1. Introduction
Psoriasis is relatively common in the general population, affecting men and women of all ages, regardless of ethnic origin, in all countries. It is a non-contagious chronic inflammatory skin condition with a complex etiology
[1][2]. This disease is T cell mediated, involving the Th17 cells secreting interleukin (IL)-17A and IL-22, which are proinflammatory cytokines that causes proliferation of keratinocyte (KC) and activation of synoviocyte
[3][4]. Psoriasis can be characterized by the hyperproliferation of the epidermal KCs, dysregulated KC differentiation, elevated vascularization and inflammation of the dermis and epidermis resulting in thickened, reddened skin appearing as a classic, well defined, erythematous scaly plaque that is itchy and flaky
[5][6][7]. Although clinical findings are noticeable on the outer layer of the skin that is composed of KCs, the formation of psoriatic plaque is an interplay between different cell types (vasculature, innate, and adaptive immune cells) and KCs across the dermal layer rather than just the epidermal inflammation
[8]. Some of the risk factors of psoriasis are family history
[9], smoking
[10], obesity
[11][12], infections
[13][14], and medications
[13]. According to the World Health Organization (WHO), nearly 100 million individuals globally are affected by psoriasis
[1]. The reported prevalence in countries ranges between 0.09% and 11.4%
[1][15]. Some studies find the prevalence rate of psoriasis could be affected by regions as Asians and some African populations showed lower prevalence rate as compared to Scandinavian and Caucasians that have prevalence rates as high as 11%
[15][16][17]. However, one study found the correlation between psoriasis prevalence and geographic latitude to be very weak
[18]. In terms of the mean age of onset of psoriasis, although there are variations across different studies, 75% of patients were <40 years old and 12% were between 50–60 years old
[16].
The concept of gut–skin axis which links the gut microbiome with skin health has garnered remarkable interest amongst researchers. The association between inflammatory skin diseases and gut microbiome is known to be mediated by dysfunctional intestinal barrier, increased inflammatory mediators and metabolites released by the microorganisms
[19][20][21]. The interplay between gut microbiota and immune system has been well established. Gut microbiome plays an important role in the immune system development and regulation of immune homeostasis through its interaction with the innate and adaptive components of the immune system
[22]. Disturbance to the gut microbiome or changes to the host–microbiome interfaces may trigger an immune response and increase risk of pathogenic invasion
[22][23]. Both systemic and local inflammation can be caused by alterations of the microbiota on the epithelial surface, leading to systemic disease susceptibility
[19]. For instance, in patients with Inflammatory Bowel Disease, local inflammation caused by the increased pro-inflammatory bacteria at gut epithelium leads to mucosal damage and increased permeability of gut mucosa
[24]. The damage of gut mucosal layer subsequently causes a surge in pro-inflammatory cytokines such as IL-12 and IFN-γ, leading to systemic inflammation
[24]. Although psoriasis is a disorder of the skin, it is recognized as a systemic inflammatory disease
[25], as it results in the inflammation of other organ systems in addition to psoriatic skin. Furthermore, psoriasis has been associated to several metabolic disorders
[7][16][17]. This is seen as psoriasis patients show greater body mass index, hypertension, hyperlipidemia, type 2 diabetes, and coronary artery disease
[26][27]. All of these effects together with obesity and inflammatory bowel disorders are psoriasis comorbidities
[7][28][29][30][31][32]. Currently, psoriasis is a disorder with no curative treatment and it can only be suppressed using various therapeutics
[33], thus, it definitely impacts the quality of life of psoriasis patients’ physically and psychologically.
In recent years, many studies have been investigating the connection between skin allostasis and homeostasis and the gastrointestinal health, with corroborative evidence showing strong bidirectional relationship between the skin and gut
[34][35]. This can be seen through the presence of bacterial DNA translocation (BT) in blood samples of psoriasis patients that has been associated with the composition of gut microbiome in recent years, which proposes the new outbreaks of active plaque psoriasis could be correlated to circulating bacterial DNA in blood from the intestinal lumen
[36]. The advancement in next generation sequencing technologies in the past few years has allowed us to have a better understanding on the intestinal microbiota composition
[37], and the effects of these microbes may have on psoriasis pathogenesis. Hence, this review discusses the gut microbiome composition, diversity, and relative abundance of healthy and psoriasis individuals, explains the gut–skin axis and the effects gut dysbiosis has on the epithelial barrier, gut microbial metabolite and the gut immunoregulatory characteristics. We will also discuss the benefits of modulating gut microbiome using probiotics and how it can improve symptoms of psoriasis.
