Immune system needs microbial exposure - Re-Connecting Nature® supports immune system by providing high biodiversity microbial exposure
Project manager, Uute Scientific Oy
MSc Johanna Kalmari received her degree in Molecular Biology and Gene Technology from the University of Eastern Finland. She has worked previously in the field of environmental biotechnology and currently works as a project manager at Uute Scientific Oy.
Biodiversity loss and urbanization has increased simultaneously with immune-mediated diseases. The immune system needs constant stimulation from the environment to function properly and distinguish harmful targets from harmless ones. In simple terms: kill pathogenic bacteria; do not kill your own cells. Exposure to environmental micro-organisms brings diversity to the skin and gut and helps our immune system suppress signaling leading to inflammation.
Re-Connecting Nature® is a microbial extract from Finnish nature, and is designed as an ingredient for consumer products to give rich microbial exposure especially for those people who are not in contact with nature on a daily basis. A new in-vitro study indicates that Re-Connecting Nature® treatment reduces the amount of pro-inflammatory cytokines released in an epidermis skin model. These results are in line with the previous university studies, in which re-introducing natural microbial diversity to the skin of daycare children, improved their blood cytokine ratio for the attenuated inflammatory signaling.
Biodiversity add immune tolerance
Urbanisation and changes in lifestyle have disconnected humans from naturally occurring biodiversity. The World Allergy Organization is concerned about the biodiversity loss that is related to urbanisation. Loss of macrodiversity (plants) in cities leads to shrinking microdiversity (microbes) with poor human microbiota exposure. This leads to poor immune tolerance and finally inflammation and clinical diseases (1). The Finnish national allergy program from years 2008-2018 changed its strategy from avoiding potential allergens to people tolerating them. This strategy managed to reduce the prevalence of allergy and asthma (2).
The Biodiversity Hypothesis states that contact with natural environments enriches the human microbiome, promotes immune balance and protects from allergies and inflammatory disorders (7). Humans have developed to co-exist with micro-organisms, and therefore contact with environmental microbes in everyday life induce immunoregulatory pathways and balance responses against foreign proteins, like allergens. The immune system has difficulties to distinguish signals of danger from non-danger, when the interplay between human and environmental microbiome is missing. For instance, the immune system may recognise pollen as virus (4). Reduced biodiversity exposure and alterations in the gut and skin microbiota are associated with many conditions including elevated inflammatory responses like asthma, allergy, inflammatory bowel disease (IBD), type1 diabetes and obesity (1,5).
On a molecular level, continuous exposure to environmental microbes through the skin, gut and respiratory tract activates positive, immunoregulatory circuits, whereas inappropriate inflammatory responses are down regulated (5). The continuous stimulation of the immune system by environmental microbes leads to the generation of suppressive regulatory T-cells (Treg) necessary to down-regulate inflammation. In the absence of stimulation (antigen) these Treg populations are likely to decrease (3,6). The interactions of the microbes with their specific receptors on, and in, immune cells are necessary for the development and maintenance of epithelial cell integrity, tolerance, and tissue repair. Without sufficient microbial stimulation another path- a self-perpetuating system of enhanced number of inflammatory mediators and microbes that tolerate it – is induced. The environment also modulates our immune system by epigenetic mechanisms where environmental factors activate or silence genes. This epigenetic modulation is especially important in early childhood, but changes can occur later as well. (5).
The microbiome on our skin and gut is important to our overall immune system functioning and health. Overgrowth of some species while relative abundance of others decrease (=dysbiosis) are contributors to diseases like atopic dermatitis (14). The microbiome on skin and in the gut includes both transient and resident microbes, and therefore at least part of the microbiome is in a dynamic interaction with the environment (1). Thus, environment affects our microbiome, and it is indicated that atopic individuals have lower biodiversity around their homes and lower diversity of Gammaproteobacteria on their skin than healthy individuals (27). Some environmental microbes are particularly important for health and have anti-inflammatory properties. For example, Gammaproteobacteria, and its genus Acinetobacter, induce immunoregulation (8,14) and prevent allergic sensitisation and lung inflammation (10). Boreal forest floor origin Mycobacterium genus have anti-inflammatory properties and is associated with the improved mood and learning while mitigating stress and depression (9,14).
There are positive results of intervention trials where direct contact with soil, enriched with added microbial biodiversity, created beneficial immunological changes (11-14). In a daycare study 28-day contact with soil diversified skin and gut microbiota, increased Treg cell frequency and changed cytokine ratio leading to a decreased inflammatory state (12). In another, long-term, study with daycare children, the daycare environment was enriched with biodiverse forest floor vegetation and peat. This exposure enriched skin’s commensal microbiota and suppressed the potentially pathogenic bacteria as compared to a standard, urban daycare environment (14).
