The role of gut microbiome in the pathogenesis of psoriasis and the therapeutic effects of probiotics.

The adult intestine hosts a huge number of diverse bacterial species, collectively referred to as the microbiome, that reside mainly in the lower gut, where they maintain a symbiotic relationship with their host. Recent research points to a central role of the microbiome in many biological processes. These microbial communities are influenced by multiple environmental and dietary factors and can modulate immune responses. In addition to local effects on the gastrointestinal tract, the microbiota is associated with effects on other organs and tissues, such as the skin. Indeed, an altered microbiome has been associated with skin disorders in several instances. Thus, in this review, we describe the recent advances regarding the interplay between gut microbiota and the skin. We explore how this potential link affects skin homeostasis and its influence on modulating the cutaneous immune response, focusing on psoriasis disorder. Finally, we discuss how to take advantage of this interplay to manage this disorder, particularly through probiotics administration. In the gastrointestinal tract, the microbiome has been proven to be important in the maintenance of the balance between effector T cells and regulatory T cells, and the induction of immunoglobulin A. Moreover, gut bacterial dysbiosis is associated with chronic inflammatory disorders of the skin, such as psoriasis. Thus, the microbiome can be considered an effective therapeutical target for treating this disorder. Despite some limitations, interventions with probiotics seem promising for the development of a preventive therapy by restoring altered microbiome functionality or as an adjuvant in specific immunotherapy. Copyright:

Introduction

Corroborative evidence describes a strong and bidirectional correlation between the gut and skin, and various studies associate gastrointestinal (GI) health with skin homeostasis and allostasis.[12] Many GI disorders are accompanied by cutaneous manifestations and the GI system, particularly its microbiome, interacts with the immune system and affects the pathophysiology of inflammatory disorders.[345] Psoriasis is an immune-mediated inflammatory skin disease, whose development depends on both genetic factors and external triggers.[67] However, its pathogenesis is still not fully understood.[8] This review discusses the role of the gut microbiome in skin diseases, with a particular focus on psoriasis.

The Gut Microbiome

The term “microbiome” refers to the set of microorganisms that live on or inside another organism. They interact with each other and with their host and can be either beneficial (symbiotic) or detrimental (pathogenic).[9] Although bacteria are the most prominent components, this collection of microorganisms also includes viruses, fungi, and protozoa that inhabit and colonize the gastrointestinal (GI) system.[1011] This collection of microbes outnumber host cells by 10-fold and contains genetic material 150 times greater than that of the host.[1112] The establishment of bacterial communities occurs mainly during the first 3 years of life;[13] however, more recent evidence indicates that GI colonization may begin in utero.[14] Bacteria in the GI communities are mainly from Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria phyla, and their composition is affected to host-associated factors, such as age, diet, and environmental conditions.[1315161718]

The gut microbiome is not homogenous throughout the GI tract. It is more diverse in the oral cavity and intestine than in the stomach, because of its acidic environment.[19] Aerobic species are mainly located in the small intestine and anaerobic species in the colon.[20] The intestinal microbiome provides significant metabolic and immune benefits to the host. Gut microbiota participates in the breakdown of indigestible complex polysaccharides and is vital for the production of certain nutritional components, such as vitamin K. It has a great influence on the host immune system. Microorganisms residing in the GI tract enable immune tolerance of dietary and environmental antigens and provide protection against potential pathogens directly, by competitively binding to epithelial cells, and indirectly, by triggering immunoprotective responses.[2122]

Commensal bacteria prime the gut immune system through specific interactions between bacterial antigens and pattern recognition receptors expressed by a variety of host cells.[22] The gut microbiome contributes to the innate and adaptive immune systems. The contribution to the adaptive immune system involves the maintenance of a balance between effector T cells (Th1, Th2, and Th17) and regulatory T cells, and the induction of immunoglobulin A[22] by stimulating dendritic cells (DCs) in the Peyer's patches (a type of gut-associated lymphoid tissue) to activate B cells, leading to production of specific immunoglobulin A antibodies.[23] Certain microbes can also contribute to intestinal epithelial barrier function through cross-talk signaling with elements of mucosal immunity.[24252627] For example, Lactobacillus rhamnosus GG, a commensal species, secretes p40, a protein that suppresses cytokine-mediated apoptosis and epithelial barrier disruption.[22]