2. Psoriasis Pathogenesis and the Cutaneous Immune System
The skin being one of the largest organs of the human body, plays a vital role in homeostasis in terms of water retention, temperature regulation, and protection of the body via skin regeneration process
[38][39]. It also helps maintain a healthy microbial ecosystem via its production of antimicrobial proteins and peptides
[40]. The role of homeostasis is highly dependent on the stratum corneum—the outermost layer of the epidermis—which is made up of 15 layers of tightly packed keratinized, anucleated, and stratified corneocytes differentiated from stem cells in the basal layer through the keratinization process
[38][39][41][42].
The skin immune system is made up of recruited and resident innate immune system (IIS) and adaptive immune system (AIS) cells which are activated by microorganisms, stimuli, and epidermal structures that crosstalk with mostly KCs to restore skin barrier
[43][44]. IIs releases signals initiating skin immune response while AIS activation prolongs inflammation
[45]. There are postulations that psoriasis has mixed pathogenesis of autoinflammatory and autoimmune states
[46]. The pathogenesis of psoriasis probably involves cross-talking of the skin’s complex network of dendritic cells (DCs), resident KCs and T cells (mostly Th17
[47]), that gives rise to immune and inflammatory route accountable for the initiation, progression and persistence of psoriasis
[48][49][50]. This development of inflammation occurs due to interference in the innate and adaptive cutaneous immune responses
[8][51].
Janus kinases (JAKs) signaling, nuclear factor kappa (NF-κB) signaling, transforming growth factor beta (TGF-β), interleukin 23–interleukin 17 (IL-23-IL-17) signaling, T cell regulation, disruption of epithelial barrier function, autophagy, and dysregulated apoptosis are all involved in psoriasis pathogenesis
[52][53][54]. Exposure of self-nucleic acids to tissue occurs as epithelial cells undergo necrosis or apoptosis after exposure to virus, bacteria, mechanical stress, or ultraviolet light. Self-DNA bound to LL-37 which is produced by KCs and is a part of the antimicrobial peptide cathelicidin that stimulates production of type 1 interferons by plasmacytoid dendritic cells (pDC). Concurrently, self-RNA bound to LL-37 stimulates myeloid dendritic cells (mDC), producing inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNFα). The production of these cytokines leads to immature T cells to transform into inflammatory T cells (mostly Th17) producing IL17 and IL-22, developing psoriatic phenotype in KCs. KCs produces proinflammatory cytokines (1L-1, IL-17 and TNFα), chemokines (CXCL20,11,10,8,2, and CXCL 1) and antimicrobial peptides (S100 proteins, psoriasin, cathelicidine, and beta defensin (BD) that draws in Th17 cells and neutrophils resulting in sustained chronic psoriasis
[55].
In lesional psoriatic skin, molecular and critical cellular pathways are brought about by the activation of dermal dendritic cells secreting IL-23 to stimulate type 3 innate lymphoid cells (ILC3) and gamma delta T cells to produce IL-17 which cause production of chemokines- interleukin 6 (IL-6), interleukin 8 (IL-8), CXCL20, CXCL2, and CXCL1- by keratinocyte, leading to leukocyte infiltration. With the presence of stimulating cytokines IL-18, IL23 and IL-1β, ILC3 releases IL-17 and IL-22 promoting keratinocyte hyperproliferation
[56]. Thus, in comparison to healthy normal skin that takes about 50 days for the transformation of basal KCs to corneocytes, psoriatic skin takes only 5 days
[57].
