Introduction

The incidence of psoriatic arthritis, a chronic inflammatory joint disease associated with the chronic inflammatory skin disease psoriasis, is still increasing [1]. Psoriatic arthritis can develop before psoriasis, but in most cases psoriasis precedes psoriatic arthritis. In a large cross-sectional observational study, one-third of patients with psoriasis were diagnosed with psoriatic arthritis after 30 years of psoriasis [2]. Although the complex etiology is still not fully investigated, genetic, immunological, and environmental factors all seem to contribute to the development of psoriatic arthritis [3]. Similar etiology is observed in other immune-mediated inflammatory diseases, including inflammatory bowel disease (IBD) [4]. One of the factors involved in the genesis and regulation of the pathogenic inflammation is the composition of the human intestinal microorganisms colonizing different anatomical locations within the human body (so-called microbiome). The notion that the human microbiome has a profound effect on immune-mediated diseases has become increasingly accepted in recent years. Although the skin, oral cavity, upper respiratory tract, and female genital tract are all colonized with microorganisms, the human gastrointestinal (GI) tract contains by far the most densely populated ecosystem, consisting of bacteria, archea, and eukaryotic microorganisms. The composition of the microbiome is specific to each individual. Without environmental factors, this composition would remain relatively stable during life. Change of composition is seen with aging [5], but aging is often concurrent with other factors, including drug use, comorbidity, and malnutrition, which taken together might possibly explain this observation. Other environmental factors, for example diet, infections, stress, disease, and drug use (e.g. antibiotics) can distort the composition of the microbiome [6–9]. The magnitude of the effect of the microbiome on the human entity is not yet fully investigated. The intestinal microbiome is able to modulate both the mucosal and the systemic immune system, exerting extra-intestinal effects at distant human body sites [10]. Thereby the intestinal microbiome may be involved in the development of immune-mediated inflammatory diseases, including psoriatic arthritis. Scarce evidence from research is available about the relationship between the microbiome and psoriatic arthritis. In this review we try to emphasize this possible connection, by examining the data from existing literature and through linking psoriatic arthritis with other immune-mediated inflammatory diseases. This connection may lead to new therapeutic approaches for treating psoriatic arthritis by modulation of the microbiome.

The Human Microbiome

The intestine of a healthy adult harbors ~1014 non-eukaryotic cells, of which bacteria are by far the most abundant and well-studied microorganisms. It is believed that the bacterial intestinal community structure consists of a relatively limited number of dominating phyla, which include Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Verrucomicrobia, and Fusobacteria. At the genus level, Bacteroides species outcompete other microbes, being the most abundant colonizers of the human gut, followed by species of the genera Faecalibacterium, Bifidobacterium, Lachnospiraceae, Roseburia, and Alistipes [11]. Many recent association and case-control studies have linked the GI tract microbiome with diseases and traits including inflammatory bowel disease (IBD), allergic diseases, rheumatoid arthritis, type I diabetes, and encephalomyelitis [12–15]. It has been established that L-carnitine from red meat is converted into substrates that are indicated to promote atherosclerosis by the intestinal microbiota in mice [16]. Furthermore, increased serum levels caused by the intestinal microbial metabolism of the choline moiety are associated with an increased risk of incident major adverse cardiovascular events [17]. Another important recent finding regarding the GI tract bacterial community is that individuals with a low GI-tract bacterial richness have an inflammatory phenotype when compared with high-bacterial-richness individuals. Furthermore, only a few bacterial species are needed to distinguish between individuals with high and low bacterial richness and to indicate the inflammatory phenotype [18]. Although the joint was previously regarded as a sterile environment, bacterial components have been found to be present in the joints of patients with rheumatoid arthritis [19]. These bacterial components may have reached the joints through the circulation or via the intestinal lymphoid system [20]. This suggests that a dysbiosis in the intestine can manifest in the joint via migration from the circulation. However, unlike the skin and intestine, where pathogens and commensals live together in symbiosis, the joint does not contain its “own” microbiome.

