|Year : 2019 | Volume
| Issue : 11 | Page : 3496-3503
The role of gut microbiome in the pathogenesis of psoriasis and the therapeutic effects of probiotics
Dalal I Alesa1, Haidar M Alshamrani2, Yahya A Alzahrani3, Dania N Alamssi4, Nada S Alzahrani2, Marwan E Almohammadi5
1 Dermatology Resident, Alnoor Specialist Hospital, Makkah, Saudi Arabia
2 Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
3 Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
4 General Practitioner, Consultant Center for Dermatology and Venereology Clinics, Makkah, Saudi Arabia
5 Faculty of Medicine, Albaha University, Albaha, Saudi Arabia
|Date of Submission||28-Aug-2019|
|Date of Decision||17-Sep-2019|
|Date of Acceptance||04-Oct-2019|
|Date of Web Publication||15-Nov-2019|
Dr. Yahya A Alzahrani
Faculty of Medicine, King Abdulaziz University, Jeddah
Source of Support: None, Conflict of Interest: None
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.
Keywords: Autoimmune disease, cytokine, inflammation, Lactobacillus, regulatory T cells, short-chain fatty acid
|How to cite this article:|
Alesa DI, Alshamrani HM, Alzahrani YA, Alamssi DN, Alzahrani NS, Almohammadi ME. The role of gut microbiome in the pathogenesis of psoriasis and the therapeutic effects of probiotics. J Family Med Prim Care 2019;8:3496-503
|How to cite this URL:|
Alesa DI, Alshamrani HM, Alzahrani YA, Alamssi DN, Alzahrani NS, Almohammadi ME. The role of gut microbiome in the pathogenesis of psoriasis and the therapeutic effects of probiotics. J Family Med Prim Care [serial online] 2019 [cited 2019 Dec 11];8:3496-503. Available from: http://www.jfmpc.com/text.asp?2019/8/11/3496/270939
| 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., 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.,, Psoriasis is an immune-mediated inflammatory skin disease, whose development depends on both genetic factors and external triggers., However, its pathogenesis is still not fully understood. 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). 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., This collection of microbes outnumber host cells by 10-fold and contains genetic material 150 times greater than that of the host., The establishment of bacterial communities occurs mainly during the first 3 years of life; however, more recent evidence indicates that GI colonization may begin in utero. 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.,,,,
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. Aerobic species are mainly located in the small intestine and anaerobic species in the colon. 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.,
Commensal bacteria prime the gut immune system through specific interactions between bacterial antigens and pattern recognition receptors expressed by a variety of host cells. 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  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. Certain microbes can also contribute to intestinal epithelial barrier function through cross-talk signaling with elements of mucosal immunity.,,, For example, Lactobacillus rhamnosus GG, a commensal species, secretes p40, a protein that suppresses cytokine-mediated apoptosis and epithelial barrier disruption.
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., 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. 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.,,
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., 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.,,, 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.,,
The gut microbiome affects skin homeostasis through its influence on the signaling pathways that coordinate epidermal differentiation. 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. 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. 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.,, 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., For instance, intestinal bacteria DNA has been isolated successfully from the plasma of psoriatic patients. Moreover, in some cases of intestinal barrier disruption, intestinal bacteria and their metabolites access the bloodstream and impair skin homeostasis after their accumulation there. 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. Such effects were possibly caused by increased serotonin release from intestinal enterochromaffin cells followed by activation of parasympathetic pathways. A considerable decrease in transepidermal water loss (TEWL), a marker of skin barrier function, was noted as well. 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. In another study, it was shown that bacterial supplementation positively affects skin barrier function. 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.,
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.,, 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. 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).,,, 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. In wound sites, Foxp3+ regulatory T cells were abundant in the treated group, whereas neutrophils were almost absent, helping to decrease time to heal. 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. 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.,
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., 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. These cells and their proinflammatory cytokines contribute directly to the pathogenesis of several chronic inflammatory dermatoses, including psoriasis, Behcet's disease, and contact hypersensitivity.,, The balance between Th17 effector cells and their counterpart regulatory T cells is greatly influenced by the gut microbiome. 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.
| 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., 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., 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 is a chronic immune-mediated relapsing-remitting inflammatory dermatosis triggered by multiple environmental and endogenous factors in genetically susceptible individuals.,,, 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. 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., 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.,,,,,,
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.,, Certain genetic and environmental factors and immune pathways have been shown to be involved in the etiopathogenesis of both diseases. For example, Th17 cells and their cytokines play essential roles in the development of psoriasis and in the pathophysiology of IBD., 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.
