Vitiligo: are microbes to blame?

Abstract

Vitiligo is a prevalent acquired depigmenting disease that is distinguished by the depletion of functional melanocytes and epidermal melanin. Despite significant advancements in comprehending vitiligo, the precise etiology and pathogenesis of the condition remain elusive. So far, the treatment of vitiligo is still one of the most difficult dermatological challenges. Thus, developing a better understanding of vitiligo pathogenesis to develop more effective treatments is very important. Vitiligo has long been acknowledged as an autoimmune disorder, and microbes serve as crucial regulators of the immune system, exerting influences on diverse autoimmune diseases. Numerous studies have revealed the involvement of microorganisms, including bacteria and viruses, in the progression of vitiligo. This review provides a concise overview of the correlation between microbes and vitiligo, while also elucidating the potential mechanisms by which microbes may influence the development of vitiligo. The ultimate objective is to offer a comprehensive understanding of the prospects for vitiligo treatment.

INTRODUCTION

Vitiligo, the most common depigmenting skin disorder, is characterized by selective melanocyte destruction and white spot formation [1]. The estimated prevalence of vitiligo is 0.5–2% of the world’s population, with no significant difference in age, gender, ethnicity, or geographic region [2]. Vitiligo brings a considerable burden on the patient’s daily life by negatively affecting them physically and psychologically [3]. As vitiligo is a complex disease, considerable mechanisms have been proposed in our understanding of the pathogenesis of melanocyte destruction in vitiligo. These mechanisms include genetic factors, autoimmune responses, oxidative stress (OS), generation of inflammatory mediators, and other mechanisms (Fig. 1) [4, 5], but the overall contribution of each of these processes is still controversial. Considerable recent progress has classified vitiligo as an autoimmune disease, and an autoimmune attack on melanocytes is considered to be a major factor leading to skin discoloration, so existing treatment strategies mainly focus on improving excessive immune activity [6]. However, vitiligo is a multifactorial disorder, and the exact cause of the disease remains an enigma, as the mechanisms underlying melanocyte disappearance are still unknown.

Fig. 1.

Pathogenesis of melanocyte destruction and current treatments for vitiligo.

So far, the treatment of vitiligo is still one of the most difficult dermatological challenges, and available treatments for vitiligo are limited. These treatments include topical and systemic immunosuppressants, phototherapy, surgical techniques, and other treatments (Fig. 1) [7]. Oral steroid therapies like oral steroid minipulse therapy are one of the effective methods for vitiligo treatment. However, the potential side-effects related to long-term use of corticosteroids limit their widespread use. Besides, the current data do not provide enough evidence to recommend other immunosuppressants like cyclophosphamide and ciclosporin in vitiligo patients. Topical corticosteroids (TCS) and topical calcineurin inhibitors (TCIs) are now widely used as first-line treatments for limited forms of vitiligo but are not safe treatment options. Furthermore, phototherapies are widespread and highly effective treatments in vitiligo. They include psoralen plus ultraviolet A radiation (PUVA), narrowband ultraviolet B radiation (NB-UVB), and 308-nm excimer laser therapies. However, the long-term risk of skin cancer is well established for PUVA, and other phototherapies are also associated with dose-dependent erythema. In addition, for patients with segmental vitiligo (SV) and other localized forms of vitiligo, surgical techniques can be reserved after the failure of medical intervention. Nevertheless, surgery is only suitable for some patients with vitiligo and does not change the overall prognosis in nonsegmental vitiligo (NSV) cases. Furthermore, other therapeutic approaches, including traditional Chinese medicine, vitamin D, camouflage, depigmentation, psychological interventions, and antioxidants like vitamin E and pseudocatalase, have been used clinically. However, vitiligo has a long treatment cycle, and all current treatments provide only short-term benefits, with disease relapse common after discontinuing treatments. In recent years, targeted drugs for immune-related pathways have been actively developed, such as the phosphodiesterase-4 inhibitor apremilast and the JAK inhibitors ruxolitinib and tofacitinib, and some of them have been used in the targeted treatment of vitiligo. On the other hand, some are now being tested in clinical trials, and their safety and reliability need to be further studied [8, 9]. Thus, developing a better understanding of disease pathogenesis to develop more effective treatments would have an enormous impact on those who suffer from vitiligo.

