This paper is part of NMJ's 2018 Microbiome Special Issue. Download the full issue here.
The association between gut health and general health has been the focus of many medical approaches, including traditional Chinese medicine, Ayurvedic medicine, and naturopathic medicine. The discovery of the gut microbiome has led to new areas of research that focus on the possible biochemical mechanisms that can relate gut health to local disease as well as the health of distant organs. The relationship of the gut to the skin, referred to as the gut-skin axis, is one emerging area of research. Here we review several potential mechanisms by which the gut may interact with the rest of the body and the skin, along with several skin-related examples. Further research is needed to delineate the biochemical mechanisms in this emerging and exciting area.
The gut and skin are both complex immune and neuroendocrine organs, and each has a community of microbes that governs the physiology of their local surroundings.1 A 3-directional communication among the brain, skin, and gut, along with influences from the immune and endocrine systems, has been identified, although not fully understood.1 Pathology of the gastrointestinal tract and diet have been shown to influence skin health.2,3 Many skin conditions have been linked to gastrointestinal inflammation, including rosacea, psoriasis, and acne.2-4 Skin lesions can also occur in association with gastrointestinal conditions such as inflammatory bowel disease (IBD) and celiac disease.5,6
The recognition that the gut and skin are connected is not new; traditional forms of medicine that have been around for thousands of years, such as Ayurvedic medicine and traditional Chinese medicine, have a gut-centric approach to health and disease. As research continues to expand in this area, the notion of a gut-skin axis has started to emerge in Western research. In this review, we aim to discuss emerging mechanisms for how the gut may influence dermatologic health.
Modes of Communication From the Gut to the Skin
The gut may communicate with the skin in several ways:
- Absorption of nutrients with a direct effect on the skin
- Absorption of nutrients that can stimulate hormonal changes that affect the skin
- Influence of gut microbiota on the immune system
- Modulation of the local microbiome that releases metabolites that may have distant effects on the skin
Absorption of nutrients with a direct effect on the skin
The absorption of nutrients and their direct effects on the skin has been a focus of several studies. For example, the intake of carotenoids has been correlated to yellowing of the skin,7,8 and beta-carotene supplementation has been studied in the prevention of sunburns.9 In addition, oral vitamin E can be delivered to the skin, especially through sebaceous glands.10
Absorption of nutrients that stimulate a change in hormones
Absorbed nutrients frequently shift hormones in the body. Examples include the influence of carbohydrates and whey protein on insulin levels, which can have an impact on the skin. As an example, whey protein may be associated with increased insulin secretion11 and has been reported as a potential culprit in acne flares.12-14 Insulin-like growth factor 1 (IGF-1) activates the sebaceous glands to produce more inflammatory mediators and more sebum,15 which may trigger a worsening of acne. Moreover, consuming more high-glycemic, refined carbohydrates may increase the concentration of IGF-1 and increase the risk of developing acne.16
The influence of gut microbiota on the immune system
The gut microbiota interact with the immune system and appear to interact with and educate the regulatory T cells that can drive inflammation elsewhere in the body.17,18 Regulatory T cells seem to play an important role in autoimmune and inflammatory skin diseases19-21 although the role of the gut microbiome remains under study in these areas.
Modulation of the local microbiome and influence on the local immune system
The microbiota and the gut epithelial lining interact and release secondary metabolites that can have distant effects on the skin. Previous studies have suggested that changes in gut microbiota and the microbiota-derived inflammatory mediators may impact chronic inflammation and the risk for cardiovascular disease, obesity, kidney disease, and diabetes.22 There is growing evidence that gut-derived mediators may communicate with the skin as well. Examples of mediators include lipopolysaccharide (LPS) and short chain fatty acids. It has been hypothesized that gut-derived LPS may play a role in acne inflammation,23 though definitive mechanistic studies are still lacking. Short-chain fatty acids have long been postulated to affect general inflammation in the body and modulate obesity, diabetes, and colon cancer risk.24,25 Short-chain fatty acids may modulate inflammation,25 and patients with acne have lower blood levels of these fatty acids than healthy controls (Sivamani, unpublished data, 2018).
While these mechanisms may not serve as a comprehensive examination of the gut-skin axis, they bring to light the gut’s ability to communicate with the skin through multiple modalities. As research continues to grow, we will gain a better understanding of which of these mechanisms, and likely other mechanisms, may serve as important mediators and thus a target for both pharmacological and nutritional intervention.
