Microbial Community of Human Skin and its Role Vitiligo Disease

Skin harbor a diverse group of microorganisms that live all together in a harmony forming a biofilm of human skin and named “skin microbiome”. This microbial community is dynamic in determining the health of our skin. Skin microbiome is involved in different function in which protection for our body from harmful diseases considered the most important function. Skin’s healthiness can be determined by the presence of specific dominating types of microbiome. Skin microbiome can be categories into three groups of microbiome: 1. commensal (harmless and very rarely associated with disease), and 2. symbiotic (beneficial co-existence with the host without any harm), 3. opportunistic pathogens (harm and induce skin disease). Disturbance in skin microbiome is related to gut microbiome dysbiosis which leads to many skin diseases including vitiligo. This disease is resulted from destruction of melanocytes which destroy its capability for melanin production and white skin patches will appear. Theory for vitiligo development is briefly discussed.


Introduction
Skin is the largest external organ of the human body and Meanwhile, underlying the papillary layer is the much thicker reticular layer, composed of dense, irregular connective tissue. This layer is supplemented with a dense of blood vessel, sensory and sympathetic nerve. The reticular layer appears reticulated (netlike) due to a tight meshwork of fibers.
The subcutaneous, inner third part of the skin is also named the hypodermal layer or superficial fascia tissues. It is primarily consisting of impenetrable mass of irregular connective tissue that housing large blood vessels and nerve. The subcutaneous layer varies in its thickness all through the body and also from human individual to another. There are a number of structures and specialized cells that exist within subcutaneous tissue, including: collagen and elastin fibers (these attach the dermis to muscles and bones), blood vessels, sebaceous glands, nerve endings, hair follicle roots and fat cells. Fat cell is largely composed the innermost of this layer forming adipose tissue.

Role and Function of Skin
The principle function of the skin can be summarized into: a. barrier and protective properties, which can be classified into: barrier from physical and mechanical damage, thermal and microbial damages; b. regulate body temperature; c. immunological function; d. metabolic function; and e. sensation and communication. a.
Barrier and protective function The function of the skin's barrier is to protect the skin and the entire body from any damage.
i. Physical and mechanical barrier: Protects the body from mechanical damage i.e. friction and impact. Elastin cells of the skin allow skin to recover its shape after deformation.
Subcutaneous tissue also proved its ability to absorbs shock. Skin is mainly impermeable to water.

Immunological function
The skin is first site of entry for foreign substances and microbes. As mentioned before, the presence of the Langerhan and keratinocyte cells, in skin epidermal layers, and blood and lymph vessels and numerous immune cells, in dermal layers, are able to identify the invaded microbes and able to prepare a defence. The immune system of the skin has elements of both the innate (nonspecific) and adaptive (specific) immune systems that work together in stepwise harmony that lead to protect the body from infection, cancer, toxins, as well as attempts to prevent autoimmunity. The skin microbiome also contributes to the homeostasis of the skin immune system. f.

Microbiome of the Skin and Risk Diseases
The term skin microbiome generally is referring to the microorganisms that reside on the human skin. Skin microbiome is covered the body in a non-observed biofilm layer that plays a major role in skin protection. Consistency and diversity of these microorganisms, forming this biofilm, are highly affected by way of two factors: what we put on our skin, and what we put in our body. As we may know that skin health are influenced by the gut microbiome and gut health in general [1,2]. Taking a daily properquality probiotic will help in keeping our skin in health condition.
Numerous researches done on the use of probiotics, in supporting a healthy gut and in sequence skin microbiome, proved their significance on human health. New researches also confirmed this relation between gut and skin, and demonstrated that anything damaging our gut microbiome also influences what's happening to the skin [3][4]. This connection is termed the gut-skin axis, and scientists are started to explore such connection to understand this dual effect. The gut and the skin are considered organs with vital immune and neuro-endocrine roles and are uniquely related in persistence and function. The intimate relationship between these organs nowadays, with great concern, has a potential to develop sever diseases like colorectal carcinoma [5,6]. Figure 1   Numerous studies have linked gastrointestinal (GI) health to skin homeostasis. To date, the most research done on acne and its development with reference to gut microbiome disorder [8][9][10] which proved a strong relation between both of them. However, the lines of communication, as mediated by gut microbes, may be direct and indirect, but ultimately influences the degree of acne severity.
Generally, the mechanism by which acne developed through inflammation of the gastrointestinal tract that known as a leaky gut.
In this condition, a part of digested food enters the bloodstream, which causes acne breakouts. When the gut microbiome becomes imbalanced or disrupted, everything including the brain to energy level to the skin is affected. Dietary regime also contributed in gut inflammation and dysbiosis of microbiome (Figure 1). To keep the gut microbiome stable state, it is suggested to add prebiotic food (such as fiber-rich food, fresh fruits, and vegetables) and probiotic food to the diet to prevent acne development and breakout [11].
There is also early evidence that that potential link between the dysbiosis in the gut microbiome and skin disorders such as psoriasis, rosacea, and atopic dermatitis including dermatitis herpetiformis and Eczema. The gut dysbiosis which lead to leaky gut in which such leakage will cause the immune system to launch an inflammatory response, leading to local and systemic inflammation, which, in turn, contributes to the mentioned disease ( Figure 1). In the case of Eczema, the gut microbiota also affect the development of autoimmune disorders, in response the gut microbes regulate T cell differentiation (and thus, gut microbiome plays an immunoregulatory role) and modify proteins present in the gut, which could produce an autoimmune response [12,13].

