes.

Gut Skin Axis

We all already know there is a gut skin axis and a lot of people try acne treatments but completely ignore improving their diet to improve their gut. If you don’t do this, it will eventually show up on your face. The concept “beauty is from within” is true when you think about it this way. For example, there was an influencer who was fired from her job as a model and she said “I am going to reveal all the secrets about modeling for you.”

She went on to say how they could not use any chemicals (only natural products), their diets were controlled, and they could not drink soda – so of course their skin was beautiful. This is because if you use chemicals on your skin day in and day out, you are destroying that protective layer. This leads to skin diseases because you are wiping out the Cutibacterium acnes and many other beneficial bacteria. So a reduction of these bacteria = an increase in skin diseases and conditions. You can choose whether to stop using the chemicals that will protect your skin microbiota.

Going Back to Nature

We also have to remember that we live in a built environment where we are not exposed to nature. We’re mostly inside where we do not meet the beneficial microbes we once would. On the news in France, there was a story about a monkey curing a skin disease itself. It took leaves from trees and after a while, it was 100% healed. It is just amazing to see that nature can offer some of the remedies that we could really benefit from. We need to go outside and play, and immerse ourselves with the microbes.

One of my interviewees Manon van Oldenbarneveld, the founder of the Back to Nature Foundation, has spent 20+ years in the probiotic industry. Within our conversation, he said, “Listen, probiotics are good, and I'm not denying their benefits, but I think there are other ways that we could improve human health and microbiota, specifically by actually going to nature.”

Many studies show that returning to nature increases your gut microbiota's diversity. We already know that fruits and vegetables microbes contribute by up to 2% of the gut microbiota ecosystem. So growing or buying good fruits and vegetables and washing them with just water and eating them as they are, gives you increased diversity. Going back to nature can improve your diversity and keep your skin and gut healthy.

Novel Products for Skin Health

Quite a few companies are leveraging existing science and translating it into products, particularly when it comes to the gut microbiome, like probiotics and prebiotics, which are mainly used to improve gut microbiome diversity. However, in the skin microbiota space, although the science is still premature and hasn’t advanced as much as the gut microbiota research, companies have quickly harnessed it. They are using prebiotics and probiotics in various products like shampoos and creams for acne, skin sensitivity, hydration, and other applications. There is one case in Italy where they use a strain for treating atopic dermatitis in children, but because it’s a dead bacterium, they classified it as a medical device rather than a cosmetic product.

A challenge with these products is that bacteria, particularly probiotics, hate water, making it difficult to keep them alive in formulations. Companies have developed a few methods to overcome this:

They are encapsulating the bacteria into microscopic spheres that crack when applied to the skin.
Using a two-compartment system, where the bacteria and formulation are separated until mixed at the time of application.
They are using an oil-based or anhydrous gel formulation to avoid water altogether, keeping the bacteria alive longer.

These methods are now being used to incorporate bacteria into cosmetic or therapeutic applications, though some consumers might find the feel of the products unusual. There are a lot of products that might not be doing this right so make sure to do your research before spending money!

How Does The Gut Affect The Brain?

The hottest topic on the streets of microbiome research is the gut-brain axis. The one who is leading the field by far is John Cryan from the APC microbiome. He's also the co-author of the Psychobiotic Revolution, along with Professor Ted Dinan (you can read our conversation with him here). Psychobiotics is a combination of psychotherapy/psychobiology and biotech. These are probiotics that are designed to improve mental health. We call these next-generation probiotics. First generation we know as:

- Bifidobacterium

- Lactobacillus

- Thermophilus

The next-generation probiotics are completely new strains that are isolated from specific healthy volunteers that we knew had the potential to modulate mental health. One of the studies that showed how the gut was connected to the brain was when they took mice, cut their vagus nerve, and saw how the mice reacted. They saw that their behaviour change compared to the other mice. We already know that many of the metabolites produced in the gut microbiome are translocated into the brain via the vagus nerve.

We have also seen that if you give some specific molecules like tryptophan, where the microbiota is intact, tryptophan is converted into other metabolites, like indole derivatives, as we call them, and then you could see an improvement in mice behaviour. The only problem we do still have in this space is that we don't have human models to try on. But at least some of the observational trials, like one in Belgium called the Flemish gut microbiome study, can look at people and make connections. They looked at people who suffered from depression and saw that there was a significant reduction in a specific bacterium called coprococcus. They then isolated this strain from healthy volunteers, developed it into a next-generation probiotic, and gave it to mice, it showed an improvement in their psychological behavior.