The Human Mycobiome

The human fungal and yeast microbial community (mycobiome) has been recently appreciated as complex and as important for health. Although some fungi are associated with the human skin, most interactions of the human host with yeast and fungi take place in the intestine. Recent studies identified hundreds of different types of fungi in oral and colonic microbiota [21, 22]. Most fungi are resident in skin, genital, and gastrointestinal mucosa without causing disease. Although the commensal Candida can become pathogenic, this typically happens in immune-suppressed individuals. Defects in the immune system, genetic predisposition, breached mucosal barrier, and microbial dysbiosis can all contribute to C. albicans infection and invasion. Upon a defect in the fungal recognition, specific pathogenic species can gain access to the host tissues and increase the severity of the inflammation [21]. We currently do not know if the non-pathogenic fungi can also increase the severity of the inflammation, or if this is a trait specific to the pathogenic Candida-like population.

Skin, epithelial, and mucosal surfaces prevent fungi from invading the deeper tissue through the expression of anti-microbial peptides, the action of the complement system, and phagocytosis assisted by the production of secretory antibodies that target fungi. Inflammatory reaction to fungi drives the adaptive immune responses. Of particular importance for the anti-fungal adaptive responses is the generation of Th17 cells [23]. IL-17 and IL-17RA signaling have been revealed to be essential for controlling Candida overgrowth and invasion [24]. Inborn IL-17/R defects are strongly correlated with the severe form of IBD, and genetic mutations in genes coding for IL-17RA and IL-17 F lead to chronic mucocutaneous candidiasis, characterized by recurrent or persistent infection of the skin, nails, and oral and genital mucosa caused by C. albicans [24]. This suggests that host immune responses to Candida and other members of the mycobiome are important for preventing invasive disease and for control of the commensal growth at mucosal surfaces. Intestinal diseases, including IBD, are likely to compromise the host’s ability to control the intestinal mycobiome, leading to a shift in the mycobiome composition. This could be of great importance for patients suffering from IBD or from related inflammatory diseases, including psoriasis and SpA, and for patients with a particular genetic background.

Interplay Between the GI Tract Microbiome and the Mycobiome

Components of the commensal microbiome are probably involved in controlling fungal growth. Studies in mice have revealed increased Candida colonization in the stomachs of antibiotic-treated mice [25, 26], and germ-free mice are highly susceptible to Candida infection [27]. Similarly, prolonged antibiotic treatment can predispose humans to fungal infection [23]. These results indicate the utmost importance of the bacterial community acting as a barrier against the outgrowth of fungal pathogens.

Commensal fungi can also protect the host from bacterial pathogens. For instance, strains of S. cerevisiae boulardii have been successfully used for treating Clostridium difficile-induced diarrhea [28, 29] and for Salmonella-induced gastroenteritis [30]. The mechanism of protection seems to be a combination of direct competition with intestinal pathogens, interaction with the host immune system, and interaction with the intestinal epithelium [30, 31]. These studies underline the fact that fungi and bacteria have often been seen as pathogens and their function as commensals and protection for the host has been underappreciated.

The Microbiome in Auto-Immunity

The intestinal microbiome has an important function in the development of a healthy immune system [32]. In a healthy individual the host and microbes interact in a harmonious way. Auto-immunity is a complex process, in which misdirected immune responses can cause inflammatory disease. It is not clear what initiates this process, although it is assumed that microbial and environmental factors can cause auto-immunity in individuals with an underlying genetic susceptibility [33]. It is known that the presence of one auto-immune disease in a patient increases the risk of developing another auto-immune disease for the same patient, and for their family. An overlap between different auto-immune diseases clearly exists, an example of which is the prevalent co-existence of psoriasis and psoriatic arthritis, of which the causal mechanism is unknown. This also explains the overlap between SpA and IBD, which share genetic and environmental factors [20]. The intestinal microbiome could be a crucial factor explaining this observation, because disturbance of the microbiome, also known as dysbiosis, can affect the immune homeostasis and thereby cause inflammation and autoimmune disease [34]. A reduced abundance of commensal bacteria, for example lactobacilli, bifidobacteria, and Faecalibacterium prausnitzii, and/or increased abundance of such pathogens as Escherichia coli, Salmonella, and Helicobacter might contribute to this dysbiosis (Fig. 1). Consequently, inflammatory immune-mediated disorders might develop. The cause of immune-mediated inflammatory disease may thus be the gut, acting at local and at distant sites.