As host immune responses play a critical role in the pathogenesis of autoimmune diseases, environmental factors with the ability to influence host immune responses appear to be intriguing candidates to study [10, 11]. For years, the microbiome has played a pivotal role as a potential environmental factor influencing immune responses [11]. The human microbiota is mainly composed of bacteria and viruses, while archaea, fungi, and other eukaryotes represent a minor proportion [12]. It has been reported that the microbiota is an important regulator of the immune system, and vice versa, the immune system can also influence the composition of the microbial community, which is referred to as dysbiosis or disruption of the microbial balance [13, 14]. Multiple lines of evidence suggest that the microbiome can shape adaptive immune responses and autoimmunity [15]. Besides, disruption of microbiome function or composition can result in immune dysregulation and subsequent immune-mediated diseases such as autoimmunity [16]. Also, microbial infection has been identified as an underlying trigger for developing autoimmunity [17]. In terms of skin diseases, it has been reported that disruption of the balance of microbial organisms can lead to skin disorders or infections [18]. Many studies have described an association between an altered skin and/or gut microbial community and the epidemiology of autoimmune dermatoses like atopic dermatitis (AD) and psoriasis [19,20,21]. In recent years, increasing studies have begun to investigate the relationship between the microbiome and vitiligo [22, 23]. In addition, viruses, important environmental factors, have also been determined to play profound roles in the pathogenesis of many autoimmune diseases, such as type 1 diabetes and rheumatic arthritis (RA) [24]. Meanwhile, numerous studies have demonstrated a link between vitiligo and the above autoimmune diseases [25]. The risk of development of vitiligo is also greater when either patients or their family members have any of several autoimmune diseases, such as type 1 diabetes mellitus, autoimmune thyroiditis, systemic lupus erythematosus (SLE), RA, inflammatory bowel disease (IBD), and alopecia areata (AA) [26]. Taken together, this evidence suggests that microbes may contribute to the pathogenesis of vitiligo.

In this review, we summarized the reports of microorganisms in vitiligo and discussed the potential mechanism of action, which might offer new insights into the role of the skin microbiota in vitiligo, providing an opportunity to develop better treatments (Fig. 2).

Fig. 2.

Microbiome associated with vitiligo and the potential mechanism of the microbiome in vitiligo.

The microbiome includes the skin microbiome, gut microbiome, Helicobacter pylori (H. pylori), hepatitis C virus (HCV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), and other viruses. IL, interleukin; OS, oxidative stress; IFN-γ, interferon-γ; TNF-α, tumor necrosis factor alpha; Th17, type 17 T helper; CXCL, chemokine (C-X-C motif) ligand.

SKIN MICROBIOME

The skin is an ecosystem that supports a wide range of microorganisms and harbors the second most abundant microbiome and is colonized by a diverse collection of microorganisms, including bacteria, fungi, and viruses [27]. Cutaneous microbiome researchers have identified that Firmicutes, Actinobacteria, Bacteroidetes, and Proteobacteria are the major commensal phyla [28]. At the genus level, the cutaneous microbiota is mainly formed by Staphylococcus, Propionibacterium, Corynebacterium, and Streptococcus [29]. The skin microbiome plays a crucial role in ensuring normal skin and a normal immune system, and microorganism imbalances can lead to various skin conditions [30, 31]. Some studies have identified that various dermatological conditions like AD and psoriasis are associated with changes in the structure of the skin microbiome [32, 33]. In addition, it has been found that the skin microbiome potentially contributes to pigmentary disorders [34]. Nowadays, scientists and researchers have been investigating the relationship between localized alterations in vitiligo skin and cutaneous microbiota (Table 1) [35, 36].

Table 1. Evidence for and against the skin microbiome being associated with vitiligo.

Microbiome	Reference	Study sample	Conclusion
Skin microbiome	Ganju et al. [35]	10 vitiligo patients	The microbial community dynamics were different in the lesional and non-lesional sites of vitiligo subjects.
	Yuan et al. [36]	60 patients with vitiligo	There were differences in microbial community dynamics of the lesional and non-lesional sites of vitiligo subjects.
	Lu et al. [22]	20 participants with active vitiligo and 20 cases of stable vitiligo	There were differences in community composition in the lesional skin of active vitiligo.
	Bzioueche et al. [40]	10 vitiligo patients and 10 controls	The lesional skin was enriched in Proteobacteria, Streptococcus, and Mycoplasma.

