Microbiome Research in Alopecia Areata: Comparison
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The continuous research advances in the microbiome field is changing clinicians’ points of view about the involvement of the microbiome in human health and disease, including autoimmune diseases such as alopecia areata (AA). Both gut and cutaneous dysbiosis have been considered to play roles in alopecia areata. A new approach is currently possible owing also to the use of omic techniques for studying the role of the microbiome in the disease by the deep understanding of microorganisms involved in the dysbiosis as well as of the pathways involved. These findings suggest the possibility to adopt a topical approach using either cosmetics or medical devices, to modulate or control, for example, the growth of overexpressed species using specific bacteriocins or postbiotics or with pH control. This will favour at the same time the growth of beneficial bacteria which, in turn, can impact positively both the structure of the scalp ecosystem on the host’s response to internal and external offenders.

  • alopecia areata
  • microbiota
  • omics
  • postbiotics

1. Alopecia Areata and Microbiota

Alopecia areata (AA) is the second most common type of hair loss disorder in humans, with a reported lifetime incidence risk of higher than 2% [1,2][1][2].
It is classified as a non-scarring autoimmune hair disorder that manifests itself as a consequence of many etiological drivers mainly genetic, environmental, and immunological [3,4][3][4]. In particular, immunity is reported to play a pivotal role [5,6][5][6].
Immune privilege (IP) collapse of the hair follicle (HF) was first described by Billingham and Silvers in 1971 [7], by the suggestion that human HFs represent an IP site. Following this, Kang et al. [8] demonstrated the downregulation of the expression of several genes important for the immunosuppressive environment in AA subjects.
Currently, the central role of IP collapse in AA pathobiology has become widely accepted in the field, with current evidence suggesting that IP in the anagen HF can sequester antigens that are produced in hair bulbs from immune recognition [9,10][9][10].
The IP collapse is a recognised prerequisite for the development of AA [11], and the mechanisms behind have been highlighted [12]. One important key factor is the upregulation of MICA or ULBP3 which are NKG2D-activating ligands [13,14,15,16][13][14][15][16].
The continuous research advances in the microbiome field are changing clinicians’ points of view about the involvement of the microbiome in human health and disease, including autoimmune diseases such as AA.
Recently, Scharschmidt et al. [17] suggested an involvement also of the HF’s microbiome on IP given the modulatory activity of the microbiome itself on the balance between chemokine secreted by keratinocytes and IP guardian secretion.
Thousands of microorganisms inhabit the skin; they represent the so-called microbiota or “skin microflora” [18]. An even more new concept is the one represented by the “microbiome”, that to say the genome of all the microorganisms, symbiotic, and pathogenic, that interact with all cell types of the body [18].
The microbiome can be considered as a “meta-organism” whose symbiosis with the human host and dynamics in terms of both species and functions can contribute to maintaining homeostasis or causing disease [19]. Most importantly, recent studies are focusing on the pathogenic role of microorganisms as well as on their importance as regulators of metabolism, immunity, and environmental adaptation of the host [19].
The host immune system, in particular, is in a strictly symbiotic relationship with the microbiome [20,21,22][20][21][22]. Microbiota and the host immune system exert bidirectional control on each other [23].
On the one hand, the microbiome can control the development, training, and function of the host immune system. Additionally, the gut microbiota composition and functionality have been reported to have roles in controlling the immunomodulation in autoimmune conditions, including alopecia areata [24,25][24][25].
On the other hand, as a result of evolution, the host immune system, in turn, acts as a kind of “pacemaker” in the maintenance of the symbiotic relationship between the host and the microbiota [25]. A new, ever-expanding field is exploring the influence of the local microbiome (e.g., in the gut) on the immunity of a different and distant site such as skin, and this is per the existence of the “gut–skin axis” [4,26][4][26].
Regardless of the gut microbiome, several factors may lead to dysbiosis in the skin microbiome and, in the end, to the development of skin disease [18].
Primarily, each different skin site harbours a different microbiome, and this depends on several factors (e.g., water content, sebaceous glands, temperature, exposure to the environment, etc.) [27]. Increasing evidence demonstrates that the human microbiome plays a key role in human health and diseases [28,29,30][28][29][30]. For example, a modification of the microbiome is implicated in chronic inflammatory conditions, including atopic dermatitis in which the enhanced skin colonisation by Staphylococcus aureus has been reported, as well as the role of specific S. aureus strains [31]. Other studies reported higher colonisation by Firmicutes with a contextual reduction in Actinobacteria in psoriatic lesions [32].
Historically, the involvement of Cutibacterium acnes (formerly, Propionibacterium acnes) in acne development is well-established [33,34,35][33][34][35]; however, more recently, a shift in this paradigm has been reported, and the involvement of other microorganisms such as S. aureus and S. epidermidis has also been highlighted [36,37][36][37].
Although it shares some characteristics with that of the skin, the microbiome of the scalp possesses some unique characteristics, such as primarily the presence of terminal HF and the higher number of sebaceous glands and blood vessels and thickness [38].
Despite other body sites (e.g., gut and skin), the implication of the role of the microbiome in the pathogenesis of AA is still considered to be little explored.
Indeed, only in the last three years have authors begun to provide evidence of the additional role of the microbiome in the pathogenesis of AA [20,39,40,41][20][39][40][41]. Undoubtedly, the discovery of the possible contribution of the gut and skin microbiota to AA represents a new field to be further explored and open to a new therapeutic approach.