Fig. 1
figure 1

Gut dysbiosis may contribute to psoriatic arthritis by overgrowth of inflammatory strains of bacteria and yeasts, by reduction of tolerogenic strains including F. prausnitzii, or by a combination of both

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The Interaction Between the Microbiome and the T Cell Population

The immune system is able to affect the composition of the microbiome, and the microbiome can modulate the immune system [35]. In the synovial membrane, synovial blood, and peripheral blood of patients with psoriatic arthritis, CD4+ and CD8+ T cell expansions have been observed [36–38]. This indicates that T cells are important in the pathogenesis of psoriatic arthritis. An abundance of activated T cells is also found in psoriasis [39]. Dysbiosis in the intestine can determinate the direction of differentiation of naive CD4+ T cells into either effector T cells or regulatory T cells (Tregs). The balance between Tregs and the T cell effector subsets Th1, Th2, and Th17 is of crucial importance for immune homeostasis. An imbalance can lead to chronic inflammation in the joint, skin, or gut. The direction of differentiation of CD4 + -naïve T cells is affected by a variety of transcription factors and cytokines. These differentiations determine tolerance for non-pathogenous antigens, including antigens from food.

A lot of research into the microbiome has been done with germ-free animals, which are animals raised in a sterile environment and thus unexposed to microorganisms. Hormannsperger et al. found that these germ-free animals had Th2-dominated immune responses. Interestingly, when the gut of the germ-free mice was colonized by microbial communities the T cell balance was easily restored. This indicates that microorganisms are essential for maintaining balance in the differentiation of naïve T cells. However, the complexity of the interaction of the microbiome and the immune system extends beyond this observation. In germ-free mice, Th17 induction was observed to be dependent on the presence of a specific bacterial species, the segmented filamentous bacteria. Microbial ATP was revealed to be responsible for the differentiation of Th17, whereas polysaccharide A from Bacteroides fragilis was found to induce Treg cells, thereby reducing the response of Th17 [40•]. Another study found that the segmented filamentous bacteria induced autoimmune arthritis through the ability to specifically promote the Th17 subset [41]. Segmented filamentous bacteria have been found to be essential for maturation of CD4+ and CD8+ T cells in mice [42]. Both CD4+ and CD8+ T cells are capable of secreting IL-17 [43]. The segmented filamentous bacteria, however, has not been detected in the human small intestine. This indicates that in humans, other species of the intestinal microbiome or mycobiome might have a large effect on the immune system and cause extra-intestinal inflammatory disease. Recent literature has focused on the effect of Th17, an important T cell subset having an important function in the pathogenesis of several inflammatory diseases, including Crohn’s disease, rheumatoid arthritis, psoriasis, and psoriatic arthritis [12, 44–46]. Th17 is a producer of the cytokines IL-17A, IL-17F, TNF, IL-21, and IL-22, and is able to stimulate osteoclast formation and bone resorption [36].

In a recent psoriasis study, the largest response was observed in patients in whom specifically Th17 was blocked, compared with patients in whom TNF-α and IL-22 were blocked. Th17 would therefore seem to be the main inducer of inflammation in psoriasis [44]. Both psoriasis and psoriatic arthritis are associated with an increased risk of cardiovascular events [47, 48]. IL-17 may be responsible for this association [49]. Thus it seems that the effect of Th17 extends beyond the skin and gut, and might be able to affect multiple organs. And, because there is an important relationship between Th17 and the microbiome and/or the GI-tract mycobiome, this may have a major effect on development of immune-mediated inflammatory disorders. Whether bacteria or yeast and/or fungi might be the primary or secondary factor in the etiology of immune-mediated disease has not yet been established, and is an important subject for future research.

The Link Between Psoriasis and Psoriatic Arthritis

The connection between the development of diseases manifesting in joint and skin has been described elsewhere in the literature [50]. The connection between psoriatic arthritis and psoriasis is evident. However, the severity of the psoriatic arthritis does not reflect the severity of the psoriasis, although both diseases are mediated by the immune system. Psoriasis lesions precede the presence of psoriatic arthritis in almost 70 % of patients; in 20 % arthritis starts before the onset of psoriasis; and in 10 % both develop simultaneously [51]. Psoriatic arthritis can occur without the development of psoriasis [52]. Both psoriatic arthritis and psoriasis are associated with environmental factors, including streptococcal pharyngitis, stressful life events, low humidity, drugs, HIV infection, trauma, smoking, and obesity [53].