There is a possibility that the modulatory effects of skin flora on inflammatory skin diseases may be associated with the gut microbiota. Imbalances of the composition of skin microbiota has been observed in numerous non-infective skin conditions such as psoriasis, acne vulgaris and rosacea, where gut dysbiosis were too, apparent in these conditions
[34]. However, there is currently no evidence to show the direct causality of the association between gut dysbiosis and skin dysbiosis. In the following sections, we will discuss the possible mechanisms on how gut resident commensals affect skin health.
3. The Gut-Skin Axis and the Gut Microbiome
There is an increasing number of studies in the recent years that are actively investigating the relationship between the gut microbiome and skin diseases, including psoriasis. This leads us to the concept of gut–skin axis which associates the microbiome and skin diseases via intestinal barrier, inflammatory mediators, and metabolites
[21]. Currently there has been large evidence regarding the presence of the gut–skin axis and its resulting inflammatory effect due to gut microbiome imbalance
[20]. The gut microbiome is mainly made up of a diverse bacterial species, but also contains protozoa, viruses, and fungi that reside mainly in the lower gut and help to maintain a symbiotic relationship with the host
[58][59][60]. Aerobic species are commonly found in the small intestine whereas anaerobic species are common in the colon
[61]. The few main bacterial communities in the gastrointestinal tract (GIT) include Firmicutes, Bacteroidota (formerly known as Bacteroidetes), Actinobacteria, and Proteobacteria phyla in which their composition is influenced by the host’s diet, age, and environmental conditions
[62][63][64][65].
Dietary, lifestyle, and genetic predisposition are key regulators of gut microbiome homeostasis
[66][67]. It has been proven that the gut microbiome is essential in regulating the intestinal permeability, metabolism, and immune system
[68][69][70][71]. The gut microbiome ensures the protection against potential pathogens indirectly by triggering immuno-protective responses and directly by binding competitively to epithelial cells and allow for immune tolerance of environmental and dietary antigens
[72][73][74][75]. An imbalance of composition and biodiversity of the gut microbes or the term “gut dysbiosis” has been associated with psoriasis and many other psoriasis-associated comorbidities such as inflammatory arthritis, chronic kidney disease, inflammatory bowel disease, metabolic syndrome, cardiovascular disease, depression, and obesity
[24][33][76][77][78][79][80].
The gut microbiome could affect skin homeostasis through systemic immunity modulation
[34]. Numerous gastrointestinal diseases have been accompanied by cutaneous manifestations and the gut microbiome’s interaction with the immune system, impacting the pathophysiology of inflammatory diseases
[81][82][83]. Gut dysbiosis causes negative impacts on the skin integrity and function
[84][85]. Some microbes affect the intestinal barrier function and skin homeostasis via cross-talking with mucosal immunity elements and signaling pathways coordinating epidermal differentiation
[34][86][87][88][89]. Besides that, there are studies that disseminate the gut microbes and their metabolites onto the skin to demonstrate their effects on the cutaneous physiology, immune system and pathology
[34][90]. For instance, metabolites such as p-cresol and phenol produced by
Clostridioides difficile (formerly known as
Clostridium difficile) are biomarkers of gut dysbiosis has been shown to enter the bloodstream and accumulate on the skin, decreasing skin moisture, impairing skin barrier integrity and epidermal differentiation and affecting keratinization
[91][92]. Hence, it is certain that the gut microbiome is associated with the skin homeostasis and does affect distant organs beyond the GIT.
The relationship between the gut microbiome and the pathogenesis of psoriasis is based upon the association between components of the innate and adaptive immune systems
[68][69][70][73][77][78][79]. Studies have proposed that the mechanism of the gut–skin axis in regards to psoriasis involves T cells function and differentiation with the imbalance of Treg and Th17 cells
[93][94]. Interaction between pattern recognition receptors expressed by host cell and bacterial antigen enables the gut immune system to be primed by commensal bacteria
[73]. The adaptive immunity is affected as these commensal bacteria ensure the balance of effector T cells and regulatory T cells and immunoglobulin A induction leading to B cells activation and thus specific immunoglobulin A antibodies production
[73][95]. An experimental model has also demonstrated that gut dysbiosis aids in Th17-mediated skin inflammation
[93][94], as well as affecting metabolite production, inducing an anti-microbial signaling changing immune cell activation through IL-23/IL-17 signaling pathway through IL-22 and interferon gamma (IFN-γ) production, resulting in hyperproliferation of keratinocytes
[66][67].