Apart from possible mechanisms, there are several lines of evidence that suggest that gut dysbiosis is involved in skin disease. We review a few of them below.
Disease-Based Examples of Gut Dysbiosis in Skin Disease
Small intestinal bacterial overgrowth and papulopustular rosacea
Often mistaken for acne, papulopustular rosacea can occur with erythematotelangiectatic rosacea, and is characterized by erythema, papules, and pustules.26 Papulopustular rosacea is not only associated with a dysbiosis of the cutaneous microbiome, but also with small intestinal bacterial overgrowth (SIBO), a dysbiosis of the intestinal tract.3,27 Oral antibiotic treatment of SIBO has been shown to induce remission in rosacea symptoms.3,28,29
Dysbiosis and psoriasis
One recent study comparing the gut microbial composition of patients with psoriasis to that of healthy patients found that psoriasis patients had an increased presence of Faecalibacterium and decreased Bacteroides compared to the healthy controls.4 A similar study found that, compared to healthy controls, psoriasis patients had an increased ratio of Faecalibacterium to Bacteroides in the intestinal microbiome and an increase in Streptococcus and decrease in both Propionibacterium and Actinobacteria on the skin’s surface.4
The recognition that the gut and skin are connected is not new; traditional forms of medicine that have been around for thousands of years, such as Ayurvedic medicine and traditional Chinese medicine, have a gut-centric approach to health and disease.
High-glycemic diet and acne vulgaris
The Standard American Diet (SAD) is a high-glycemic diet rich in processed fast foods, refined carbohydrates, animal proteins, and omega-6 polyunsaturated fatty acids.30 Seventy-five percent of Americans consume a Standard American Diet.31 Studies have shown that consuming a Standard American Diet increases pro-inflammatory mediators.31 Leucine, an amino acid found in animal protein and dairy products, stimulates the mammalian target of rapamycin complex 1 (mTORC1);32 mTORC1 then activates SREBP,33 which is a transcription factor that drives lipogenesis in the sebocytes. Sebocytes convert leucine into fatty acids and sterols to synthesize sebaceous lipids.33 Overaction of mTORC1 through the consumption of a SAD increases the secretion of androgen hormones such as testosterone, which activates mTORC1 to stimulate the sebaceous follicles to produce more sebum.33 Acne is recognized to be an mTORC1-driven disease of civilization and diet.32,33 Areas where high-glycemic diets are not consumed, such as in isolated hunter-gatherer communities, have extremely low rates of acne.34
Inflammatory bowel disease and various skin lesions
Crohn’s disease and ulcerative colitis are the 2 main categories of IBD.6 Their pathophysiology is not limited to the gastrointestinal tract; IBD is associated with extraintestinal manifestations in 6% to 47% of patients.6 In 25% of patients with IBD, the extraintestinal manifestations precede the diagnosis of Crohn’s or ulcerative colitis.6 The cutaneous extraintestinal manifestations of IBD include erythema nodosum, pyoderma gangrenosum, Sweet's syndrome, and oral lesions.6 Erythema nodosum is the most commonly reported skin lesion associated with IBD, and pyoderma gangrenosum reflects IBD in its most severe state.6 Although the mechanism is not well-understood, information collected from a clinical trial suggested that blockade of tumor necrosis factor (TNF) may play a role in the pathogenesis of these skin conditions in IBD.6
Celiac disease and dermatitis herpetiformis
Dermatitis herpetiformis is an extremely pruritic eruption seen on the buttocks and the extensor surfaces of the extremities. It affects approximately 17% of patients with celiac disease,5 though it may not be detected until up to 10 years after the celiac disease diagnosis.5 In most cases, dermatitis herpetiformis in patients with celiac disease indicates poor adherence to a gluten-free diet.5
The Role of Probiotics
Oral probiotics act locally when ingested, but can have effects on distant organ systems through the immune system.35 Through interactions with lymphoid tissue, probiotics may regulate the release of inflammatory cytokines that are often increased in various skin conditions.36 Indeed, there are several lines of evidence supporting the use of probiotics for skin conditions.