The same pattern of dysbiosis found in IBD patients has been described in psoriatic patients regardless of the occurrence of IBD. 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 More Details coli, Salmonella More Details sp., Helicobacter sp., Campylobacter sp., Mycobacterium sp., and Alcaligenes sp. Moreover, colonization of the skin or gut (or both) by Staphylococcus aureus, Malassezia, and Candida albicans exacerbates psoriasis. 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.
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., This species is much less abundant in the gut of psoriatic patients than in healthy ones. 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.,,,,, 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.
| 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. Probiotic supplementation, the oral administration of living beneficial gut bacteria, has a potential role in the management and prevention of various skin conditions.,,,,
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. Moreover, a recent study showed that psoriasis has been associated with gut dysbiosis. 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. 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. 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. 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. 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.
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. Most skin disorders which managed at primary care improve and most patients are satisfied with the care they receive for their skin lesions. 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. 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
Conflicts of interest
There are no conflicts of interest.
| References|| |
O'Neill CA, Monteleone G, McLaughlin JT, Paus R. The gut-skin axis in health and disease: A paradigm with therapeutic implications. BioEssays 2016;38:1167-76.
Levkovich T, Poutahidis T, Smillie C, Varian BJ, Ibrahim YM, Lakritz JR, et al.
Probiotic bacteria induce a 'glow of health'. PLoS One 2013;8:e53867.
Gloster HM, Gebauer LE, Mistur RL. Cutaneous manifestations of gastrointestinal disease. In: Gloster HM, Gebauer LE, Mistur RL, editors. Absolute Dermatology Review. Cham: Springer; 2016. p. 171-9.
Shah KR, Boland CR, Patel M, Thrash B, Menter A. Cutaneous manifestations of gastrointestinal disease: Part I. J Am Acad Dermatol 2013;68:189.e1-21.
Thrash B, Patel M, Shah KR, Boland CR, Menter A. Cutaneous manifestations of gastrointestinal disease: Part II. J Am Acad Dermatol 2013;68:211.e1-33.
Ayala-Fontanez N, Soler DC, McCormick TS. Current knowledge on psoriasis and autoimmune diseases. Psoriasis 2016;6:7-32.
Capon F. The genetic basis of psoriasis. Int J Mol Sci 2017;18:2526.
Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med 2009;361:496-509.
Riiser A. The human microbiome, asthma, and allergy. Allergy Asthma Clin Immunol 2015;11:35.
Power SE, O'Toole PW, Stanton C, Ross RP, Fitzgerald GF. Intestinal microbiota, diet and health. Br J Nutr 2013;111:387-402.
Ipci K, Altıntoprak N, Muluk NB, Senturk M, Cingi C. The possible mechanisms of the human microbiome in allergic diseases. Eur Arch Otorhinolaryngol 2016;274:617-26.
Wu GD, Lewis J. Analysis of the human gut microbiome and association with disease. Clin Gastroenterol Hepatol 2013;11:774-7.
Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, et al.
Human gut microbiome viewed across age and geography. Nature 2012;486:222-7.
Moles L, Gómez M, Heilig H, Bustos G, Fuentes S, de Vos W, et al.
Bacterial diversity in meconium of preterm neonates and evolution of their fecal microbiota during the first month of life. PLoS One 2013;8:e66986.
Bäckhed F, Roswall J, Peng Y, Feng Q, Jia H, Kovatcheva-Datchary P, et al.
Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe 2015;17:690-703.
Harmsen HJ, Wildeboer-Veloo AC, Raangs GC, Wagendorp AA, Klijn N, Bindels JG, et al.
Analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods. J Pediatr Gastroenterol Nutr 2000;30:61-7.