Traumatic injury and tissue damage can cause inflammation and, consequently, T cell activation. A characteristic of psoriasis is the “Koebner phenomenon”, referring to the development of psoriatic skin lesions at the sites of physical trauma. Because psoriatic arthritis can also be initiated by traumatic injury, a “deep Koebner” effect might be present in the joint [54]. Chronic inflammation may occur after trauma, depending on the genetic background of the individual and, hypothetically, on the composition of the intestinal microbiome. If the patients’ immune system is Th17-dominated the abnormal inflammatory response may persist, resulting in chronic joint inflammation. The same theory can be applied to other environmental initiators, for example infection.

The Skin Microbiome

The skin, in contrast with the joint, has its own microbiome. The skin microbiome has been implicated in the pathogenesis of psoriasis [55, 56]. Given that up to 30 % of psoriasis patients develop psoriatic arthritis, the skin microbiome may also be involved in the etiopathogenesis of psoriatic arthritis. Recently, Castelino et al. postulated a causal effect for the skin microbiome in psoriatic arthritis. They posit that individuals with psoriasis who develop psoriatic arthritis might have a different composition of the skin microbiome compared with patients without psoriatic arthritis [57•]. This theory can also be applied to individuals who develop psoriatic arthritis without psoriatic skin lesions. Naik et al. revealed that the skin microbiome seems to contain an autonomous microbiome, affecting the local T cell subsets and local inflammation, but does not seem to affect distant sites [58]. However, scarce evidence is available on this subject. The intestinal microbiome, in contrast, has the ability to affect the systemic immune system and distant organs [10]. Taurog et al. found that a germ-free environment was able to prevent development of gut and joint inflammatory diseases in HLA-B27 transgenic rats. In contrast, the skin and genital lesions were unaffected by the germ-free environment in this study [59]. Possibly a Th17-dominated immune response in the gut and joint will not necessarily manifest in the skin as well, because distinct microbes in the skin may prevent the development of psoriasis plaques in some individuals. Although the skin microbiome might contribute to the presentation of psoriasis with psoriatic arthritis, we argue that the effect of the intestinal microbiome extends beyond the effect of the skin microbiome. We also believe, despite the lack of evidence, that the intestinal microbiome does have an effect in the development of such inflammatory skin disorders as psoriasis, which should be investigated.

The Link Between the Gut, Joint, and Skin

Besides the connection between the joint (psoriatic arthritis) and skin (psoriasis), there is also a relationship between the joint and the gut. Psoriatic arthritis belongs to the family of the SpA, associated with HLA B27, although it was previously believed to be most related to rheumatoid arthritis [60]. Involvement of the intestinal microbiome and the presence of gut inflammation in rheumatoid arthritis are described elsewhere in the literature [10, 61]. Research indicating the relationship of psoriatic arthritis and the gut has been primarily performed within the SpA group [62]. Members of the SpA family include ankylosing spondylitis, reactive arthritis, undifferentiated SpA, arthritis in IBD, and the pauci-articular and axial forms of psoriatic arthritis. All subtypes share clinical, radiological, and genetic characteristics evidently different from those of other chronic inflammatory joint diseases, for example rheumatoid arthritis. The presence of gut inflammation in psoriatic arthritis has been reported in several studies [63–66]. In two of these studies it was observed that gut inflammation was only found in the forms of psoriatic arthritis belonging to the SpA concept, not in the polyarticular group. In these studies it was also noted that the frequency of gut inflammation was found to be lower in psoriatic arthritis than in the other members of the SpA group. Mielants et al. described the strong relationship between SpA and IBD, and suggested that they could be regarded as distinct phenotypes of shared immune-mediated inflammatory pathways [67].

As well as the connections between joint and skin and between joint and gut, a connection also exists between gut and skin. An evident association is present between psoriasis and IBD, and they have similarities in genetics and pathogenesis [68, 69]. Furthermore, because stress-induced skin inflammation is associated with an alteration of the composition of the intestinal microbiome, it is even possible that a gut–brain–skin axis might be present [70].

Thus, because psoriatic arthritis is associated with both psoriasis and IBD [71], an overlap exists between the joint and both the gut and the skin. Therefore both entities may be involved in the pathogenesis of inflammatory joint diseases, including psoriatic arthritis. The microbiome may be the conductor, or at least a mediator, of the common inflammatory pathways seen in these immune-mediated diseases. This hypothesis might also apply to other extra-intestinal manifestations of IBD and to extra-cutaneous manifestations of psoriasis.