The skin microbiome composition can be impacted by environmental factors such as ultraviolet (UV) light, which is associated with skin health [37]. UV light is more intense in summer, and it was observed that the incidence and annual prevalence of vitiligo peaked in summer [38, 39], which indirectly indicates that the skin microbiome might be involved in the development of vitiligo. Besides, Ganju et al. found that the microbial community dynamics were different in lesional and non-lesional sites of vitiligo subjects, with non-lesional areas showing greater diversity and higher correlation [35]. Notably, Corynebacterium (genus) and Corynebacteriaceae (family) were observed to have higher abundances in non-lesional samples, while Flavobacteriales (order), Gammaproteobacteria (class), and Flavobacteria (class) had significantly higher abundances in lesional samples, suggesting that these microbial changes could influence the development and severity of vitiligo. A similar result was discovered in another study, which also found that NB-UVB exposure, one of the most effective treatments for vitiligo, might eliminate these differences [36]. In addition, to explore whether dysbiosis is involved in the pathogenesis of vitiligo progression, one study further analyzed the bacterial population in the skin lesions of active and stable vitiligo [22]. That study discovered that there was no significant difference in the richness and uniformity of microbes in vitiligo lesions, but there were differences in community composition, with Streptomyces and Streptococcus significantly elevated in the lesional skin of active vitiligo. Another study also found that Proteobacteria, Streptococcus, and Mycoplasma were enriched in lesional skin [40]. Altogether, the above studies indicate that skin microflora disorder may be involved in the development of vitiligo and that maintaining the skin flora balance might be a potential therapeutic target for vitiligo.

Nowadays, data on the involvement of the skin microbiome in the pathogenesis of vitiligo remains sparse. We discuss the potential mechanisms through which the skin microbiome might participate in the disease of vitiligo. As an autoimmune disease, an important mechanism of vitiligo is the abnormal immune function [6]. The skin microbiome can be regulated by innate and adaptive immune responses, and the microbiome also functions in educating the immune system [28]. Cytokines have a vital role as mediators of the immune reaction, and it has been reported that interleukin-1 (IL-1), a pro-inflammatory cytokine, could inhibit melanogenesis and might be responsible for the progression of active vitiligo [41, 42]. The skin microbiome controls the expression level of IL-1, a cytokine involved in the initiation and amplification of immune responses, which in turn regulate the function of T cells [43]. Relevant studies have shown that the pathogenesis of vitiligo mainly involves T cells, such as helper T cells (Th) and regulatory T cells (Treg) [4]. The balance of T helper cell subsets and Treg is affected by specific microbial species [44]. Hence, we speculate that the skin microbiome might participate in the development of vitiligo by regulating the expression of IL-1. In addition, a large number of studies have shown that OS plays an important role in the occurrence and development of vitiligo [45]. High levels of OS markers such as reactive oxygen species (ROS) in the skin cause melanocyte destruction, leading to the depigmentation area characteristic of this disease [46]. The effect of environmental factors on the skin microbiome can be vital for maintaining the balance of skin OS levels [47]. A commonly proposed mechanism is the molecular damage derived from excessive ROS, resulting in perturbed epithelial homeostasis and altered biodiversity of the skin microbiome, with microbes in turn impacting ROS [48]. Thus, the skin microbiome might take part in the development of vitiligo by influencing the balance of the skin OS level through ROS accumulation. Further research is needed to elucidate the above hypothesis.

GUT MICROBIOME

The gut harbors the highest number of microbes [49]. The predominant bacterial phyla in the human gut microbiome are obligate anaerobes Bacteroidetes and Firmicutes, and facultative anaerobes, such as Actinobacteria, Proteobacteria, Verrucomicrobia, and Archaea, are present in lesser abundances [50]. Gut microbiome alterations are linked to the pathogenesis of allergic, cardiovascular, neurodevelopmental, IBD, multiple sclerosis (MS), RA, and other conditions [51]. Moreover, there is increasing evidence connecting the skin condition with the gastrointestinal microbiome, which has been described as the gut-skin axis [52]. Recent insights have defined the critical role of the gut microbiome in maintaining immune homeostasis and in the development of autoimmune diseases [53]. It has been reported that the gut microbiome could affect skin homeostasis through systemic immunity modulation [54]. Furthermore, gut dysbiosis could induce autoimmune skin diseases like psoriasis and AD [55]. Additionally, it has also been observed that vitiligo patients have a high rate of comorbidity with IBD [56], another autoimmune disease associated with an aberrant intestinal microbiome [57]. In recent years, increasing studies have begun to explore the relationship between the gut microbiome and vitiligo (Table 2) [23, 58].

Table 2. Evidence for and against the gut microbiome being associated with vitiligo.