In addition, there are a number of studies regarding the concept of gut–skin axis which showed that gut dysbiosis can induce inflammatory skin diseases
[20]. One of the many mechanisms by which gut microbiome may cause skin impairment is presented in animal studies with evidence demonstrating that gut dysbiosis causes chronic systemic inflammation as a result of pro-inflammatory cytokine secretion causing an imbalance between activated effector T cells and increased epithelial permeability
[34][73]. Intestinal barrier dysfunction and subclinical gut inflammation can be observed in psoriasis patients, and thus, this lead to the postulation that gut dysbiosis is associated with psoriasis
[96][97].
Gut dysbiosis activates the proinflammatory state via alterations to the metabolic environment and activation of specific pattern recognition receptors (PRPs) present on epithelial cells. This causes the gut permeability to increase as cytokines such as TNF alter the integrity of tight junctions between epithelial cells. The increase in epithelial permeability stimulates effector T cells activation, causing an imbalance between the T cells and Treg cells which leads to autoimmune diseases development. A positive feedback mechanism is involved as the proinflammatory cytokines magnifies the epithelial permeability, which further exacerbate chronic systemic inflammation and thus greater impairment to the intestinal barrier resulting in the entry of metabolites, toxins, and bacteria into the systemic circulation
[34][73][98]. As these microorganisms enter the circulation, they could be activated, shedding their inflammatory cell wall components (lipoteichoic acid and lipopolysaccharide), possibly promoting or maintaining the pro-inflammatory state
[99]. On top of that, gut dysbiosis can produce endotoxin-peptidoglycan superantigens to stimulate inflammatory and autoimmune states related to psoriasis. The microorganisms in the gut produce toxins triggering an immune response that causes psoriatic patients to present with positive detection of gut bacterial antigen in a skin test
[100]. In line with this model, biomarkers for intestinal permeability such as claudin 3 and fatty acid binding protein are elevated in psoriasis patients
[99].
Effects of Gut Dysbiosis on Gut Microbial Metabolite and the Gut Immunoregulatory Characteristic
The gut microbiome plays a role in the immunoregulatory characteristics of the gut. Gut microbes may produce or even increase the beneficial metabolites or specific immune modulating molecules such as polysaccharide A, short chain fatty acids (SCFAs) and retinoic acid via the fermentation of dietary fibers
[73][101][102][103]. They are involved in the homeostasis between effector and regulatory T cells
[73][102], aiding the anti-inflammatory responses via upregulation of lymphocytes and regulatory T cells
[101]. However, the specific microbes involved in the modulation of these immune modulating molecules for such mechanism seen in psoriasis are yet to be distinguished
[19]. The production of short chain fatty acids (SCFAs) and trimethylamine can affect disease state and health status of a subject
[76]. SCFAs have a role in protecting against the progression of certain inflammatory disease
[103]. For example, propionate and butyrate produced by the gut microbiota have been shown to have anti-inflammatory properties
[104]. Butyrate has the key role of maintaining barrier integrity
[105], as it can cease the activity of histone deacetylase causing a rise in regulatory cells which impacts wound healing and hair follicle stem cell differentiation
[100]. Butyrate, which is also known to be primarily produced by
Faecalibacterium prausnitzii, functions to decrease oxidative stress, supplies energy for colonocytes and triggers Treg cells, allowing anti-inflammatory action, hence, conferring immune tolerance to sites other than the GI system
[106][107]. Consequently, a drop in both propionate and butyrate microbiota producers can trigger a proinflammatory state of the gut and affect the gut barrier integrity
[108]. In addition, SCFAs are involved in the apoptosis and activation of immune cells. Evidence of chronic systemic inflammation demonstrated in animals is the main consequence of intestinal dysbiosis, due to the secretion of pro-inflammatory cytokines causing epithelial to be more permeable and effector T cells to be activated
[34][73]. By taking sodium butyrate as an example, it has important effects on tumor growth factors (TGF-β), protease enzymes, and cell cycle. Several studies showed that by exposing sodium butyrate to human keratinocyte (HaCaT) cells, it prompts apoptosis by 50% via death receptors Fas upregulation accompanied with activation of caspases 3 and 8. It also helps in cell proliferation and terminal differentiation as demonstrated in the rise in expression levels of TGF-β and p52
[109].