Li M, Wang M, Donovan SM. Early development of the gut microbiome and immune-mediated childhood disorders. Semin Reprod Med 2014;32:74-86.
Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al.
A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010;464:59-65.
Ursell LK, Clemente JC, Rideout JR, Gevers D, Caporaso JG, Knight R. The interpersonal and intrapersonal diversity of human-associated microbiota in key body sites. J Allergy Clin Immunol 2012;129:1204-8.
Mowat AM, Agace WW. Regional specialization within the intestinal immune system. Nat Rev Immunol 2014;14:667-85.
Boyle RJ, Lahtinen SJ, Tang MLK. Probiotics and skin. In: Pappas A, editor. Nutrition and Skin. New York: Springer; 2011. p. 111-27.
Kosiewicz MM, Dryden GW, Chhabra A, Alard P. Relationship between gut microbiota and development of T cell associated disease. FEBS Lett 2014;588:4195-206.
Suzuki K, Kawamoto S, Maruya M, Fagarasan S. GALT: Organization and dynamics leading to IgA synthesis. Adv Immunol 2010;107:153-85.
Bik EM. Composition and function of the human-associated microbiota. Nutr Rev 2009;67(Suppl 2):S164-71.
Purchiaroni F, Tortora A, Gabrielli M, Bertucci F, Gigante G, Ianiro G, et al.
The role of intestinal microbiota and the immune system. Eur Rev Med Pharmacol Sci 2013;17:323-33.
Rajilić-Stojanović M, de Vos WM. The first 1000 cultured species of the human gastrointestinal microbiota. FEMS Microbiol Rev 2014;38:996-1047.
Sirisinha S. The potential impact of gut on your health: Current status and future challenges. Asian Pac J Allergy Immunol 2016;34:249-64.
Kim YG, Udayanga KG, Totsuka N, Weinberg JB, Núñez G, Shibuya A. Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi- induced PGE2. Cell Host Microbe 2014;15:95-102.
Baba H, Masuyama A, Yoshimura C, inventors; Calpis Co Ltd, assignee. Promoter of differentiation and keratinization of epidermic cell and functional beverage/food for promotion of keratinization of epidermis. United States patent US 8,097,246. 2012 Jan 17.
Abhishek S, Palamadai Krishnan S. Epidermal differentiation complex: A review on its epigenetic regulation and potential drug targets. Cell J 2016;18:1-6.
Weaver CT, Elson CO, Fouser LA, Kolls JK. The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. Annu Rev Pathol 2013;8:477-512.
Gaur M, Dobke M, Lunyak VV. Mesenchymal stem cells from adipose tissue in clinical applications for dermatological indications and skin aging. Int J Mol Sci 2017;18:208.
Forbes JD, Van Domselaar G, Bernstein CN. The gut microbiota in immune-mediated inflammatory diseases. Front Microbiol 2016;7:1081.
Meijer K, de Vos P, Priebe MG. Butyrate and other short-chain fatty acids as modulators of immunity: What relevance for health? Curr Opin Clin Nutr Metab Care 2010;13:715-21.
Loser K, Beissert S. Regulatory T cells: Banned cells for decades. J Invest Dermatol 2012;132:864-71.
Samuelson DR, Welsh DA, Shellito JE. Regulation of lung immunity and host defense by the intestinal microbiota. Front Microbiol 2015;6:1085.
Horii Y, Kaneda H, Fujisaki Y, Fuyuki R, Nakakita Y, Shigyo T, et al.
Effect of heat-killed Lactobacillus brevis
SBC8803 on cutaneous arterial sympathetic nerve activity, cutaneous blood flow and transepidermal water loss in rats. J Appl Microbiol 2014;116:1274-81.
Ogawa M, Saiki A, Matsui Y, Tsuchimoto N, Nakakita Y, Takata Y, et al.
Effects of oral intake of heat-killed Lactobacillus brevis
SBC8803 (SBL88™) on dry skin conditions: A randomized, double-blind, placebo-controlled study. Exp Ther Med 2016;12:3863-72.
Gueniche A, Philippe D, Bastien P, Reuteler G, Blum S, Castiel-Higounenc I, et al.