Microbiome	Reference	Study sample	Conclusion
Gut microbiome	Ni et al. [23]	30 vitiligo patients and 30 matched healthy controls	There was a characteristic lower Bacteroidetes: Firmicutes ratio in individuals with vitiligo compared with healthy controls.
	Dellacecca et al. [58]	10 mice untreated, 10 mice treated with ampicillin, 8 mice treated with neomycin	Ampicillin treatment was associated with accelerated depigmentation and reduced bacteria in fecal pellets.
	Luan et al. [59]	25 patients with non-segmental vitiligo and 25 matched healthy controls	Compared with healthy controls, the alpha diversity of intestinal microbiome in vitiligo patients was significantly reduced.
	Mao et al. [60]	Number of single-nucleotide polymorphisms (SNPs) = 16,380,442; ncase = 131; ncontrol = 207,482	There was an association between disease duration and Ruminococcus in vitiligo.
Helicobacter pylori(H. pylori)	Doğan et al. [68]	68 patients with vitiligo and 65 patients with telogen effluvium (TE)	The rates of H. pylori positivity, H. pylori CagA, and IgG in serum in the vitiligo group were significantly higher than in the TE group.
	Bakry et al. [69]	75 patients with non-segmental vitiligo and 75 healthy people as a control group	H. pylori infection was positive in 49 (65.3%) vitiligo cases compared with 18 (24%) in the control group (***p=0.001).
	Rifaioğlu et al. [70]	34 patients with vitiligo and 30 matched healthy controls	The frequency of H. pylori infection was higher in the patient with vitiligo than in the control (*p=0.012).

One case-control study, which consisted of 30 patients diagnosed with advanced non-segmental vitiligo and 30 healthy controls, revealed that there was a characteristic lower Bacteroidetes/Firmicutes ratio in individuals with vitiligo compared with healthy controls [23]. Meanwhile, the study also found that disease duration was notably negatively associated with Corynebacterium 1 and Psychrobacter but positively correlated with Ruminococcus 2. The administration of antibiotics has the potential to diminish the population of gut bacteria and enhance the excretion of bacterial constituents. Dellacecca et al. explored the changes in pigmentation of vitiligo mice after treatment with oral antibiotics [58]. Their study showed that ampicillin treatment was associated with accelerated depigmentation and reduced bacteria in fecal pellets, suggesting that there is a connection between gut dysbiosis and ampicillin-induced depigmentation. Moreover, metagenomic sequencing revealed that compared with healthy controls, the alpha diversity of the intestinal microbiome in vitiligo patients was significantly reduced [59]. At the species level, comparison of patients with vitiligo with healthy controls revealed that the relative abundance of Staphylococcus thermophiles was decreased and that that of Bacteroides fragilis was increased [59]. In addition, a Mendelian randomization study uncovered an association between disease duration and Ruminococcus in vitiligo [60]. In sum, these studies provide a clue indicating that gut microbiome dysbiosis might be involved in the pathogenesis of vitiligo.

It is well known that ROS formation is relevant to vitiligo [45]. According to several studies, the cross-talk between redox imbalance and gut dysbiosis may have critical effects on the gut-skin axis due to its essential interactions with OS [61]. Like the skin microbiome, one commonly proposed mechanism of the role of gut microbiome in vitiligo is the molecular damage derived from excessive ROS, resulting in perturbed epithelial homeostasis and altered biodiversity of the gut microbiome. Microbes in turn impact ROS [48]. In addition, another study showed that ampicillin treatment correlated with reduced bacteria in fecal pellets and that ampicillin can induce ROS formation in bacteria [58]. So, we suspected that gut dysbiosis takes part in the pathogenesis of vitiligo through the production of ROS. Furthermore, Ni et al. found that IL-1β, a relatively sensitive serological marker of vitiligo progression, was negatively correlated with gut microbes like Corynebacterium 1, Jeotgalibaca, and Psychrobacter [23]. Additionally, Mao et al. investigated the genes aligned with the instrumental variables of gut microbes, which showed a marked causal association with vitiligo [60]. They further identified significant enrichment in inflammatory signaling pathways through a KEGG pathway enrichment analysis, including the IL-17 signaling pathway, chemokine signaling pathway, and cytokine-cytokine receptor interaction. This indicates the potential mechanisms by which gut microbes might influence the progression of vitiligo through cytokines and chemokines [60]. However, the exact mechanism of the gut microbiome involved in the pathogenesis of vitiligo still needs further study.