Many studies on human and other animals mention that the intestinal microbiome's influence extends to extracolonic sites and contributes to the function, and dysfunction, of distant organ systems.[228] For instance, short-chain fatty acids (SCFAs), which are produced from dietary fibers fermented by the gut microbiome, have a protective role against the progression of some inflammatory disorders, including allergy and arthritis, in addition to colitis.[28] Moreover, intestinal dysbiosis has been linked to metabolic, neurodegenerative, and neoplastic diseases. Altered gut microbiota may favor the production of effector over regulatory T cells, thereby disrupting the balance between them and contributing to the development of autoimmune disorders. For example, segmented filamentous bacteria in the gut have been associated with a variety of Th17-mediated diseases. Through mechanisms not yet fully understood, the gut microbiome's influence clearly extends beyond the GI system. In that regard, the skin has a complex and close connection with the gut.[22228]

Role of the gut microbiome in skin homeostasis and allostasis

The skin maintains body homeostasis by effectively performing several functions, such as protection, temperature regulation, and water retention. To do so, the skin undergoes constant renewal and epidermal turnover, in the process of skin regeneration.[2930] Epidermal cells originate from stem cells in the basal layer of the epidermis and then differentiate while migrating to the skin surface into 3 cell types—basal cells, spinous cells, and granule cells—before ultimately becoming corneocytes, which make up the outermost layer of the epidermis, the stratum corneum. This process of epidermal differentiation also referred to as keratinization is under the control of specific transcriptional programs.[29303132] It is a highly regulated process that results in a stratum corneum of ~15 layers of densely keratinized, stratified, and anucleated corneocytes tightly held together. This stratum of multiple lipid bilayers constitutes an effective skin barrier with the ability to limit evaporation, preserve skin moisture, and protect the organisms from invasion of organisms and substances.[293132]

The gut microbiome affects skin homeostasis through its influence on the signaling pathways that coordinate epidermal differentiation.[1] Though not yet fully elucidated, the mechanisms whereby intestinal microbiota exert their influence on skin homeostasis appear to be related to their modulatory effect on systemic immunity.[1] Certain gut microbes (Bacteroides fragilis, Faecalibacterium prausnitzii, and bacteria that belong to Clostridium cluster IV and XI) and their metabolites (retinoic acid and polysaccharide A) promote the aggregation of regulatory T cells, lymphocytes that facilitate anti-inflammatory responses.[33] Another class of metabolites, SCFAs, regulates both the activation and apoptosis of immune cells. Specifically, butyrate inhibits histone deacetylase activity, leading to the proliferation of regulatory cells involved in various physiological functions of skin, including regulation of hair follicle stem cell differentiation and wound healing.[343536] In addition, there is new evidence that the gut microbiome may affect cutaneous physiology, pathology, and immune response more directly, through the dissemination of intestinal microbiota and their metabolites from the gut to other tissues, including the skin.[136] For instance, intestinal bacteria DNA has been isolated successfully from the plasma of psoriatic patients.[1] Moreover, in some cases of intestinal barrier disruption, intestinal bacteria and their metabolites access the bloodstream and impair skin homeostasis after their accumulation there.[1] These findings indicate a direct connection between the gut microbiome and skin homeostasis that has just begun to be explored.

The beneficial effects of intestinal bacteria on skin health and appearance have been documented in several studies on rodents and humans. In rats, oral administration of Lactobacillus brevis SBC8803 resulted in decreased tone of cutaneous arterial sympathetic nerve and increased cutaneous blood flow.[37] Such effects were possibly caused by increased serotonin release from intestinal enterochromaffin cells followed by activation of parasympathetic pathways.[37] A considerable decrease in transepidermal water loss (TEWL), a marker of skin barrier function, was noted as well.[37] Noteworthy, similar outcomes were observed in human clinical research. After taking L. brevis SBC8803 orally for 12 weeks, human subjects had significantly decreased TEWL and increased corneal hydration.[38] In another study, it was shown that bacterial supplementation positively affects skin barrier function.[39] Volunteers who took Lactobacillus paracasei NCC2461 supplements orally for 2 months had decreased skin sensitivity and TEWL, an effect attributed to increased circulating levels of transforming growth factor-beta (TGF-β), which is a cytokine known to affect epidermal barrier integrity.[139]

