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Abstract
The skin, besides being the largest interface between the body and the external environment, also forms an ecological niche which is populated by almost a trillion microorganisms. These, collectively known as the cutaneous microbiome, form a dynamic yet well-controlled system that resists invasion by pathogenic microorganisms, functioning as the so-called ‘microbiological barrier’, modulating the body’s immune response, indirectly playing a crucial role in the pathogenesis of several inflammatory diseases. The composition and complexity of the microbiome are yet to be fully understood. The term ‘dysbiosis’ originally was coined in 1908 for a change in the gut microbiome. The potential role of ‘cutaneous dysbiosis’ in human dermatophytic infections, especially in the backdrop of the current epidemic of chronic, recurrent and treatment-resistant dermatophytosis, is understandably a topic of interest. The purpose of this review was to assess all studies using culture-independent methods for analysing the skin microbiome in various dermatophyte infections. The PubMed and Google Scholar databases were searched using the terms ‘microbiome’, ‘dysbiosis’, ‘dermatophytes’, ‘dermatophytosis’ and ‘tinea’. All studies involving the use of standard sequencing methods for the study of the microbiome in various dermatophytoses were included. A total of four studies assessing the local skin microbiome associated with dermatophytic infections were found—one for tinea capitis, one for onychomycosis (in both psoriatic and nonpsoriatic nails) and two studying patients of tinea pedis. The studies determined the microbiological patterns in patients and compared them with healthy individuals using sequencing methods. Significant differences in the species diversity and counts of the various microorganisms between patient and control groups were demonstrated in all. However, cross-sectional design and the absence of pre- and post-treatment data along with a limited sample size were the major limitations in all of them. No data regarding other forms of tinea, most importantly, tinea cruris, corporis, faciei, etc. were found. The existing studies demonstrate a change in the microbiome or dysbiosis associated with cases of dermatophytosis, but are inadequate to determine a causal association. The changes may also be wholly or partly attributed to the effect of the infection. Further longitudinal studies from different regions of the world, also involving other forms of dermatophytosis, are required to provide a clearer insight and a more representative picture.
Keywords: Key Words: Dermatophytosis, dysbiosis, microbiome, tinea
Introduction 
The fact that the skin functions as a physical, chemical and microbiological barrier between the internal milieu and the external environment is well known. Its function as an organ of interaction with the external environment is no less important. The approximation of skin surface area of 2 sq m for an adult is a gross underestimation of its true magnitude and has been calculated disregarding its numerous appendages like pilosebaceous units and sweat glands. Together with its appendages, the skin accounts for 25–30 sq m of surface area for an average adult, making it one of the largest interactive surfaces for the human body.[1] This surface is home to numerous phyla and species of resident microbial population consisting of bacteria, fungi, viruses, protists and archaea. A staggering count of around 1012 microorganisms are estimated to inhabit this environmental niche and compose the ‘microbiome’ of the skin.[2] The role of this microbiome as an effective immunological modulator and its contribution to the cutaneous microbiological barrier is only recently being recognised and the complexity of its mechanisms and interactions still remain to be properly elucidated. The interactions, between the host and the microbiome and amongst the components of the microbiome itself, are complex. The microbial communities modify the host responses and are, in turn, modified by it. The various communities interact with each other and stimulate or inhibit the growth of one another, thus maintaining the equilibrium of the different species. During homeostasis, the microbiome often forms the first line of defence against invading microorganisms, maintaining the integrity of the cutaneous barrier. They compete with potential pathogens for space and nutrients and, thus, deter their invasion by a mechanism termed as ‘colonisation resistance’.[3] This is mediated by a variety of molecules with specific anti-infectious roles, many of which have been isolated and studied and belong to the class of antimicrobial peptides (AMPs) and short-chain fatty acids. On the other hand, the microbes modulate the host immunity to promote and facilitate their own immune acceptance by decreasing the inflammatory immune response against their own exposed antigenic structures via pattern recognition receptors (PRRs). The host immune system must be able to tolerate the commensals while eliminating the pathogens. This requires a very finely modulated immune response which the cutaneous microbiome achieves.[4] Thus, any qualitative or quantitative change in this microbiome, known as ‘dysbiosis’, can have significant implications in local immune responses, inflammation and invasion by pathogenic organisms. The term was originally coined by Metchnikoff in 1908 to define pathologic changes of intestinal microflora composition.[5]