HELICOBACTER PYLORI (H. pylori)

Helicobacter pylori is a Gram-negative bacterium that can naturally colonize the human gastric mucosa [62]. It is well known that H. pylori infection is closely associated with gastrointestinal diseases, including but not limited to, chronic gastritis, gastric ulcer, duodenal ulcer, and gastric cancer [63]. In recent years, the relationship between H. pylori infection and extragastric manifestations has attracted the attention of many researchers [64, 65]. It has been found that infection with H. pylori is closely related to the body’s immune reaction. There is growing evidence that infection with H. pylori is a significant factor that results in serious autoimmune diseases, such as IBD, autoimmune metabolic diseases, and autoimmune liver diseases [66]. Furthermore, it has been reported that H. pylori is associated with several dermatological diseases, including chronic spontaneous urticaria (CSU), psoriasis, AD, pityriasis versicolor (PV), and AA [67]. Recently, studies have shown that H. pylori infection might participate in the development of vitiligo (Table 2) [68, 69].

A prospective study that aimed to evaluate the relationship between H. pylori and vitiligo recruited 68 patients with vitiligo and 65 patients with telogen effluvium (TE) [68]. In that study, all participants were tested for H. pylori IgG and CagA, and the urea breath test (UBT) was utilized to detect the presence of H. pylori infection. The study found that the rates of H. pylori positivity, H. pylori CagA, and IgG in serum in the vitiligo group were significantly higher than in the TE group (*p<0.05). The study also discovered that the number of patients with dyspepsia was significantly higher in the vitiligo group than in the controls (*p<0.05). In addition, another study evaluated the relationship between active vitiligo and H. pylori infection [69]. It selected 75 patients with non-segmental vitiligo and 75 healthy people as a control group. The study found that H. pylori infection was positive in 49 (65.3%) vitiligo cases compared with 18 (24%) in the control group (***p=0.001). Similar results were obtained in another study, which found that the frequency of H. pylori infection was 64.7% in patients with vitiligo and 33.3% in controls according to the carbon 14 (C¹⁴) UBT (*p=0.012) [70]. In sum, H. pylori infection may play a role in the pathogenesis of vitiligo or act as a triggering factor, and future studies with larger patient groups are needed to understand the role of H. pylori in vitiligo as an etiological or initiating factor.

Until now, there has been no clear explanation of the potential pathogenic mechanisms of H. pylori on vitiligo. It has been suggested that the mechanism of the autoimmune pathogenesis of vitiligo was the destruction of functional melanocytes by autoimmune triggering factors, including cytotoxic T cells [71]. Cytokines have a crucial role in regulating immune responses [72]. A study by Gholijani et al. revealed that the production of inflammatory cytokines like IL-1, IL-6, interferon-γ (IFN-γ), and tumor necrosis factor (TNF) α was increased in patients with vitiligo [73]. Meanwhile, research has shown that the levels of cytokines such as IFN-γ, TNF-α, and IL-1 are high in the stomachs of H. pylori-positive patients [74]. Hence, we speculated that H. pylori infection might participate in the pathogenesis of vitiligo by increasing the production of inflammatory cytokines, which subsequently affect the skin microenvironment and result in the loss of functional melanocytes. However, this is just speculation, and more research is needed to explore the underlying mechanisms.

VIRUSES

Do viruses cause vitiligo? In fact, studies have linked vitiligo to viruses like hepatitis virus, cytomegalovirus (CMV), and human immunodeficiency virus (HIV) (Table 3) [75,76,77]. A vitiligo virus might kill melanocytes by attacking DNA, and viruses have been implicated as agents for vitiligo [78]. Copious studies have indicated that virus invasion participates in the pathogenesis of vitiligo [79,80,81,82].

Table 3. Evidence for and against viruses being associated with vitiligo.