2. Studying the Microbiota by Omics Techniques

The study of the interaction between the host and the microbiota in terms of the specific genes, metabolites, and proteins they produced is presently feasible owing to the advent of “omics” techniques that allow delineating novel roles for microbes in health [56][42]. For many decades, the knowledge regarding microbiota was limited to culture-based techniques. Despite their limitations, however, they were fundamental for microbiota characterisation in the past and are still used today as the starting point for microbiome studies. The main limitations are that they are labour-intensive and not high-throughput, and they are unable to detect the virome and archaea. “Omics” techniques fall under the great hat of systems biology techniques; they include metataxonomic, metagenomic, metabolomic, metabonomic, transcriptomic, and proteomic approaches and allow the comprehension of the microbiota inhabiting a given ecosystem, not only in terms of populations but also in terms of its functionality. The metataxonomic approach is a high-throughput technology used to characterise the entire microbiota and create a metataxonomic tree, aiming to describe the relationships between all sequences obtained [57][43] (Figure 1a).
Figure 1. Schematic representation of omics techniques: (a) metataxonomic; (b) metagenomic; (c) metatranscriptomic; (d) metabolomic and metabonomic; (e) metaproteomic.
In the metagenomic technique, first used by Handelsman et al. [58][44], shotgun sequencing of DNA is used, followed by mapping to a reference database, to characterise the metagenome, to provide information on the potential function of the microbiota in a given ecosystem (Figure 1b). The metabolomic approach, first introduced in 1998, refers to the determination of the metabolic profile in any given ecosystem [59][45] (Figure 1c). Further advancement of metabolomic analyses led to the development of the metabonomic approach [60][46], which is the analysis of metabolites in a more complex system (e.g., faecal samples, urines, plasma, etc.) (Figure 1c). The metatranscriptomic method is the analysis of ribonucleic acid (RNA) using high-throughput sequencing. This technique helps provide information on the transcriptomic profile of the microbiota of a given ecosystem [57][43] (Figure 1d). The last one, the metaproteomic approach, first described by Rodriguez-Valera in 2004 [61][47], refers to the characterisation of the entire protein content of a clinical sample at a given point in time without discriminating proteins from microbiota and the host (Figure 1e). The advantages of the above-cited omic technologies, compared with more traditional methods, are higher sensitivity and resolution [62][48]. Indeed, the use of all these techniques found application, for example, in diseases such as inflammatory bowel disease (IBS) [63][49], general gut dysbiosis [64][50], and cancer [65][51], but its field of application was also recently extended to skin and hair diseases [41,66,67,68][41][52][53][54]. To understand the function of microbial communities in a given ecosystem, including skin and scalp, it is necessary to determine which genes and/or metabolites are expressed. Metabolites and small molecules produced by the microbial population act as signal molecules for the communication between the host and microbiota [69][55]. Consequently, a change in the microbial population, for example, in the case of a disease, reflects changes in this system of communication and the pathways involved [70][56]. For this reason, the use of omics is becoming no longer a negligible issue in microbiome studies. This is particularly true in the study of the microbiome in AA considering the impact of macro and micronutrients on hair physiology as the involvement of inflammatory and immunological pathways. Resident scalp microorganisms encounter epidermal cells, such as keratinocytes and immune system cells, by interacting with them and also changing their metabolic activity and transcriptomic framework. These changes can be deeply investigated using the Kyoto Encyclopaedia of Genes and Genomes (KEGG) [71][57], a metagenomic-based analysis, allowing the representation of cellular functions in a given ecosystem at a high level of resolution. This analysis has been previously used by other authors in studies about skin microbiome [72,73,74][58][59][60]. KEGG analysis integrates current knowledge on molecular interaction networks and consists of three types of databases: pathways (PATHWAY database), genomic from genome projects (GENES/SSDB/KO databases), and biochemical compounds and reactions (COMPOUND/GLYCAN/REACTION databases). Pathways related to the cellular response to external stress, membrane transport, vitamins, amino acid metabolism, carbohydrate metabolism, energy metabolism, replication and repair, and immunological response can be investigated by KEGG analysis [75][61].