A systematic review and meta-analysis of randomized controlled trials concluded that, although Lactobacillus plantarum and Lactobacillus rhamnosus did not have a significant effect on SCORAD (scoring atopic dermatitis) scores in children with atopic dermatitis, Lactobacillus fermentum, Lactobacillus salivarius, and a mixture of 4 different strains (Lactobacillus rhamnosus GG, L rhamnosus LC705, Bifidobacterium breve, and Propionibacterium freudenreichii ssp Shermanii) did.37,38 In acne patients, oral supplementation of Lactobacillus decreased the levels of IGF-1 fourfold compared to no probiotic supplementation.39 In another study, patients with acne who were supplementing with Lactobacillus acidophilus, Lactobacillus delbrueckii, and Bifidobacterium bifidum along with conventional antibiotic treatment experienced increased resolution of their acne and better tolerance of the antibiotic treatment.40
Despite these promising results, there remain many questions. Further research is needed to better understand how specific strains should be chosen and dosed. Most of the research has focused on bacteria, and it is not known if fungal microbiota and probiotics that are inclusive of fungi are important.
While questions still remain, there is no doubt that further research into the gut microbiome and how it contributes more widely to general health is exciting. As our knowledge grows regarding how food, probiotics, and the gut microbiome modulate health, it is our hope that our dietary and lifestyle patterns will shift toward both healthier skin and a healthier metabolic state.
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- Kucharska A, Szmurlo A, Sinska B. Significance of diet in treated and untreated acne vulgaris. Postepy Dermatol Alergol. 2016;33(2):81-86.
- Agnoletti AF, DE Cole E, Parodi A, et al. Etiopathogenesis of rosacea: a prospective study with a three-year follow-up. G Ital Dermatol Venereol. 2017;152(5):418-423.
- Codoner FM, Ramirez-Bosca A, Climent E, et al. Gut microbial composition in patients with psoriasis. Sci Rep. 2018;8(1):3812.
- Salmi TT, Hervonen K, Kurppa K, Collin P, Kaukinen K, Reunala T. Celiac disease evolving into dermatitis herpetiformis in patients adhering to normal or gluten-free diet. Scand J Gastroenterol. 2015;50(4):387-392.
- Greuter T, Navarini A, Vavricka SR. Skin manifestations of inflammatory bowel disease. Clin Rev Allergy Immunol. 2017;53(3):413-427.
- Pezdirc K, Hutchesson MJ, Williams RL, et al. Consuming high-carotenoid fruit and vegetables influences skin yellowness and plasma carotenoids in young women: a single-blind randomized crossover trial. J Acad Nutr Diet. 2016;116(8):1257-1265.
- Pezdirc K, Hutchesson MJ, Whitehead R, Ozakinci G, Perrett D, Collins CE. Fruit, vegetable and dietary carotenoid intakes explain variation in skin-color in young caucasian women: a cross-sectional study. Nutrients. 2015;7(7):5800-5815.
- Kopcke W, Krutmann J. Protection from sunburn with beta-carotene--a meta-analysis. Photochem Photobiol. 2008;84(2):284-288.
- Ekanayake-Mudiyanselage S, Kraemer K, Thiele J. Oral supplementation with all-rac- and RRR-alpha-tocopherol increases vitamin E levels in human sebum after a latency period of 14-21 days. Ann N Y Acad Sci. 2006;1031(1):184-194.
- Salehi A, Gunnerud U, Muhammed SJ, et al. The insulinogenic effect of whey protein is partially mediated by a direct effect of amino acids and GIP on beta-cells. Nutr Metab (Lond). 2012;9(1):48.
- Cengiz FP, Cevirgen Cemil B, Emiroglu N, Gulsel Bahali A, Onsun N. Acne located on the trunk, whey protein supplementation: is there any association? Health Promot Perspect. 2017;7(2):106-108.
- Simonart T. Acne and whey protein supplementation among bodybuilders. Dermatology. 2012;225(3):256-258.
- Silverberg NB. Whey protein precipitating moderate to severe acne flares in 5 teenaged athletes. Cutis. 2012;90(2):70-72.
- Kim H, Moon SY, Sohn MY, Lee WJ. Insulin-like growth factor-1 increases the expression of inflammatory biomarkers and sebum production in cultured sebocytes. Ann Dermatol. 2017;29(1):20-25.
- Bowe WP, Joshi SS, Shalita AR. Diet and acne. J Am Acad Dermatol. 2010;63(1):124-141.
- Russler-Germain EV, Rengarajan S, Hsieh CS. Antigen-specific regulatory T-cell responses to intestinal microbiota. Mucosal Immunol. 2017;10(6):1375-1386.