Skin Pigmentation and Vitiligo Disease
Melanocytes, exist in various tissues in the body including the skin, are responsible for melanin pigment production. In the skin, they are localized in the dermal-epidermal interface at the distal epidermal layer. Melanocyte cells have dendrites that projected between epidermal cells where they transfer melanosomes to keratinocytes [14][15][16]. One melanocyte is associated with nearly 30-40 surrounding keratinocytes through its dendrites. The symbiotic relation between these two cell types, melanocyte and the pool of associated keratinocytes, form an entire unit and is coined as the "epidermal melanin unit". This symbiotic unit plays a role in melanin transfer from melanocyte to keratinocyte cells and gives the skin its color.
For transfer the melanin, from melanocyte to keratinocyte cells, different frequented stages should be occurred by which single melanosomes, the specialized pigment-containing organelles, are released in a keratinocyte cytosol and reach the perinuclear area. Moreover, the amount and type of melanin produced, that transferred to the keratinocytes with subsequent integration, aggregation and degradation, impacts skin complexion coloration [17,18]. Two major classes of melanin are produced pheomelanin, an orange to red pigment, and eumelanin, a brown to black pigment. They differ in their color and the way of synthesis.
However, both melanin classes are driven from a single precursor, the amino acid L-tyrosine, and their synthesis involves melanogenic enzymes such as tyrosinase (TYR), a copper-dependent enzyme; tyrosinase-related protein 1 (TYRP1); and tyrosinase-related protein-2 or dopachrome tautomerase (TYRP2) [19,20]. Therefore, the multistep process, which in need to allow the production of melanin pigment of different classes, is called melanogenesis.
Regulation of melanogenesis is controlled by transcript factor named microphthalmia-associated transcription factor (MIFT) with others that belong to MiT family factors [20]. These factors regulate the expression of specific genes, from promoters containing specific sequences, for proteins involved in pigment synthesis, for melanosome structural proteins, as well as proteins involved in melanosome trafficking which responsible for melanin production [21][22][23]. Therefore, any defect of these sequences for melanin production will attribute for skin decolorization.

Vitiligo and Skin Microbiome
Simply vitiligo is skin disease and can be identified as an autoimmune disease that gives rise to patches of white skin as a resulted from melanocyte destruction. As we mentioned above, gut-skin axis microbiome play a great role in skin diseases which related to disturbance in their normal microbiome. Therefore, gut dysbiosis lead to dysbiosis of skin microbiome and in sequence  Another theory is vitiligo disease results from a complex interaction of environmental, genetic, and immunologic factors, which ultimately contribute to melanocyte destruction, resulting in the characteristic depigmented lesions [30,31]. All of these hypothesis lead to destroying the melanocytes and sequentially the melanin production which ended with appearance of white patches.

Conclusion
In conclusion, our review may shad a light on the important of skin microbiome, which highly related to gut microbiome and immune system homeostasis, and its role in vitiligo development.
Meanwhile, host-microbe interactions and genetically determined the variation of skin properties might be linked to skin dysbiosis. The alterations in skin microbiome also play a role in cellular stress on melanocytes and destruction of melanosome or the melanogenesis process that lead to vitiligo pathophysiology state.