The intestinal microbiome also contributes to skin allostasis, the restoration of homeostasis after a disturbance or stressor, by acting on both innate and adaptive immunity.[284041] Intestinal bacteria can enhance the response to the disruption of skin barrier function. For example, the administration of Lactobacillus helveticus decreases the severity of sodium dodecyl sulfate-induced dermatitis and reduces TEWL levels.[42] Another study showed improved recovery of skin barrier function with decreased signs of reactive skin inflammation—including mast cell degranulation, vasodilation, edema, and tumor necrosis factor-alpha (TNF-α) release—following the administration of L. paracasei CNCM I- 2116 (ST11).[42434445] In mice, accelerated wound healing was observed after the consumption of Lactobacillus reuteri. Although the healing process through microscopic examination of wounds revealed the usual histomorphologic stages of wound healing in both probiotic-treated and untreated mice, the time required for complete healing was markedly reduced in the treated group.[46] In wound sites, Foxp3+ regulatory T cells were abundant in the treated group, whereas neutrophils were almost absent, helping to decrease time to heal.[46] The gut microbiome also supports the restoration of skin homeostasis after ultraviolet (UV) radiation exposure. Oral administration of Lactobacillus johnsonii for 10 days protects hairless mice against UV-induced contact hypersensitivity, an effect attributed to a reduction in epidermal Langerhans cells and an increase in systemic interleukin (IL)-10 levels.[47] In a placebo-controlled study, L. johnsonii La1 oral supplementation secured cutaneous immune homeostasis in 54 healthy volunteers following UV radiation exposure. This effect was mediated by the normalization of epidermal expression of CD1a, a transmembrane glycoprotein structurally similar to major histocompatibility complex that presents self and microbial glycolipids to T cells.[4849]

Commensal gut bacteria can promote skin allostasis by influencing T-cell differentiation in response to various immune stimuli. Oral administration of Lactobacillus casei DN-114 001 impairs differentiation of CD8+ T cells into cutaneous hypersensitivity effector cells and decreases their recruitment to the skin when exposed to 2,4-dinitrofluorobenzene.[5051] Other targets of GI tract microbiome include Th17 cells, which are abundant in both the skin and intestine, as both organs are in direct contact with the environment.[31] These cells and their proinflammatory cytokines contribute directly to the pathogenesis of several chronic inflammatory dermatoses, including psoriasis, Behcet's disease, and contact hypersensitivity.[525354] The balance between Th17 effector cells and their counterpart regulatory T cells is greatly influenced by the gut microbiome.[52] In the GI tract, Th17 cells can be eliminated in the intestinal lumen or may acquire a regulatory phenotype with immunosuppressive characteristics (rTh17), which restricts pathogenicity.[53]

Dysbiosis and Immune Disorder

Intestinal dysbiosis is a state of imbalanced gut microbiome that eventually has a negative impact on skin function and integrity. Phenol and p-cresol, which are metabolic products of aromatic amino acids, can get into the bloodstream and accumulate in the skin, disruption both skin barrier integrity and epidermal differentiation. These metabolites are produced by certain pathogenic bacteria, such as Clostridium difficile, and are considered as biomarkers of disturbed gut microbiota with adverse outcomes. Indeed, high serum levels of p-cresol are associated with reduced skin hydration and impaired keratinization.[5556] As a result of intestinal dysbiosis, epithelial permeability increases, which triggers the activation of effector T cells and disrupts their balance in relation to immunosuppressive regulatory T cells. Proinflammatory cytokines further enhance epithelial permeability, which leads to a vicious cycle of chronic systemic inflammation.[122] These are a few mechanisms whereby a disturbed gut microbiome results in impaired skin function. Next, we discuss mechanisms by which intestinal dysbiosis contributes to a common skin disorder, that is, psoriasis.