Microbiome	Reference	Study Sample	Conclusion
Hepatitis C Virus (HCV)	Yamamoto and Nishioka [87]	5 cases of vitiligo	5 vitiligo patients with HCV seropositivity
	El-Serag et al. [85]	34,204 patients who were hospitalized with HCV (cases) and 136,816 randomly selected patients without HCV (controls) who were hospitalized during the time period.	HCV-infected patients had an approximate 2-fold increase in vitiligo as compared with controls.
	Podányi et al. [88]	1 vitiligo patient	A patient with vitiligo in the setting of HCV infection.
	Tsuboi et al. [75]	A 38-year-old man with vitiligo	Patient with active HCV infection.
	Ma et al. [79]	23,509 HCV-infected patients and 94,036 controls	Patients with HCV infection had a significantly increased risk of developing vitiligo in comparison with the control group.
	Fawzy et al. [89]	108 vitiligo patients	Adult-onset vitiligo was significantly associated with HCV-seroreactivity.
	Akbayir et al. [86]	20 patients (12 women and 8 men) with classical clinical and histologic features of vitiligo	The seroprevalence of HCV in vitiligo patients was not different from that of a control group.
	Arican et al. [95]	121 vitiligo patients (63 female and 58 male) and 114 ageand sex-matched control subjects	There was no direct association between HCV infection and vitiligo.
	Adiloglu et al. [96]	11 patients (six with bilateral and five with unilateral vitiligo)	There was no direct association between HCV infection and vitiligo.
Cytomegalovirus (CMV)	Grimes et al. [76]	29 patients with vitiligo and 22 control subjects	CMV DNA was identified in 38% of the patients studied, 21% had indeterminate results, whereas results were negative in all control subjects.
	Toker et al. [98]	20 vitiligo patients	Previous or concurrent CMV infections might trigger the pathogenetic mechanisms for vitiligo or induce the progression of the disease.
	Zhuang et al. [80]	56 progressive vitiligo patients and 26 healthy controls	The positive rate of anti-CMV IgM the anti-CMV IgM levels were significantly higher in vitiligo patients than that in healthy controls.
	Akar et al. [99]	34 patients with vitiligo, 15 healthy subjects and 15 patients with other dermatoses	CMV DNA sequences were not detected in the specimens of any patients with vitiligo or in the control subjects.
	Pichler et al. [105]	40 Austrian vitiligo patients	CMV DNA and CMV IgM antibodies could not be detected in the vitiligo patients.
Human immunodeficiency virus (HIV)	Duvic et al. [110]	1,000 patients with AIDS-related complex (ARC) or AIDS	Five patients with HIV positive over a short period of time developed vitiligo.
	Antony et al. [77]	A 60-year-old male with vitiligo in association with HIV	Repigmentation occurred following initiation with highly active antiretroviral therapy (HAART).
	Trope et al. [111]	1 vitiligo patient	Vitiligo immediately resulted in partial improvement after introduction of antiretroviral therapy.
	Tojo et al. [81]	A 56-year-old man with vitiligo	Vitiligo in association with HIV-infected.
	Xuan et al. [82]	A 26-year-old male with vitiligo	Vitiligo in association with HIV-infected.
Varicella-zoster virus (VZV)	Lewis et al. [113]	A case of vitiligo	A good melanin regeneration following anti-VZV treatments with valacyclovir.
	Gauthier et al. [114]	40 patients with Segmental vitiligo (SV), Control samples were obtained from three herpes zoster (HZ), and 10 generalized vitiligo lesions	A positive detection of VZV antigen was statistically correlated with the epidermis with recent SV and in the dermis with long-lasting SV.
Endogenous virus (EV)	Sreekumar et al. [116]	101 Smyth line (SL) chicken and 101 control (BL) chickens	The EV genes are associated in the induction of autoimmune vitiligo.
Herpes simplex types 1 and 2 (HSV-1/2)	Ribeiro et al. [117]	51 patients with vitiligo and 51 age- and gender-matched controls	Compared with controls, anti-herpes simplex types 1 and 2 (HSV-1/2) IgG was significantly more frequent in vitiligo patients.

Hepatitis C virus

Hepatitis C virus (HCV), a hepatotropic and lymphotropic virus, mainly infects hepatocytes [83]. Along with hepatic diseases, skin is one of the most commonly affected organ systems in HCV-infected patients [84]. HCV infection is related to skin diseases such as psoriasis, porphyria cutanea tarda, and lichen planus [84]. Recently, HCV infection has been found to be associated with vitiligo [75]. However, the possibility of correlation between HCV and vitiligo is still controversial [85,86,87].

Yamamoto and Nishioka described 5 vitiligo patients with HCV seropositivity [87]. Podányi et al. presented a vitiligo patient with HCV infection [88]. Tsuboi et al. reported a case of vitiligo with inflammatory raised borders in a patient with active HCV infection [75]. Moreover, Ma et al. found that HCV-infected patients had a significantly increased risk of developing vitiligo (aHR=6.45) compared with their control group [79], and a similar result was observed by another study [85]. Furthermore, adult-onset vitiligo was significantly associated with HCV seroreactivity, suggesting HCV may be the triggering factor for vitiligo [89].