4. Alterations in the Alpha and Beta Diversity of Gut Microbiome in Psoriasis Patients
In many microbiome-profiling studies, the diversity indices allow further characterization of microbiota population
[110]. In terms of assessing the alpha diversity using Shannon’s Diversity index of the gut microbiome in psoriasis, a systematic review reported that in 8 out of 10 studies that looked at alpha diversity, most of them failed to demonstrate remarkable changes between psoriasis and normal control
[21][102][111][112][113]. However, only one study among them showed increased diversity
[108], two other studies showed lower diversity
[114][115], and one study presented similar diversity but lower community richness in psoriatic samples when compared with normal controls
[116]. There was also high variability in terms of Shannon’s biodiversity index of the psoriatic patients, in which bacterial DNA translocation positive psoriatic patients having a more stable and lower variability in diversity as compared to BT negative psoriatic patients. According to Codoner et al., in a human microbiome project of 300 healthy controls (HC) and 52 psoriasis subjects, the microbiome diversity of psoriasis patients was found to be greater than the healthy controls
[108]. However, according to Scher et al. whose study involved only 17 HC, 15 psoriasis subjects, and 16 psoriatic arthritis subjects, results show psoriasis subjects had lower microbial diversity
[114]. This is consistent with study conducted by Hidalgo-Cantabrana et al. which found that psoriasis patients presented with severe dysbiosis, a lower diversity of gut microbiota and an alteration of the relative abundance for some bacterial taxa
[115]. Therefore, even with a similar alpha diversity index, microbial communities can still have a shift in composition without sharing any taxa
[117]. To sum it up, there were no significant differences in alpha diversity between healthy controls and psoriasis individuals based on similar indices of most studies
[21]. However, there are conflicting data regarding the alpha diversity which could be due to differences in sequence library preparation, DNA extraction, sample collection and data analyses
[40]. Besides that, it is hypothesized that instead of the number of bacterial species, the differential abundance of bacteria may be the cause of gut dysbiosis in psoriasis
[21].
On the other hand, beta diversity differed significantly between psoriasis and healthy controls in all studies included in the systematic review
[21]. Having said that, it was reported that the differences in beta diversity achieve statistical significance only for psoriatic patients who have BMI < 25
[21].
5. Alterations in the Relative Abundance of Gut Microbiome of Psoriasis Patients
In a study conducted by Codoner et al. which involves analyzing the feces of 52 psoriatic patients via 16S rRNA, an average of 85,000 sequences per sample was found and the “psoriasis microbiome” which is the defined microbial structure of psoriatic patients were different compared to healthy individuals. Hence, differing in gut microbial composition, which was reported to also be linked with BT
[108].
A number of studies concluded revealed that there is a relationship between gut dysbiosis and psoriasis
[21]. There are studies demonstrating an inverse relationship in the relative abundance of Bacteroidota and Firmicutes at the phylum level as well as the presence of 16 phylotypes differing at the genus level
[116]. It was found that at the phylum level, the relative abundance of Bacteroidota were lower and the relative abundance of Firmicutes were higher in psoriasis patients
[102][112][115]. However, study by Huang et al. states vice versa
[116]. This could be due to the small and diverse sample size that includes other psoriasis variants such as pustular, arthritis, plaque, and erythrodermic
[21]. When it comes to Proteobacteria, the level was decreased in psoriatic patients
[102][115]. Actinobacteria on the other hand had conflicting results in which some had an increased level
[102][115], and some had a drop
[114][118]. The drop in Actinobacteria presented by some studies
[114][118], proposes that Actinobacteria has a protective role as it includes
Bifidobacterium spp. that could suppress autoimmunity, decrease intestinal inflammation and induce Tregs
[119][120].