Psoriasis

Psoriasis is a chronic immune-mediated relapsing-remitting inflammatory dermatosis triggered by multiple environmental and endogenous factors in genetically susceptible individuals.[57585960] Clinically, psoriasis usually appears as recurrent episodes of well-demarcated scaly erythematous plaques and, in rare cases, it can manifest as generalized life-threatening erythroderma.[61] Histologic features that characterize psoriasis include acanthosis, reflective of a state of keratinocyte hyperproliferation, and parakeratosis, indicative of dysregulated keratinocyte differentiation. Another characteristic of this disease is increased vascularization, which allows the accumulation of inflammatory subpopulations of neutrophils, dendritic cells, and T lymphocytes.[5962] Several treatments were developed as the pathophysiology of psoriasis became better understood. In the past, treatments focused on antiproliferative approaches, as its pathophysiology was considered merely a hyperproliferative skin disorder. Recently, after the discovery of elevated IL-17 levels in psoriatic lesions, therapies shifted the focus to Th17 cells. Cytokines released by Th17 cells promote the expression of the IL-10 cytokine family, including IL-20 and IL-22 cytokines, which causes keratinocyte hyperproliferation. After the discovery of the Th17 pathway, most clinical and mechanistic evidence indicate that psoriasis is primarily driven by the IL-23/IL-17/Th17 axis.[63646566676869]

Psoriasis is commonly associated with inflammation in other organ systems. In patients with inflammatory bowel disease (IBD), 7%–11% of patients are also diagnosed with psoriasis, indicating a strong association with GI inflammation.[546070] Certain genetic and environmental factors and immune pathways have been shown to be involved in the etiopathogenesis of both diseases.[54] For example, Th17 cells and their cytokines play essential roles in the development of psoriasis and in the pathophysiology of IBD.[7071] The intestinal microbiome produces metabolites that have immune-modifying potential and alter the balance between immune tolerance and inflammation. One of the mechanisms whereby these metabolites act is through their effect on the differentiation of naïve T cells into either regulatory or Th17 lineages. These cells have distinct metabolic demands. In general, effector T cells are anabolic and depend on glycolysis as their source of adenosine triphosphate (ATP). However, memory and resting T cells are considered catabolic and depend on fatty acids, amino acids, and glucose to generate ATP through oxidative phosphorylation. The main transcription factors of the lipogenic and glycolytic pathways are adenosine monophosphate-activated kinase and rapamycin, respectively. Both serve as energy sensors and are regulated by nutrients availability in the gut lumen, which can be modulated by the resident microbiota.[72]

The same pattern of dysbiosis found in IBD patients has been described in psoriatic patients regardless of the occurrence of IBD.[73] It is characterized by the depletion of symbiont bacteria, including Lactobacillus spp., Bifidobacterium spp., and F. prausnitzii, and the colonization by certain pathobionts, such as Escherichia coli, Salmonella sp., Helicobacter sp., Campylobacter sp., Mycobacterium sp., and Alcaligenes sp.[73] Moreover, colonization of the skin or gut (or both) by Staphylococcus aureus, Malassezia, and Candida albicans exacerbates psoriasis.[74] Another similarity between psoriasis and IBD is the reduced abundance of 2 beneficial bacteria species (Parabacteroides and Coprobacillus) observed in patients with psoriasis and psoriatic arthritis and in those with IBD. Decreased levels of bacteria from beneficial phyla may lead to deleterious consequences, including poor regulation of intestinal immune responses that might affect distant organ systems.[73]

Faecalibacterium prausnitzii, a beneficial microbial inhabitant of the large intestine, provides many benefits to the host. It serves as a significant source of butyrate, an SCFA that provides energy for colonocytes, reduces oxidative stress, and exerts anti-inflammatory action by triggering regulatory T cells, thereby conferring immune tolerance beyond the GI system.[7576] This species is much less abundant in the gut of psoriatic patients than in healthy ones.[77] Furthermore, intestinal dysbiosis generates endotoxin-peptidoglycan superantigens that induce autoimmune and inflammatory conditions associated with psoriasis. An immune response is triggered in response to the toxins produced by microorganisms in the gut and psoriatic patients exhibit positive skin test to gut bacterial antigens.[787980818283] It has also been proposed that the far-reaching effects of intestinal dysbiosis stem from dissemination gut microbes and their metabolites through sites of disrupted intestinal barrier. This would allow them to enter the systemic circulation and target directly distant organs, including the skin and joints. Accordingly, DNA of gut microbial origin has been isolated from the blood of patients with active psoriasis.[84]