The mechanism by which vitiligo development is associated with HCV remains unclear. A previous review reported that HCV-induced ROS production was considered to be a major factor contributing to HCV-associated pathogenesis [90]. Thus, we speculate that HCV may participate in the pathogenesis of vitiligo in a ROS-dependent manner. HCV infection enhanced the type 17 T helper (Th17) cell commitment, which could affect the pathogenesis of autoimmune diseases [91, 92]. Wang et al. found that Th17 cells were increased in leading edge vitiligo biopsies [93]. Meanwhile, in patients with non-segmental vitiligo, the body surface area of lesions is positively correlated with elevated Th17 cell frequencies [94]. These findings indicate that HCV participation in the development of vitiligo might be by inducing Th17 cells.

Contrary to the above results, one report indicated that there was no difference in the seroprevalence of HCV in vitiligo patients and a control group in Turkey, indicating that HCV infection may not be involved in the pathogenesis of vitiligo [86], and similar results were reported by Arican et al. [95] and Adiloglu et al. [96]. In sum, the possible effect of HCV on vitiligo needs to be clarified by further studies.

Cytomegalovirus

Cytomegalovirus (CMV) infection and vitiligo have many common features, including their association with autoimmune diseases like RA and MS [26, 97], which supports the potential contribution of CMV in vitiligo. The role of CMV in vitiligo is controversial, and there are not many studies available in the literature with opposite results [98, 99].

One study reported that CMV DNA was identified in 38% of the patients studied, whereas the results were negative in all controls [76]. CMV infections might trigger the pathogenetic mechanisms for vitiligo or induce the progression of the disease [98]. Furthermore, other research revealed that both the positive rate and the levels of anti-CMV IgM were significantly higher in vitiligo patients than in controls [80]. The vitiligo area scoring index (VASI) is widely used to assess the extent of skin depigmentation seen in vitiligo patients [100]. Of note, the VASI scores were higher in vitiligo patients positive for anti-CMV IgM than those who were negative for anti-CMV IgM [80]. Hence, we speculate that vitiligo may be triggered by CMV infection.

Vitiligo and CMV infection are both associated with immunologic abnormalities [6, 101]. CMV infection could potentially mediate the destruction of melanocytes in vitiligo by inducing aberrant humoral and cell-mediated immunologic responses [76]. Furthermore, excessive CXCL10 (chemokine (C-X-C motif) ligand 10) and CXCL16 in the epidermis has been established to play key roles in the skin trafficking of autoreactive melanocyte-specific CD8⁺ T cells, which has been recognized as the main cause of melanocyte death in vitiligo [102, 103]. Interferon-induced helicase C domain 1 (IFIH1) encodes melanoma differentiation-associated 5 protein (MDA5), which can sense the invasion of viruses, and has been identified as a susceptible gene for vitiligo [104]. The expression of MDA5 is higher in some progressive vitiligo patients, and CMV invasion significantly activated MDA5 and further potentiated the keratinocyte-derived CXCL10 and CXCL16 [80]. These data indicated that virus infection is correlated with vitiligo and that the MDA5 pathway might play a key role via promotion of the secretion of CXCL10 and CXCL16.

Contrary to the above research, one study reported that CMV DNA sequences were not detected in vitiligo patients, and a similar result was discovered in another study, suggesting that the CMV is unlikely to participate in the pathogenesis of vitiligo [99, 105]. Taken together, the role of CMV in the vitiligo still needs to be clarified.

Human immunodeficiency virus

Human immunodeficiency virus (HIV) belongs to a family of RNA viruses called retroviruses and can result in the acquisition of immune deficiency syndrome (AIDS) [106]. Actually, the skin is commonly affected in the course of HIV infection [107]. HIV infection was associated with skin disorders such as opportunistic infections, psoriasis, and seborrheic dermatitis [108, 109]. Recently, research has discovered that HIV infection is associated with the disease of vitiligo [110, 111].

In 1987, Duvic et al. first reported the association of vitiligo with HIV [110]. In their study, 5 HIV-positive patients developed vitiligo over a short period of time. Antony and Marsden also reported a case of vitiligo in association with HIV, in which repigmentation occurred following initiation with highly active antiretroviral therapy (HAART) [77]. Similarly, a patient with extensive vitiligo showed partial improvement after antiretroviral therapy [111]. Furthermore, several studies have also reported cases of vitiligo in association with HIV infection [81, 82]. Overall, if the reported associations are more than coincidence, HIV may indeed serve as a trigger factor for vitiligo.

