Although the skin is the largest organ in the human body, its role is often reduced to aesthetic purposes. Nothing could be further from the truth: skin plays a key role in almost every system in the human body.

Two layers of the immune system

First of all, the skin is the first layer of the immune system that protects us from pathogens, pollutants, allergens and UV radiation. Epidermis and dermis (two layers of the skin) produce antibacterial peptides that fight pathogenic bacteria, viruses and fungi, Moreover, skin (just like the gut) has a microbiome (a group of microorganisms), which protects us from pathogens. Interestingly, the skin and gut microbiomes are closely connected to each other and form the so-called microbiome-skin-gut axis (1). For that reason, many people with atopic eczema suffer also from gastrointestinal disorders (such as irritable bowel syndrome or inflammatory bowel disease) (2,3). Moreover, the formation of the optimal intestinal microflora in infants is one of the most important factors reducing the risk of developing eczema (4). This is not a surprising discovery, after all, the intestines are the second layer of the immune system, that is, the second line of defense against the outside world. Dysfunction of the intestinal immune barrier very often leads to a dysfunction of the immune barrier of the skin, and vice versa.

Skin and gut barriers: two layers of the immune system

Skin is an endocrine organ

Few people realize that the skin is also a part of the endocrine system. Vitamin D (mainly produced in the epidermis during exposure to sunlight) is actually a hormone (or pro-hormone), not a vitamin. Vitamin D receptors are found in almost all tissues of the human body, which shows how many roles it plays in maintaining health (5). Interestingly, sunlight falling on the skin can lead to increased secretion of sex hormones (including testosterone), and thus increased sex drive (6). In this way, the skin also influences our perception and behavior. Of course, hormones also affect many aspects of how the skin functions. Interestingly, women with eczema (as well as psoriasis) often observe worsening of the symptoms several days before the onset of their period (7). The course of eczema during pregnancy is also a fascintaing phenomenon, you can learn more about it here.

Beyond the skin barrier damage

These are just a few of the many functions of human skin. However, this is enough to realize that the dysfunction of the skin barrier will always be the cause or the consequence of the dysfunction of another system. This brings us to what atopic eczema really is: an extremely complex inflammatory disease, partly caused by genetic predisposition and partly by environmental factors (8). Much can be said about the pathogenesis of eczema, but for now it is enough to know that all paths lead to a skin barrier defect. As a result, the first line of protection against the outside world is lost. When the epidermal skin barrier is damaged, allergens, pathogens and contaminants can reach the antigen presenting cells. Upon activation, these cells migrate to the lymph nodes in the dermis and induce the secretion of inflammatory mediators (such as Th2 cytokines, TNF-α, and IFN-γ). Inflammation further damages the skin barrier by inducing the death of keratinocytes and impairing the function of tight junction proteins (both structures are the basic 'building blocks’ of the impermeable skin barrier). At the same time, the activity of pathogens also leads to keratynocyte death and increase in inflammation via the release of toxins (such as the α-toxin produced by the s. aureus bacteria) (9). Moreover, the composition of the microbiome is dominated by pathogenic bacteria, viruses and fungi, which often lead to infections. As a result of damage to the lipid barrier of the skin, excessive water loss occurs, and the skin becomes dry, flaky and cracks.

Inflammation is a desired response of the immune system when facing an infection or injury. However, the problem arises, when there is a constant threat, as the barrier no longer holds back the dangerous organisms and substances. This leads to development of chronic inflammation, the impact of which goes well beyond the skin manifestations of eczema.

Mental burden of eczema

It is worth remembering that eczema also carries a huge mental burden. Pain and itching are common causes of sleep disorders and increases in stress levels. For many patients, stress is also one of the main factors that exacerbate the symptoms of eczema and further damages gut barrier, leading to a vicious cycle (10). Moreover, the itching itself is often so intense that it stops persons with eczema from taking part in daily activities and enjoying life. On top of that, many people experience shame and low self-esteem related to the appearance of the skin. All these factors lead to an increase in the risk of developing depression and alcohol-related diseases (11, 12). Moreover, chronic inflammation itself can cause depressive symptoms (13).

This brings us to the third, and perhaps the most important, barrier in the human body, i.e. the blood-brain barrier. When the intestinal barrier is damaged, not only bacteria but also their products, such as lipopolysaccharides (LPS), can enter the bloodstream. Once the LPS is in the bloodstream, it can reach the blood-brain barrier and damage it (14, 15). When this barrier is damaged, LPS and other harmful substances can reach the brain and cause neuroinflammation. Healthy individuals given LPS injections exhibited depressive symptoms and experienced a sense of social isolation. They also had increased amounts of pro-inflammatory cytokines (such as TNF-alpha and IL-6). These symptoms were not observed in the control group, which received a saline injection (16). Perhaps one of the reasons why depression is so common in people with eczema is that inflammation also spreads to the brain as a result of damage to the blood-brain barrier. Currently, this hypothesis has not been confirmed, but we know that eczema is the disease of damaged barriers. The potential improvement in the condition of the blood-brain barrier is just an additional reason to pay attention to the condition of the gut.

Food allergies and intolerances

Most people with eczema also experience food allergies or intolerances (17), which are not always properly diagnosed. As a result, many patients follow restrictive diets, which often (but not always) make no sense (18). It is worth noting that long-term dietary restriction contributes to the already overwhelming stress load and it may lead to nutritional deficiencies.

Side-effects of treatments

Finally, many patients have to manage burdens associated with the long-term use of oral (and perhaps also topical) glucocorticoids in severe eczema cases (19,20). There is no doubt that glucocorticosteroids are extremely effective and can dramatically improve the quality of life of people with eczema. However, the problem arises when a modifiable cause of symptoms exists, but it is never identified. Instead, patients are prescribed glucocorticoids for years, which only temporarily mask inflammation and may cause side effects.

Is there hope?

It all sounds quite pessimistic. However, understanding the complex nature of eczema (as well as many other inflammatory diseases) gives us many new tools to control and mitigate symptoms. The single most important tool is nutrition.  There is no (and there will never be) a universal diet for improving eczema symptoms in every patient, because each case is different. However, a properly selected nutritional strategy that takes into account the individual needs of the patient can bring satisfactory results in the functioning of the entire body. I purposely avoid the phrase 'holistic care’ as it tends to often be associated with woodoo and homeopathy. However, in diseases as complex as atopic eczema, the approach must in fact be comprehensive and personalized. From skin to gut, from gut to brain: atopic eczema reminds us how complex and truly fascinating the human body is.

Bibliography

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  2. Meisinger, C., & Freuer, D. (2021). Causal Association Between Atopic Dermatitis and Inflammatory Bowel Disease: A 2-Sample Bidirectional Mendelian Randomization Study. Inflammatory bowel diseases, izab329. Advance online publication. https://doi.org/10.1093/ibd/izab329.
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