Randomised double-blind placebo- controlled study of the effect of Lactobacillus paracasei
NCC 2461 on skin reactivity. Benef Microbes 2014;5:137-45.
Benyacoub J, Bosco N, Blanchard C, Demont A, Philippe D, Castiel-Higounenc I, et al.
Immune modulation property of Lactobacillus paracasei
NCC2461 (ST11) strain and impact on skin defences. Benef Microbes 2014;5:129-36.
Chen YH, Wu CS, Chao YH, Lin CC, Tsai HY, Li YR, et al. Lactobacillus pentosus
GMNL-77 inhibits skin lesions in imiquimod-induced psoriasis-like mice. J Food Drug Anal 2017;25:559-66.
Baba H, Masuyama A, Yoshimura C, Aoyama Y, Takano T, Ohki K. Oral intake of Lactobacillus helveticus
-fermented milk whey decreased transepidermal water loss and prevented the onset of sodium dodecylsulfate-induced dermatitis in mice. Biosci Biotechnol Biochem 2010;74:18-23.
Branchet-Gumila MC, Boisnic S, Le Charpentier Y, Nonotte I, Montastier C, Breton L. Neurogenic modifications induced by substance P
in an organ culture of human skin. Skin Pharmacol Appl Skin Physiol 1999;12:211-20.
Guéniche A, Benyacoub J, Philippe D, Bastien P, Kusy N, Breton L. Lactobacillus paracasei
CNCM I-2116 (ST11) inhibits substance P-induced skin inflammation and accelerates skin barrier function recovery in vitro
. Eur J Dermatol 2010;20:731-7.
Philippe D, Blum S, Benyacoub J. Oral Lactobacillus paracasei
improves skin barrier function recovery and reduces local skin inflammation. Eur J Dermatol 2011;21:279-80.
Poutahidis T, Kearney SM, Levkovich T, Qi P, Varian BJ, Lakritz JR, et al.
Microbial symbionts accelerate wound healing via the neuropeptide hormone oxytocin. PLoS One 2013;8:e78898.
Guéniche A, Benyacoub J, Buetler TM, Smola H, Blum S. Supplementation with oral probiotic bacteria maintains cutaneous immune homeostasis after UV exposure. Eur J Dermatol 2006;16:511-7.
Dougan SK, Kaser A, Blumberg RS. CD1 expression on antigen-presenting cells. In: Moody DB, editor. Current Topics in Microbiology and Immunology. Heidelberg: Springer; 2007. p. 113-41.
Peguet-Navarro J, Dezutter-Dambuyant C, Buetler T, Leclaire J, Smola H, Blum S. Supplementation with oral probiotic bacteria protects human cutaneous immune homeostasis after UV exposure – double blind, randomized, placebo controlled clinical trial. Eur J Dermatol 2008;18:504-11.
Chapat L, Chemin K, Dubois B, Bourdet-Sicard R, Kaiserlian D. Lactobacillus casei
reduces CD8+T cell-mediated skin inflammation. Eur J Immunol 2004;34:2520-8.
Hacini-Rachinel F, Gheit H, Le Luduec JB, Dif F, Nancey S, Kaiserlian D. Oral probiotic control skin inflammation by acting on both effector and regulatory T cells. PLoS One 2009;4:e4903.
Van Beelen AJ, Teunissen MB, Kapsenberg ML, de Jong EC. Interleukin-17 in inflammatory skin disorders. Curr Opin Allergy Clin Immunol 2007;7:374-81.
Esplugues E, Huber S, Gagliani N, Hauser AE, Town T, Wan YY, et al.
Control of TH17 cells occurs in the small intestine. Nature 2011;475:514-8.
Huang BL, Chandra S, Shih DQ. Skin manifestations of inflammatory bowel disease. Front Physiol 2012;3:13.
Dawson LF, Donahue EH, Cartman ST, Barton RH, Bundy J, McNerney R, et al.
The analysis of para-cresol production and tolerance in Clostridium difficile
027 and 012 strains. BMC Microbiol 2011;11:86.
Miyazaki K, Masuoka N, Kano M, Iizuka R. Bifidobacterium fermented milk and galacto-oligosaccharides lead to improved skin health by decreasing phenols production by gut microbiota. Benef Microbes 2014;5:121-8.