There was another study in Belgium where they looked into Parkinson's disease. They used faecal microbiota transplantation. Faecal microbiota transplantation is taking the stool of healthy people and transferring that to disease patients in a few different ways:

- Through an enema

- Put into pills

So for around 84 patients with moderate Parkinson's disease symptoms, they looked to see how much better their movement, constipation, and colon transit. When these patients received a transplant from the healthy volunteers, they did improve for some parameters including their motor functions and the colon transit.

All that to say, we are at the beginning of the S curve of modulating the gut microbiome to improve mental health through different modalities, next-generation probiotics, and FMT. There is also still a lot of research to be done.

Gut-Brain Axis Mechanisms of Action

The problem with trying to figure out which mechanism of action elicits a mental health benefit is that multiple factors could influence it. I have personally never tried to pinpoint it in the space of the microbiome because there are so many variables. If you looked into a microbiome, there would be 250-350 different strains that people would have. This is not to mention the host's genetics, immunity, state of mind, diet, or where you live.

When it comes to the gut-brain axis, there is one particular pathway that seems to have a very interesting influence – which is the tryptophan metabolism pathway. All of these indole derivatives seem to have a significant impact on different connections that eventually lead to improving cognitive function and other conditions related to gut barrier function.

The gut barrier functions as a protective shield, preventing harmful molecules in the gut lumen from entering the bloodstream and spreading throughout the body, eventually reaching the brain. The more toxins that cross this barrier into the bloodstream, the worse the potential health outcomes. Therefore, improving gut barrier function is crucial. Similarly, just as improving skin barrier function is important for preventing transepidermal water loss (which helps maintain skin moisture and elasticity) the same principle applies to the gut. Strengthening the gut barrier is a priority.

One example of how this can be achieved is through the presence of indole derivatives, like indole propionic acid. Some studies show that an increase in indole propionic acid in the intestines is linked to an increase in health span, which refers to the length of time a person remains healthy, as opposed to lifespan, which is simply how long they live. Enhancing these indole derivatives appears to contribute to a longer and healthier life.

Tryptophan and Milk Kefir

Some studies show that if you include tryptophan in the diet you would improve cognition (in mice models). So I would put my money that harnessing that specific tryptophan pathway could eventually lead to some interesting therapies but I do not think it will be just one bacterium to fix it all. I could imagine that you would take some synbiotics like next-generation probiotics and supplement them with other key metabolites or key substrates like tryptophan. This would allow the metabolism to kick off and translate that pathway to something meaningful that the brain can benefit from.

From my research, the brain appears sterile. This means it only receives information or molecules that you get them from other locations, such as the gut, through the vagus nerve. This means that if you want to influence the brain, you need to pass through the gut which means that the gut microbiome plays a significant role in the process. If you want them to play a role in the process, you want to give them the best diet possible for them to produce the right metabolites to reach the brain. So a probiotic implementation is good but if they don't find what they can feed on to produce those metabolites, there is no reason. This is why I am more in favour of a synbiotic approach where you supplement probably with tryptophan or other substrates plus the next-generation probiotics that eventually would have an impact.

IPA (Indole-3-propionic acid) is a known metabolite that benefits mental health. I have seen some data on rye, chesnuts, and some other foods that can help the bacteria produce more of this particular metabolite. -Kriben Govender

Tryptophan is the start of the chain of reaction and then there are at least two different reactions in the process that leads you to finally reaching the level of IPA. At least one reaction is 100% controlled by bacteria. Eating food that is rich in tryptophan can only benefit your mental health. Science still needs to prove this but tryptophan should be in your priority list in terms of amino acids that you should be taking from different food sources, not necessarily in supplementation.

Milk kefir and other fermented foods are great additions to your diet. I personally take probiotics because I’ve found a balance of strains that work for me, and I rotate them to ensure diversity. However, I highly recommend incorporating low-tech, natural products like homemade fermented foods, kefir, and yoghurt, as well as fruits and vegetables that your body can tolerate. It’s important to note that some people with IBD or IBS may have trouble tolerating certain fruits and vegetables.

Increasing the diversity of your microbiome isn't achieved through probiotics or prebiotics alone it can come from a variety of approaches. If you're looking for a quick boost, you can certainly take a concentrated probiotic pill. But for long-term balance and consistency, it’s essential to include a variety of foods, particularly fruits, vegetables, and fermented products, in your diet.