The microbiome in health
The earlier efforts at characterisation of the microbiome composition depended entirely on culture of the individual organisms and invariably missed or underestimated the organisms which were unable to grow on artificial media or had fastidious growth requirements.[6],[7] Modern methods of amplicon sequencing (16s rRNA for bacteria and internal transcribed spacer 1 - ITS1 - for fungi) and shotgun metagenomic sequencing have removed this bias and have improved our understanding of the composition in its entirety, providing details of not only the species but also the various strains.[8],[9]
The composition of the microbiome varies according to the cutaneous site. Moist areas like the axilla, groin, cubital and popliteal fossa show a predominance of Actinobacteria (Corynebacterium)(36–51%), Firmicutes (Staphylococcus) (24–34%), Proteobacteria (11–16%) and Bacteroidetes (6-9%), while sites rich in sebaceous glands like scalp, face, chest and back are rich in Cutibacterium. Dry skin of forearms, hands, buttocks and legs shows a rich diversity with proteobacteria, corynebacteria, bacteroides and other firmicutes. The feet and soles show the greatest fungal diversity with almost 40 to 80 genera inhabiting the sites.[10],[11],[12] The commonest fungal species isolated are Malassezia spp., Cryptococcus spp., Rhodotorula spp., Aspergillus spp., Epicoccum spp. and Malassezia spp., comprising around 80% of the whole fungal flora. Malassezia and Cutibacterium show a far greater predominance in adults than in children.[10]
The fact that dysbiosis of cutaneous and gut microbiome is associated with inflammatory skin diseases like atopic dermatitis, psoriasis and acne vulgaris is now well recognized.[10] However, its role in dermatophytic infections is still not well studied. With the recent spate of chronic, persistent and difficult-to-treat dermatophytosis, the potential role of the cutaneous microbiome and its dysbiosis must be evaluated. Thus, the aim of this review was to assess all studies using culture-independent methods for analysing the skin microbiome in dermatophyte infection.
Materials and Methods Medical literature databases like PubMed and Google Scholar were searched using the terms ‘microbiome’, ‘dysbiosis’, ‘dermatophytes’, ‘dermatophytosis’ and ‘tinea’. All articles including studies, case series and case reports published in English were considered. Studies involving superficial fungal infections other than dermatophytoses like candidiasis or pityriasis versicolor were excluded for the purpose of the review. Only studies using standard sequencing methods for the study of the microbiome were included.
Results A total of four studies were found. The results of these studies are presented in [Table 1].
Table 1: Findings of studies assessing the microbiome composition and characteristics associated with various dermatophytic infectionsA study by Tao et al.[13] comparing the scalp microbiome amongst three groups, children with tinea capitis, healthy children and adults without any scalp dermatoses, found distinct differences in the bacterial and fungal communities colonising lesional and non-lesional skin of the scalp in children with tinea capitis compared to healthy children. The diversity of the bacterial and fungal communities was far greater in the former group than in the latter. The study further explored the microbiome of scalp of healthy children and healthy adults in order to investigate the cause of susceptibility of children to tinea capitis and found significant differences between the two groups, with greater species diversity in children than in adults. Trichophyton, the most common pathogen of dermatophytosis, was detected in most healthy volunteers but only in very low relative numbers.
A study by Wang et al. studying the nail microbiome in psoriatic and nonpsoriatic patients with onychomycosis analysed the microbial composition of toenails in four different groups (nonpsoriatic patients with onychomycosis (NPOM-37 patients), patients with nail psoriasis and onychomycosis (POM-25 patients), nail psoriasis without onychomycosis (P-27 patients) and 38 healthy controls.[14] The study included both dermatophytic and non-dermatophytic causes of onychomycosis. Trichophyton rubrum was isolated in 35 (94.59%) patients of the NPOM group and 12 (48.00%) POM patients. The potential interactions, synergistic or antagonistic amongst the bacterial and fungal communities, were also investigated, and Trichophyton was found to be strongly negatively correlated with the bacterial genera Corynebacterium and Anaerococcus and the fungal genera Alternaria, Cladosporium, Malassezia, Aspergillus and Trichoderma while positively correlated with Staphylococcus. A negative correlation between the counts of Staphylococcus was observed with Corynebacterium, Propioniferax and Anaerococcus.