At the family level, the relative abundance of some gut bacteria increased, for example,
Enterococcaceae [111],
Ruminococcaceae,
Lachnospiraceae [112][115],
Coriobacteriaceae,
Eggerthellaceae,
Peptostreptococcaceae, and
Clostridiales Family XIII [115], whereas others, such as
Prevotellaceae [112][115],
Lactobacillaceae,
Desulfovibrionaceae,
Pasteurellaceae,
Barnesiellaceae,
Rikenellaceae,
Marinifilaceae,
Burkholderiaceae,
Victivallaceae,
Tannerellaceae,
Streptococcaceae [115],
S24-7,
Verrucomicrobiaceae [111], and
Porphyromonadaceae [114], decreased
[21]. There were conflicting reports on the changes of relative abundance of the following bacteria families, namely
Bacteroidaceae,
Veillonellaceae,
Erysipelotrichaceae, and
Bifidobacteriaceae. Some studies reported that these families were increased in patients with psoriasis
[111][115], while some reported reduction of these families in psoriasis
[112][114][115].
At the genus level, some of the bacteria with increased relative abundance are
Bacillus,
[116] Subdoligranulum,
Slackia [115],
Christensenella,
Dorea,
Coprococcus [102],
Collinsella,
Blautia,
Ruminococcus [102][115],
Streptococcus [116],
Enterococcus [111], and
Lactococcus [116], whereas those whose relative abundance dropped are
Allobaculum,
Alistipes,
Barnesiella [115],
Gordonibacter,
Carnobacterium,
Rothia,
Thermus,
Granulicatella [116],
Coprobacillus [114], and
Paraprevotella [102][115]. However, there were conflicting findings
[21], for
Parabacteroides [114][115][116],
Lachnospira,
Sutterella [102][116],
Bacteroides [108][111][115],
Faecalibacterium [102][108][115],
Akkermansia [108][111], and
Bifidobacterium [102][114][115]. Studies by Codoner et al. showed a decrease in
Bacteroides but an increase in
Faecalibacterium,
Ruminococcus, and
Akkermansia in psoriatic patients via PCR analysis
[108]. However, Scher et al. found
Pseudobutyrivibrio,
Ruminococcus, and
Akkermansia to be lower in both psoriasis patients and psoriatic arthritis patients
[114]. Although the gut microbiome composition of skin limited disease (i.e., psoriasis) is different from those of psoriatic arthritis
[114], these changes in the gut microbiome are in fact similar to IBD which is one of psoriasis’s comorbidities
[114][121]. Both
Ruminococcus and
Akkermansia are mucin-degrading bacteria producing SCFA’s that are essential in maintaining the gut mucosal barrier
[114][122]. Besides that, Scher et al. also found
Akkermansia to have an inverse relationship with SCFAs (butyrate, acetate) and fecal soluble IgA
[114]. The association between gut microbiota and psoriasis based on phylum, genus, and family level is illustrated in
Figure 1.
Figure 1. The association between gut microbiota and psoriasis. Data extracted from Scepanovic et al.
[110], Calcinaro et al.
[119], Lavasani et al.
[120], Kostic et al.
[122], Scher et al.
[123], and Eppinga et al.
[124].
Lastly, at the species level, those found to drop significantly in psoriasis patients are
Akkermansia muciniphila [111],
Faecalibacterium prausnitzii [123][124],
Parabacteroides distasonis, and
Prevotella copri [102], while
Escherichia coli [124],
Dorea formicigenerans,
Ruminococcus gnavus,
Collinsella aerofaciens [102], and
Clostridium citroniae [111], were increased
[21], as shown in
Figure 2. In a study analyzing the microbial composition of healthy controls and vulgaris psoriasis patients conducted by Tan et al., it was found that psoriasis patients had a tremendous drop in
Akkermansia muciniphila [111]. The drop in
Faecalibacterium prausnitzii was consistent in two studies
[123][124]. Psoriasis is affected by the drop in
Akkermansia muciniphila and
Faecalibacterium prausnitzii as these bacteria are considered a beneficial microbe responsible for SCFA production thus are protective against systemic inflammatory diseases including IBD, atherosclerosis, and obesity, and is vital in strengthening gut epithelium integrity
[107][111][125][126][127][128][129][130].
This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10051037