The theories for the pathogenesis of vitiligo in HIV patients are as follows [112]: First, HIV could directly infect melanocytes. Second, polyclonal B cell activation could occur, leading to the production of autoantibodies against melanocytes. Third, the production of gamma interferon might result in cellular cytotoxicity against melanocytes. Fourth, human T cell leukemia virus infection might alter the equilibrium among helper, suppressor, and cytotoxic cells. Fifth, pathogenesis could involve combinations of any of the aforementioned factors. However, the above theories are just speculation, and further studies are needed to clarify the pathogenesis of HIV in vitiligo.

Other viruses

Lewis et al. found that a case of SV showed good melanin regeneration following anti-Varicella-zoster virus (VZV) treatments with valacyclovir [113]. Furthermore, positive detection of VZV antigen was statistically correlated with the epidermis with recent SV and in the dermis with long-lasting SV [114]. Endogenous virus (EV) genes, related to some autoimmune diseases [115], have been reported to be associated with the induction of vitiligo in the Smyth line (SL) chicken model [116]. Ribeiro et al. found that compared with controls, anti-herpes simplex type 1 and 2 (HSV-1/2) IgG was observed significantly more frequently in vitiligo patients [117]. In sum, exposure to the above pathogens may be a risk factor for the development of vitiligo.

CONCLUSION AND PROSPECTS

Vitiligo is a common multifactorial skin disorder triggered by a variety of factors, including emotional stress, physical trauma, and chemical exposure to imbalances in endogenous neural factors, metabolites, cytokines, or hormones [118]. Although considerable progress has recently been made in our understanding of vitiligo, the cause and pathogenesis of vitiligo remain unclear. The treatment of vitiligo is still one of the most challenging issues in dermatology, highlighting the need for improved treatment options. Nowadays, researchers are actively exploring the relationships between microbiome changes and the development of vitiligo, aiming to identify potential therapeutic targets.

Pathogen infections have been associated with autoimmunity. Increasing evidence indicates that the microbiome (i.e., bacteria, viruses, etc.) participates in the development of autoimmune dermatosis [119]. For example, Zhu et al. demonstrated that gut microbiota facilitated chronic spontaneous urticaria [120]. Furthermore, numerous studies have shown that patients with psoriasis have obvious skin and gut dysbiosis [21]. In addition, many studies suggest that a variety of microorganisms, including fungal pathogens, HIV, HCV infection, and human papillomavirus, play a pivotal role in the induction and exacerbation of psoriasis [121]. Likewise, Lu et al. discovered that compared with healthy controls, patients with AA had significantly different intestinal microbial communities [122].

In our review, we speculate that the microbiome may be involved in the occurrence and development of vitiligo. In conclusion, most studies support that the skin microbiome, gut microbiome, H. pylori, and HIV are possibly correlated with vitiligo, while the findings regarding the correlations of HCV and CMV with the occurrence of vitiligo are relatively contradictory. In sum, the association between pathogen infections and vitiligo still remains elusive, and further studies are needed to verify any association.

Probiotics are reported to have a favorable effect on the skin microbiome, which can reduce inflammation and enhance the overall health of the skin barrier by creating a balance in the microbiome on the skin [123]. Nowadays, probiotic bacteria have been used to create a variety of treatments. The potential of oral probiotics as a treatment for skin diseases has increased. Some studies have revealed the efficacy of probiotics in the management of some skin conditions, like psoriasis, acne, and AD [55]. Xie et al. reported a case of AA that demonstrated the success of fecal microbial transplantation (FMT) [124]. In addition, Touni et al. found that oral neomycin administration impacted the gut microbiome, that it delayed the development of vitiligo in mice, and that topical antibiotics might likewise allow the microbiome to preserve skin health and delay depigmentation [125]. Furthermore, Antony et al. discovered that repigmentation occurred in a vitiligo patient following initiation with HAART [77]. Similar results were reported by Trope et al. and Lewis et al. [111, 113].

According to the above studies, the microbiome has a significant impact on the maintenance of skin health. The use of microbiome-targeted treatments may be a useful strategy for maintaining the overall skin health and managing various skin disorders. With in-depth research on microbes involved in vitiligo, modifying the microbiome composition using agents like probiotics or other similar agents may be an effective alternative for the treatment of vitiligo in the future. This could minimize the adverse effects associated with traditional therapies and enhance medication effectiveness, which in turn would reduce symptoms and improve the quality of life for vitiligo patients. We believe that this will provide a breakthrough for new therapeutic interventions for the chronic autoimmune disease vitiligo.

CONFLICT OF INTEREST

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.