The microbiome in tinea pedis was analysed in two different studies by Liu et al. and Wang et al.[15],[16] Both studies showed that there were significant differences in the microbiome of the toe webs between healthy participants and cases of tinea pedis with greater bacterial or fungal diversity in the former group. Interestingly, Liu et al.[15] also found the fungal composition in cases with recurrent tinea pedis currently in remission to be different from that of the healthy controls. Interrelationship amongst the fungal and bacterial components were also studied by both researchers. While Liu et al.[15] reported T. rubrum to be positively correlated to Corynebacterium minutissimum and negatively correlated to C. tuberculostearicum, S. pettenkoferi and Paracoccus sphaerophysae, Wang et al.[16] reported that Streptococcus showed strong positive correlation with Trichophyton but negative correlation with Aspergillus, Rhizopus, Alternaria and Malassezia.
These studies suffered from the limitation of having small number of cases in individual groups, thus lacking the statistical power for deriving valid conclusions. All were cross-sectional in nature. Lack of follow-up and longitudinal data for pre- and post-treatment phases precluded any interpretation regarding the cause/effect relationship of the observed dysbiosis with the disease. No studies involving other common forms of dermatophytoses like tinea corporis, tinea cruris and tinea faciei were found.
Discussion The available studies regarding the altered cutaneous microbiome associated with the dermatophytic infections provide us a very preliminary insight into a co-existing dysbiosis but are inadequate to clarify if the alteration is due to the infection or is a primary defect contributing to invasion by dermatophytes and their inadequate clearance by the immune system. Interestingly, all these studies have been performed over a limited geographical area in China. Whether these findings can be extrapolated to other regions or ethnicities is not known. The effect of ethnicity on the microbial composition has indeed been documented.[17] The various ethnic groups like the Chinese, the African Americans, the African continental group, the East Asians, the Hispanics and the Caucasians appear to differ from each other in their microbiome composition.[18],[19],[20]
Our knowledge regarding the cutaneous microbiome and its crosstalk within its various microbial components as well as with the human immune system is very recent and still grossly incomplete. Preliminary studies regarding its role in various inflammatory skin diseases suggest that the effects of the microbiome in shaping our immune response are far more complex and more far-reaching than previously understood.[21],[22],[23]
In the perspective of the recent spate of chronic, recurrent, clinically bizarre and difficult-to-treat dermatophytic infections all over the world, which has been difficult to attribute to a single host or pathogen factor alone, the concept of cutaneous dysbiosis as a contributory factor appears attractive. The link between the two is almost unexplored but it is theoretically plausible that an underlying cutaneous dysbiosis may play a role of some magnitude towards the pathogenesis of these dermatophytoses. The replacement of Trichophyton rubrum by Trichophyton mentagrophytes (more specifically Trichophyton indotineae) as the predominant pathogenic species[24],[25] might explain a lot, but not all of the changes that we have witnessed. This change in the pattern of predominant species has happened quite rapidly over a short period of just a decade. Age, gender and environmental factors are known to affect the composition of the microbiome.[26],[27] Whether a change or dysbiosis in the microbiome over the last decade in response to changing lifestyle and environmental conditions may have facilitated this species shift of the pathogenic dermatophytes is an unanswered question.
This is a very important question to answer, indeed, if we consider the fact that a new pathogenic fungal species not only arose in a particular country within such a short span of time, but became the predominant pathogen causing dermatophytosis. This gains more significance as T. indotineae has rapidly become ubiquitous across the globe.[24],[25] As of now, this phenomenon, which is almost unprecedented in the history of medical mycology, has defied any straitlaced explanation. The emergence of the pathogen has been linked with the abuse of topical steroid-containing fixed-dose combination creams and erratic treatment with antifungal agents that are so very prevalent in India. However, other than the observation that the emergence followed the flooding of the Indian market by irrational superpotent clobetasol propionate-containing fixed drug topical combinations (previously moderately potent betamethasone was the favoured agent, that had gone out favour after being brought under price control), there is nothing to pin the blame on topical steroids alone. In any case, topical steroid abuse in India has a long history and conjectures, however, well-intentioned, do not constitute evidence.