Parisi R, Symmons DP, Griffiths CE, Ashcroft DM. Global epidemiology of psoriasis: A systematic review of incidence and prevalence. J Invest Dermatol 2013;133:377-85.
Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the United States. J Am Acad Dermatol 2014;70:512-6.
Kulig P, Musiol S, Freiberger SN, Schreiner B, Gyülveszi G, Russo G, et al.
IL-12 protects from psoriasiform skin inflammation. Nat Commun 2016;7:13466.
Takeshita J, Grewal S, Langan SM, Mehta NN, Ogdie A, Van Voorhees AS, et al.
Psoriasis and comorbid diseases: Epidemiology. J Am Acad Dermatol 2017;76:377-90.
Mari NL, Simão ANC, Dichi I. n-3 polyunsaturated fatty acids supplementation in psoriasis: A review. Nutrire 2017;42:5.
Roberson EDO, Bowcock AM. Psoriasis genetics: Breaking the barrier. Trends Genet 2010;26:415-23.
Baba H, Masuyama A, Takano T. Effects of Lactobacillus helveticus
-fermented milk on the differentiation of cultured normal human epidermal keratinocytes. J Dairy Sci 2006;89:2072-5.
Fitch E, Harper E, Skorcheva I, Kurtz SE, Blauvelt A. Pathophysiology of psoriasis: Recent advances on IL-23 and Th17 cytokines. Curr Rheumatol Rep 2007;9:461-7.
Guttman-Yassky E, Lowes MA, Fuentes-Duculan J, Zaba LC, Cardinale I, Nograles KE, et al.
Low expression of the IL- 23/Th17 pathway in atopic dermatitis compared to psoriasis. J Immunol 2008;181:7420-7.
Ma HL, Liang S, Li J, Napierata L, Brown T, Benoit S, et al.
IL- 22 is required for Th17 cell–mediated pathology in a mouse model of psoriasis-like skin inflammation. J Clin Invest 2008;118:597-607.
Gaffen SL, Jain R, Garg AV, Cua DJ. The IL-23–IL-17 immune axis: From mechanisms to therapeutic testing. Nat Rev Immunol 2014;14:585-600.
Warren R, Menter A, editors. Handbook of Psoriasis and Psoriatic Arthritis. Cham: Springer; 2016.
Salem I, Ramser A, Isham N, Ghannoum MA. The gut microbiome as a major regulator of the gut-skin axis. Front Microbiol 2018;9:1459.
Eppinga H, Konstantinov SR, Peppelenbosch MP, Thio HB. The microbiome and psoriatic arthritis. Curr Rheumatol Rep 2014;16:407.
Verstockt B, Van Assche G, Vermeire S, Ferrante M. Biological therapy targeting the IL-23/IL-17 axis in inflammatory bowel disease. Expert Opin Biol Ther 2016;17:31-47.
Omenetti S, Pizarro TT. The Treg/Th17 axis: A dynamic balance regulated by the gut microbiome. Front Immunol 2015;6:639.
Scher JU, Ubeda C, Artacho A, Attur M, Isaac S, Reddy SM, et al.
Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheumatol 2014;67:128-39.
Fry L, Baker BS. Triggering psoriasis: The role of infections and medications. Clin Dermatol 2007;25:606-15.
Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermudez-Humaran LG, Gratadoux JJ, et al. Faecalibacterium prausnitzii
is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA 2008;105:16731-6.
Lopez-Siles M, Khan TM, Duncan SH, Harmsen HJ, Garcia-Gil LJ, Flint HJ. Cultured representatives of two major phylogroups of human colonic Faecalibacterium prausnitzii
can utilize pectin, uronic acids, and host-derived substrates for growth. Appl Environ Microbiol 2011;78:420-8.
Eppinga H, Sperna Weiland CJ, Thio HB, van der Woude CJ, Nijsten TE, Peppelenbosch MP, et al.
Similar depletion of protective Faecalibacterium prausnitzii
in psoriasis and inflammatory bowel disease, but not in hidradenitis suppurativa. J Crohns Colitis 2016;10:1067-75.