- Sun M, He C, Cong Y, Liu Z. Regulatory immune cells in regulation of intestinal inflammatory response to microbiota. Mucosal Immunol. 2015;8(5):969-978.
- Haeberle S, Wei X, Bieber K, et al. Regulatory T-cell deficiency leads to pathogenic bullous pemphigoid antigen 230 autoantibody and autoimmune bullous disease [published online ahead of print April 26, 2018]. J Allergy Clin Immunol.
- Melnik BC, John SM, Chen W, Plewig G. T helper 17 cell/regulatory T-cell imbalance in hidradenitis suppurativa/acne inversa: the link to hair follicle dissection, obesity, smoking and autoimmune comorbidities [published online ahead of print March 24, 2018]. Br J Dermatol.
- Owczarczyk-Saczonek A, Czerwinska J, Placek W. The role of regulatory T cells and anti-inflammatory cytokines in psoriasis. Acta Dermatovenerol Alp Pannonica Adriat. 2018;27(1):17-23.
- Al-Obaide MAI, Singh R, Datta P, et al. Gut microbiota-dependent trimethylamine-n-oxide and serum biomarkers in patients with T2DM and advanced CKD. J Clin Med. 2017;6(9).
- Bowe WP, Logan AC. Acne vulgaris, probiotics and the gut-brain-skin axis - back to the future? Gut Pathog. 2011;3(1):1.
- Schwarz A, Bruhs A, Schwarz T. The short-chain fatty acid sodium butyrate functions as a regulator of the skin immune system. J Invest Dermatol. 2017;137(4):855-864.
- McNabney SM, Henagan TM. Short chain fatty acids in the colon and peripheral tissues: a focus on butyrate, colon cancer, obesity and insulin resistance. Nutrients. 2017;9(12).
- Mikkelsen CS, Holmgren HR, Kjellman P, et al. Rosacea: a clinical review. Dermatol Reports. 2016;8(1):6387.
- Gallo RL, Nakatsuji T. Microbial symbiosis with the innate immune defense system of the skin. J Invest Dermatol. 2011;131(10):1974-1980.
- Parodi A, Paolino S, Greco A, et al. Small intestinal bacterial overgrowth in rosacea: clinical effectiveness of its eradication. Clin Gastroenterol Hepatol. 2008;6(7):759-764.
- Drago F, De Col E, Agnoletti AF, et al. The role of small intestinal bacterial overgrowth in rosacea: A 3-year follow-up. J Am Acad Dermatol. 2016;75(3):e113-e115.
- Totsch SK, Quinn TL, Strath LJ, et al. The impact of the Standard American Diet in rats: Effects on behavior, physiology and recovery from inflammatory injury. Scand J Pain. 2017;17:316-324.
- United States Department of Agriculture. Dietary Guidelines for Americans 2015-2020. Current eating patterns in the United States. https://health.gov/dietaryguidelines/2015/guidelines/chapter-2/current-eating-patterns-in-the-united-states/. Accessed July 30, 2018.
- Melnik B. Dietary intervention in acne: Attenuation of increased mTORC1 signaling promoted by Western diet. Dermatoendocrinol. 2012;4(1):20-32.
- Melnik BC. Acne vulgaris: The metabolic syndrome of the pilosebaceous follicle. Clin Dermatol. 2018;36(1):29-40.
- Cordain L, Lindeberg S, Hurtado M, Hill K, Eaton SB, Brand-Miller J. Acne vulgaris: a disease of Western civilization. Arch Dermatol. 2002;138(12):1584-1590.
- Kober MM, Bowe WP. The effect of probiotics on immune regulation, acne, and photoaging. Int J Womens Dermatol. 2015;1(2):85-89.
- 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(3):e4903.
- Huang R, Ning H, Shen M, Li J, Zhang J, Chen X. Probiotics for the treatment of atopic dermatitis in children: a systematic review and meta-analysis of randomized controlled trials. Front Cell Infect Microbiol. 2017;7:392.
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- Jung GW, Tse JE, Guiha I, Rao J. Prospective, randomized, open-label trial comparing the safety, efficacy, and tolerability of an acne treatment regimen with and without a probiotic supplement and minocycline in subjects with mild to moderate acne. J Cutan Med Surg. 2013;17(2):114-122.