On the other hand, there is documentary evidence that pharmacologic use in patients is dwarfed by veterinary, agricultural and horticultural usage of antibiotics and antifungals that interfere with the normal human microbiota and lead to resistance to commonly used anti-infectives. In a landmark review on antimicrobial resistance, undertaken to tackle drug-resistant infections globally, an independent Commission set up by the UK Government and the Wellcome Trust, it was documented that, inter alia, 50% of the total acreage of European cereal and grapevine production is treated at least once a year and every tulip bulb is dipped in azoles.[28] The omnipresent food preservatives consist of thiabendazole, imazalil, etc. The global health impact of all these economic activities is incalculable, and the effect of these on the human microbiome may be considerable. Our interest in the interactions of the human microbiome and that of cutaneous dysbiosis in the as-yet incompletely explained growth of a recalcitrant dermatophytic species is, thus, not difficult to fathom.
The immense rise in cases of tinea corporis, cruris and faciei and its extension into the scalp in adults without a similar increase in the incidence of truly isolated tinea capitis, tinea pedis or onychomycosis is also puzzling.[29] Surprisingly there are no studies regarding any dysbiosis associated with these common forms of dermatophytoses. It is a matter of conjecture if the topological variation in the microbiome plays a role in rendering certain sites less favourable to invasion by the newer species of Trichophyton as it is already known that the constitution of the microbiome varies with cutaneous sites.[30]
Ethnic and geographic variations in the microbiome have been documented.[18],[19],[20] However, the possibility that the microbiome composition may show individual variation is an interesting proposition and is theoretically plausible. The colonising microbes are initially acquired during delivery and early postnatal phase from the maternal skin due to transmission of the organisms between mother and child. Subsequent contact with the environment increases the diversity of colonising species.[26] Amongst individuals living together, similar groups of organisms have been isolated, giving rise to a concept of shared microbiota.[31],[32] Also, genetic influence on the bacterial composition of the axillary microbiome has been reported and the genetic makeup of an individual may determine his/her microbial signature.[17] Thus, the microbiome may show individual variations or variations between different families or closely related groups. This might contribute to the observed clustering of dermatophytosis in certain families and its persistence in certain individuals with high chronicity and recurrence in spite of seemingly adequate therapy.
All these are interesting hypotheses which might fill in the gaps in the jigsaw of the current epidemic of dermatophytosis. Our current state of knowledge does not permit us to say if there is more to these than mere conjecture. Neither do we know if it is possible to define a healthy microbiome nor is it more of a utopian concept.[33] However, the seemingly multifarious impact of the microbiome or its changes has the potential to open up new vistas for therapeutic interventions. Manipulating the microbiome by ‘transplantation’ of beneficial microorganisms to enhance its protective function or use of microbe-derived products as specific anti-infective agents are already under evaluation for other infective and non-infective diseases[22],[34],[35],[36],[37] and may in future form part of our preventive and therapeutic armamentarium against dermatophytes.
Conclusion The concept of the cutaneous microbiome as part of the human host and its interplay with the host immune system and other pathogenic organisms is relatively recent and has become a field of active research. Research attempting to explore the relationship between dermatophytosis and dysbiosis of the microbiome is still at a very nascent stage. The existing studies have used sequencing techniques to isolate the microorganisms in cases and controls as single-point cross-sectional studies and have merely succeeded in demonstrating alterations of the commensal microorganisms or ‘dysbiosis’ in a small number of cases of tinea capitis, pedis and onychomycosis. If any of these differences in the microbial composition is epidemiologically or clinically significant at all is difficult to ascertain in the absence of follow-up sampling. Further, longitudinal studies are the need of the hour if the true cause-and-effect relationship of these dysbiotic changes and associated dermatophytosis has to be assessed. Large-scale studies from different geographic regions are also essential in the backdrop of the global nature of the dermatophytosis pandemic. The findings from the existing studies cannot be generalised as they are limited to a small geographic area. Keeping in mind the relative increase in the incidence of tinea corporis, cruris and faciei, it would be pertinent to study these forms of dermatophytoses. The importance of a proper understanding of the microbiome and its interaction with the invading dermatophytes cannot be overemphasised as it holds the promise to open up a completely new field of therapeutic and preventive interventions. Together with the upcoming field of skin metabolomics, it may lead to a more holistic understanding of the dynamic and functional aspect of the human skin and its role in shaping the body immunity and its response to both infective and non-infective diseases.
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Conflicts of interest
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References 
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