Baker BS, Laman JD, Powles A, van der Fits L, Voerman JS, Melief MJ, et al.
Peptidoglycan and peptidoglycan-specific Th1 cells in psoriatic skin lesions. J Pathol 2006;209:174-81.
Baker BS, Powles A, Fry L. Peptidoglycan: A major aetiological factor for psoriasis?. Trends Immunol 2006;27:545-51.
Gyurcsovics K, Bertók L. Pathophysiology of psoriasis: Coping endotoxins with bile acid therapy. Pathophysiology 2003;10:57-61.
Korotky NG, Peslyak MY. Psoriasis as a consequence of incorporation of beta-streptococci into the microbiocenosis of highly permeable intestines (a pathogenic concept). [Article in Russian]. Vestn Dermatol Venereol 2005;1:9-18.
Qayoom S, Ahmad QM. Psoriasis and Helicobacter pylori
. Indian J Dermatol Venereol Leprol 2003;69:133-4.
] [Full text]
Stenina MA, Kulagin VI, Rudkovskaya ZV. Role of disturbances of intestine barrier function in pathogenesis of psoriasis in children. [Article in Russian]. Vestn Dermatol Venereol 2003;2:20-3.
Ramírez-Boscá A, Navarro-López V, Martínez-Andrés A, Such J, Francés R, Horga de la Parte J, et al.
Identification of bacterial DNA in the peripheral blood of patients with active psoriasis. JAMA Dermatol 2015;151:670.
Huang YJ, Marsland BJ, Bunyavanich S, O'Mahony L, Leung DY, Muraro A, et al.
The microbiome in allergic disease: Current understanding and future opportunities—2017 PRACTALL document of the American Academy of Allergy, Asthma and Immunology and the European Academy of Allergy and Clinical Immunology. J Allergy Clin Immunol 2017;139:1099-110.
Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al.
The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 2014;11:506-14.
Grant MC, Baker JS. An overview of the effect of probiotics and exercise on mood and associated health conditions. Crit Rev Food Sci Nutr 2017;57:3887-93.
Sánchez B, Delgado S, Blanco-Míguez A, Lourenço A, Gueimonde M, Margolles A. Probiotics, gut microbiota, and their influence on host health and disease. Mol Nutr Food Res 2016;61:1600240.
Sarao LK, Arora M. Probiotics, prebiotics, and microencapsulation: A review. Crit Rev Food Sci Nutr 2015;57:344-71.
Szántó M, Dózsa A, Antal D, Szabó K, Kemény L, Bai P. Targeting the gut-skin axis–probiotics as new tools for skin disorder management?. Exp Dermatol 2019. doi: 10.1111/exd. 14016.
Hidalgo-Cantabrana C, Gomez J, Delgado S, Requena-Lopez S, Queiro-Silva R, Margolles A, et al.
Gut microbiota dysbiosis in a cohort of patients with psoriasis. Br J Dermatol 2019. doi: 10.1111/bjd.17931.
Nermes M, Kantele JM, Atosuo TJ, Salminen S, Isolauri E. Interaction of orally administered Lactobacillus rhamnosus
GG with skin and gut microbiota and humoral immunity in infants with atopic dermatitis. Clin Exp Allergy 2010;41:370-7.
Groeger D, O'Mahony L, Murphy EF, Bourke JF, Dinan TG, Kiely B, et al. Bifidobacterium infantis
35624 modulates host inflammatory processes beyond the gut. Gut Microbes 2013;4:325-39.
Vijayashankar M, Raghunath N. Pustular psoriasis responding to probiotics – A new insight. Our Dermatol Online 2012;3:326-8.
St Sauver JL, Waner DO, Yawn BP, Jacobesen DJ, McGree ME, Pankratz JJ, et al.
Why patients visit their doctors: Assessing the most prevalent conditions in a defined American Population. Mayo Clin Proc 2001;88:56-67.
Estrada Castanon R, Andersson N, Hay R. Community dermatology and the management of skin diseases in developing countries. Trop Doct 1992;22:3-6.
Saavedra JM. Use of probiotics in pediatrics: Rationale, mechanisms of action, and practical aspects. Nutr Clin Pract 2007;22:351-65.