Serotonin and GABA

Tryptophan is converted into serotonin and melatonin through specific pathways. Do you think this conversion has notable benefits? I’m aware there’s ongoing debate about serotonin’s role in mental health, especially when it comes to SSRIs, such as Prozac and similar medications. So, what’s your take on this? Do you believe serotonin still significantly impacts mental health, or do you think more research is needed? - Kriben Govender

To be honest, I’m not the best equipped to answer definitively, as it’s more in the realm of neuroscience. However, I do know that around 90% of serotonin is produced in the gut, which could be telling, right? So, why is that? I think a more interesting question beyond serotonin is: What other molecules might influence mental health? For instance, GABA (gamma-aminobutyric acid) comes to mind. It’s derived from microbial metabolites like butyric acid. We know that certain bacteria in the gut produce butyrate, a short-chain fatty acid, which is then converted into GABA. If we took a cohort of healthy people and those with mental health issues and analysed their stool, we’d likely find lower concentrations of GABA in those suffering from mental health conditions. So, while serotonin may be a factor, it’s probably not the only one. GABA, being a key neurotransmitter, also plays a significant role, and it’s largely produced by gut bacteria.

I agree that GABA, along with indole propionic acid (IPA), is crucial, but I do think there’s still something important about serotonin. SSRIs have been used for decades, so there’s clearly something happening there in terms of improving mental health in people with anxiety and depression. We just need more research to fully understand the mechanisms at play. -Kriben Govender

Microbiome Personalised Medicine

Microbiome personalised medicine is one of the most challenging questions in both research and commercialisation. It brings up the use of microbiome data as a potential insight, particularly with the rise of gut microbiome testing kits, where you send a sample, it’s analysed, and then you’re provided with recommendations. However, we’re not quite there yet in terms of making these tests actionable. Most of these kits only provide data on your microbiota composition, but don’t offer practical advice on what to do with that information. While some do provide guidance, we’re still far from making this data genuinely useful.

The concept of personalisation is key here. Yes, we can analyse a person’s microbiota and understand its composition, but biology is complex and we need to treat it with respect. We can't oversimplify the role of microbiomes in health. I think that relying solely on microbiome data for personalised medicine would be a mistake. While microbes are a significant part of us (representing roughly equal numbers of cells and 130 times more genes) humans also have genetic factors, immune systems, and various other elements that microbes alone don’t account for.

In my view, for microbiome data to be actionable, it must be combined with other types of data, such as blood tests or genetic information. This allows us to see both sides:

- What the microbes are doing

- How the human host is responding

By integrating these data points on the microbes, immune status, blood, and genetics, you could develop a truly personalised approach to therapy or prevention. Relying on microbiome data alone may provide some level of personalisation, but I don’t believe it will have a meaningful impact on health outcomes. The most successful approaches have used microbiome data alongside other human data.

Women's Health

The vaginal microbiome is the most interesting topic for me at the moment. Women's Health had suffered from ignorance and lack of innovation for decades. Therapies for:

- Bacterial vaginosis

- Candida

- Fertility

- Endometriosis

And so many other issues. There is growing hope in addressing issues related to a low-diversity vaginal microbiota, often dominated by Lactobacillus species. A notable example involved transferring vaginal fluids from a healthy woman to a woman who had experienced five miscarriages – this woman became pregnant just five months later. Companies are now working on translating this concept into practical treatments. The idea of transferring healthy vaginal microbiota to women facing fertility challenges or other related issues is gaining traction, and it should be a priority for biotech startups and pharmaceutical companies. The vaginal microbiota is more accessible and easier to monitor than the gut so it makes it a promising area for therapeutic development. If any therapy related to microbiota reaches the market soon, this is likely to be one of the first!

Amines Top Gut Health Tip

I recommend my fruit smoothie full of blueberries and strawberries. It keeps me energised and going during the day and it is great for your gut.

In conclusion, Dr. Zorgani's insights into the fascinating world of microbiome science reveal a powerful connection between our skin, gut, and mental health. As we explore the potential of bacteria like Cutibacterium acnes in improving skin health, we also gain an understanding of how the gut-brain axis impacts mental well-being through microbial metabolites. From the use of natural remedies and precision therapies to the importance of a diverse diet rich in probiotics and prebiotics, it’s clear that maintaining a healthy microbiome is essential for overall health.

While research is ongoing, the advancements in microbiome-related products, personalised medicine, and women’s health offer exciting possibilities for the future. As we continue to learn more about these complex ecosystems within us, the potential for innovative treatments that blend nature and science is vast. Make sure to connect with Dr Amine Zorgani and share this with a friend who would benefit from this information!