3. Modulation of Microbiota in Alopecia Areata

A link between AA and gut microbiome could be hypothesised following recent evidence on the involvement of short-chain fatty acids, mainly butyric acid, derived from microbial metabolism in the gut and the differentiation of peripheral Treg lymphocytes [90][62]. These last are the important immunological mediators of AA [91][63]. One of the main drivers of the gut microbiome is diet [97][64], and much research focused on establishing the role of diet in shaping the microbiome; this was also reported as regards the skin microbiome [98,99][65][66]. Indeed, diets have been reported to affect skin physiology and microbiome. Therefore, the existence of a gut–skin microbiome axis has been well-established for many dermatological diseases including atopic dermatitis [100][67]. The role of diet in AA can also be hypothesised [101,102][68][69]. Firstly, an unbalanced diet can lead to a lower intake of some macronutrients and micronutrients, and this can have an impact on gut microbial composition and functionality as well as the microbiome inhabiting the scalp up to the perifollicular region [101][68]. Hair is a fast-growing element, which needs a balanced supply of nutrients to grow correctly [9,102][9][69]. Under this assumption, targeted dietary approaches could represent a further therapeutic option or adjuvant therapy for AA subjects. Even though there is presently no scientific basis for the hypothesis that, for example, the syndrome of “leaky gut” may be one of the etiological factors of AA, the latter shares some genetic characteristics with other autoimmune diseases (rheumatoid arthritis, diabetes I, celiac disease, systemic lupus erythematosus (SLE), psoriasis, multiple sclerosis, etc.) in which the association of the disease with an altered intestinal permeability has been demonstrated [103][70]. Suggested therapies include, among others, diet, additional nutritional supplementation with probiotics or botanical extract, a gluten-free or low-FODMAP diet, a low-sugar diet, or an antifungal diet. Additionally, restoring the unbalanced gut microbiota with a healthy one via FMT could represent useful therapeutic options, as reported above [101][68]. The rationale behind the usefulness of “rebalancing” the gut microbiome is linked to the improvement of the absorption and synthesis of nutrients (amino acid/proteins, biotin, SCFAs, and vitamin D), which are also essential for hair follicle tropism and immunomodulation, and this, ultimately, results in hair regrowth [104][71]. However, current legislative limitations and the scarcity of clinical trials pose the need for larger studies before implementing FMT in the panel of the treatments currently available and approved for AA. Indeed, gut dysbiosis should not be considered a localised phenomenon. Alteration in the gut microecology as in the microbiome functionality may have consequences on the general inflammatory and immunological state of the host up to involving the scalp ecosystem and physiology [98][65]. The evidence of the modification of fundamental pathways of the immune and inflammatory responses and pathways involved in the transport of micronutrients, such as vitamin D (VitD) on the scalp of subjects affected by AA, could be the first stage for an evaluation of etiological agents important in the knowledge of AA. Various autoimmune diseases have been associated with a deficiency in VitD [105][72]. Indeed, VitD is strictly linked with skin immunity since it can regulate lymphocyte functionality, dendritic cell maturation, and cytokine secretion [105][72]. In particular, it suppresses T-helper 1 and T-helper 17 cell formation, and this leads to a decrease in inflammatory cytokines [105][72]. A deficiency of this vitamin has also been reported in AA [106][73]. Therefore, topical calcipotriol has been successfully used for treating AA [107,108,109][74][75][76]. Using a meta-analysis, Lee et al. [110][77] reported a higher prevalence of VitD deficiency in AA subjects than in the control group. Most interestingly, according to several lines of evidence, the decrease in serum VitD levels significantly and inversely correlates with AA severity [111[78][79],112], also in children [113][80]. The production of IFN-γ by human peripheral blood mononuclear cells (PBMCs) and CD4+ T cells was significantly decreased by Vit D [114,115,116][81][82][83]. This suggested that VitD might probably counteract the IP collapse in AA by modulating the production of IFN-γ [106][73]. Therefore, the evidence of VitD deficiency in the AA could be a consequence of the decreased expression of some bacterial-related pathways. Indeed, human studies have reported significant associations between vitamin D and microbiome composition [117][84] Therefore, as stated by Thompson et al. [76][85], a deficiency in micronutrients might also contribute to AA through dysregulation of immune cell function, DNA synthesis, and oxidative stress induction. Indeed, the use of topically applied probiotics may be a natural, targeted treatment approach to several skin disorders in which a dysbiosis of the microbiome could be hypothesised, including AA. There is a growing amount of research reporting evidence of the health-promoting effect of probiotics on skin health [119][86]. Probiotics act primarily by increasing levels of beneficial bacteria or, indirectly, by influencing the immune system which, in turn, influences the host microbiome. However, the use of live bacteria on skin poses several challenges. For this reason, they are usually used in topical formulation in the form of non-viable microorganisms with the same probiotic activity and health benefits as viable microorganisms but safer than live probiotics [120][87]: They are the so-called “paraprobiotics” [120][87]. A new open perspective in the field is that represented by “postbiotics”. The term refers to molecules released by beneficial bacteria that are responsible for the beneficial effects of probiotics themselves [120,121][87][88]. They include peptides, enzymes, short-chain fatty acids (SCFAs), antimicrobial peptides (AMPs), polysaccharides, cell-surface proteins, vitamins, plasmalogens, and organic acids [121][88]. The mechanisms implicated in their health benefits are not fully elucidated, but a recent study reported different functional properties (e.g., antimicrobial, antioxidant, and immunomodulatory) [121][88].

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