Modulation of the Gut Microbiota for Treatment and Prevention (Restoration of the Gut Ecosystem)

The diet greatly affects the gut microbiome within either a short or a long timeframe. In addition to the role of long-term dietary habits in shaping bacterial composition, short-term dietary changes might drastically alter gut bacteria communities as well. The elucidation of the gut microbiome's influence on inflammatory disease provides an opportunity to purposely modify the microbiome with therapeutic aims.[85] Probiotic supplementation, the oral administration of living beneficial gut bacteria, has a potential role in the management and prevention of various skin conditions.[6986878889]

Probiotics and psoriasis

Although data on probiotic supplementation in psoriasis treatment are limited, promising outcomes have been documented. Psoriasis is often associated with intestinal inflammation, such as IBD, the pathophysiology is closely associated with the dysbiosis of the gut.[90] Moreover, a recent study showed that psoriasis has been associated with gut dysbiosis.[91] One study was shown that Lactobacillus pentosus GMNL-77 administration (as a probiotic) in an imiquimod-induced psoriasis mouse model results in significantly less erythema, scaling, and epidermal thickening when compared with untreated control mice.[41] In another study, the same probiotic suppressed the expression of TNF-α, IL-6, and proinflammatory cytokines in the IL-23/IL-17 cytokine axis.[92] Though the mechanism for reduced T-cell activity was unclear, the authors proposed that this effect was mediated by the suppression of CD103+ dendritic cells, intestinal antigen-presenting cells that modulate regulatory T cells in the GI tract.[93] Furthermore, in a placebo-controlled study of psoriasis patients, Bifidobacterium infantis 35624 supplementations led to significantly decreased plasma levels of TNF-α when compared with the placebo group.[92] The effectiveness of probiotic treatment was highlighted in a case severe pustular psoriasis that had been unresponsive to steroids, dapsone, and methotrexate. After initiating Lactobacillus sporogenes supplementation 3 times per day, the patients showed significant clinical improvement within 2 weeks, with almost complete remission after 4 weeks.[94]

Primary care and skin conditions

The primary care physicians are the first line of managing skin conditions. Disorders related to the skin accounted (>44 million) office visits in the United States in 2015 which is according to the Centers for Disease Control and Preventions (CDCs). Also, skin disorders remain among the top 20 leading reasons for office visits to family physicians. Moreover, an epidemiological study conducted to assess the most prevalent conditions in American Population found that skin diseases to be the most common reason for the clinic visit.[95] Most skin disorders which managed at primary care improve and most patients are satisfied with the care they receive for their skin lesions.[96] The primary physicians should have a high index of clinical suspicion for skin disorder in primary care to early intervention and proper management.

Conclusion

Basic research and clinical studies demonstrate the contribution of gut microbiome to host homeostasis, allostasis, and the pathogenesis of diseases. Through complex immune mechanisms, the gut microbiome has the ability to affect distant organ systems, including the skin. By modulating microbiome communities, probiotics might be beneficial in the prevention and treatment of inflammatory skin diseases including psoriasis. Future studies should aim to elucidate the complex mechanisms underlying the gut-skin axis with special focus on the therapeutic potential of long-term modulation of the gut microbiome through administration of probiotics. Most of the probiotics containing lactic acid-producing bacteria strains are nonpathogenic and nontoxigenic. More than 70 clinical studies on food containing microbial ingredients have been conducted to investigate the potential side effects of probiotics and none has shown any adverse effects.[97] Therefore, probiotics have the potential to treat psoriasis, and other skin diseases, through its effect on gut microbiome communities with low risks of adverse effects.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.