Therapeutic Approaches for Psoriatic Arthritis

Modulation of the Immune System

It is already known that modulation of the immune system is an effective therapy for psoriatic arthritis and for other inflammatory diseases. However, this approach treats the symptoms and not the cause. Available therapies targeting the immune system, and thereby the gut, skin and joint, are such immunosuppressants as methotrexate and TNF antagonists, which are effective for all psoriatic arthritis, IBD, and psoriasis.

Antibiotic Treatment and the Microbiome

An interesting observation is the effect of antibiotic treatment on SpA, including psoriatic arthritis [72, 73]. At present, the mechanism for its efficacy has not been elucidated. It is known that antibiotics alter the composition of the intestinal microbiome. Consequently the immune system might also adapt, resulting in immunosuppression and thereby a therapeutic response in cases of inflammatory joint disease. Although the effect of antibiotic treatment seems to be temporary [74], use in infancy and frequent use might have permanent consequences for the composition of the microbiome [9, 75]. The disturbance of the microbiome may lead to a higher risk of invasion by pathogens and a lower protection from commensals. Western diseases, including IBD [76, 77] and possibly psoriatic arthritis, may develop after this disturbance of the microbiome. Therefore, the use of antibiotics for treating psoriatic arthritis needs to be carefully evaluated in future studies.

Modulation of the Microbiome: A Novel Therapeutic Approach

Probiotics and Prebiotics

Probiotics are defined as live organisms which, when administered in adequate amounts, confer a health benefit to the host. The objective of the use of probiotics is to restore the balance in the intestinal microbiome by administering commensal bacteria, of which bifidobacteria and/or lactobacilli are most common. Other bacteria used as probiotics are lactococci and streptococci, and more promising probiotics are being developed [78]. Mechanisms of action include improvement of the intestinal barrier function, modulation of the immune system, protection against pathogens, and production of enzymes and metabolites. Probiotics used in combination with prebiotics are referred to as synbiotics, optimizing the modulation of the microbiome. Prebiotics are defined as “non-digestible, but fermentable, foods that beneficially affect the host by selectively stimulating the growth and activity of one species or a limited number of species of bacteria in the colon” [79]. The use of probiotics is proved to be safe but is limited in its potency. The most recent examples revealed that probiotic Lactobacillus casei and paracasei-produced lactocepin can selectively degrade pro-inflammatory chemokines, resulting in reduced immune-cell infiltration and reduced inflammation in experimental IBD models. The authors have argued that, because immune cell recruitment is a major pro-inflammatory mechanism, probiotics might be of broad therapeutic relevance for a range of inflammatory diseases, including IBD, allergic skin inflammation, and psoriasis [80].

Modulation by diet with, for example, seal oil is also described in literature. In a small study, treatment of psoriatic arthritis with seal oil was followed by a subjective improvement, which is also obtained for rheumatoid arthritis and IBD-related joint pain [81].

Faecal Microbiota Transplantation (FMT)

Faecal microbiota transplantation is a new therapeutic approach for modulation of the intestinal microbiota, in which a suspension of fecal matter from a healthy individual is infused into the gastrointestinal tract of another person. The objective of FMT is not solely to alter the composition of the microbiota, as with probiotics, but to replace and repair the disruption of the microbiota. FMT is therefore expected to be a more potent therapy. This therapy has proved effective for Clostridium difficile infection [82], in case studies of IBD [83], and for increasing insulin sensitivity of individuals with metabolic syndrome [84]. Additional research is required to prove the efficacy and safety of this therapy when applied to other diseases.

Conclusions

The host immune system must be tuned to tolerate constant exposure to environmental and commensal microorganisms, and to evoke active immune and inflammatory responses only against invasive fungi or bacterial pathogens. We are just beginning to understand that microbes can have an important function in regulating the pathogenic inflammation of immune-mediated disease. The contribution of the microbiome to the etiopathogenesis of psoriatic arthritis in susceptible individuals remains to be investigated.

Outstanding Questions

What is the mechanism of the gut–joint–skin axis in health and disease?

How factors including host genetics, medication, lifestyle, and nutrition can determine microbiome composition and cause immune-mediated inflammatory disease?

What is the cause–effect relationship between the microbiome and inflammatory diseases including psoriatic arthritis?