Microbial structures like lipoproteins are recognised by Pattern Recognition Receptors (PRR) that are found on various type of cells, including keratinocytes on skin (29,30). As these cells recognise bacterial molecular structures, an immune response was also reported with heat inactivated microbes (10,28). Re-Connecting Nature® is a patented and pioneering microbial extract developed at the Universities of Tampere and Helsinki. It contains over 600 bacterial species, including beneficial Acinetobacter and Mycobacterium, in safe form: inactivated but biochemically recognisable by our immune system to give needed natural exposure. Re-Connecting Nature® is currently available in cosmetics provided by many manufacturers and also in textiles made by Ruskovilla®.
Re-Connecting Nature® in a lotion created significant immunological response in skin model
Uute Scientific latest study was performed by a partner using an in-vitro skin model. The target was to study the effects of Re-Connecting Nature® on skin microbiome, barrier proteins and cytokine secretion. Cytokines are signal molecules that regulate our immune responses, and are secreted by many types of cells including epithelial cells like keratinocytes. Some cytokines promote and some down-regulate inflammation responses with some having more complex roles. The test model included laboratory grown stratified epidermis, on which three skin commensal bacteria (S. epidermis, C. striatum. C. acnes) were grown. The defense test included pathogenic S. aureus. Re-Connecting Nature® extract was used in four different concentrations (0,5%, 1%, 5%, 10%) in a cosmetic lotion. Controls included untreated and vehicle (= just the lotion) treated skin organoids.
According to the microbial results, Re-Connecting Nature® at low concentrations (0,5%, 1%) had a neutral effect on the growth of S. epidermis and C. acnes and a prebiotic (=growth supporting) effect on the growth of C. striatum. At higher concentrations there was more interference, which may be due to limited number of microbes and short time exposure (24h) used in this model. At the defense test with S. aureus challenge, Re-Connecting Nature® did not have any significant effect on the growth of tested microbes, apart from the highest concentration (10%), where significant inhibitive effect was seen on the growth of pathogenic S. aureus. In future studies, it would be interesting to see if there is an inhibitive effect on pathogens at the lower concentrations.
Histological results showed that Re-Connecting Nature® has no negative effect on the important skin barrier proteins (Loriclin, Claudin, Filaggrin and Ki67) expression in the skin model, not even at high concentrations. Immunological results showed that Re-Connecting Nature® treatments reduced the levels of cytokines released in the skin model. In the situation where only three commensal microbes were present, Re-Connecting Nature® treatments significantly reduced five pro-inflammatory cytokine levels (IL-4, IL-12p70, IL-13, TNFα, IFNγ) compared to the vehicle control. In defense test with S. aureus, Re-Connecting Nature® treatments reduced significantly seven pro-inflammatory cytokine levels (IL-1β, IL-2, IL-4, IL-12p70, IL-13, TNFα, IFNγ) compared to vehicle. Importantly, immunological responses were detected even with the lowest concentration (0,5%). Based on these results the recommended concentration to use Re-Connecting Nature® in products varies between 0,5 – 4%.
Skin benefits of Re-Connecting Nature®
Based on the literature and in-vitro study presented here, several possible skin benefits can be associated to Re-Connecting Nature® products. Re-Connecting Nature® extract at recommended concentrations supports natural microbiome diversity, and it may prevent overgrowth of pathogenic S. aureus. Re-Connecting Nature® may also support the skin barrier function by reducing levels of inflammatory cytokines, especially IL-4, IL-13, TNFα and IFNγ, which are linked to the impaired function of the skin barrier in several studies (15-21). In atopy skin barrier disruption occurs, with overgrowth of S. aureus, and levels of IL-4 and IL-13 (18,31) are elevated. Furthermore, there is itching, which is at least partly mediated by IL-4 (22). There is need for more trials however based on the literature and this in-vitro study, Re-Connecting Nature® has strong potential for relieving symptoms of atopic skin.
The skin barrier disruption can also occur without any clinical skin disorders. The function of the skin barrier begins to fail and the rate of its repair declines after age of 55. Low-grade inflammation has been observed in ageing skin (23). Psychological stress disrupts the skin barrier, which may be related to stress-induced pro-inflammatory cytokine secretion (16). Some cytokines, like TNFα and IFNg, also inhibits collagen synthesis (24,25). Reducing the amount of pro-inflammatory cytokines helps maintain the normal skin barrier function and collagen production in aging skin and in skin under stress. Reducing the amount of IFNg may also lead to faster skin regeneration and repair (25). UV-radiation induced sunburn reactions are related to inflammatory events, like the production of TNFα and IL-1b (26). Lowering levels of pro-inflammatory cytokines may reduce the redness and irritation caused by sunburn.
The literature review links lowered levels of proinflammatory cytokines to skin benefits. Combining these findings to our skin model study results opens promising new avenues for the use of Re-Connecting Nature® in different products to achieve these benefits. Naturally, we will generate more results focusing next on in-vivo studies. While creating skin benefits, we are helping to prevent immune-mediated diseases.
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