Unraveling the gut-skin axis in atopic dermatitis: exploiting insights for therapeutic strategies

Abstract

Gut microbiota exert functions of high importance in the intestine. Furthermore, there is increasing evidence for its role in immune regulation and maintenance of homeostasis in many physiological processes taking place in distant tissues. In particular, in this review, we explore the impact of metabolites produced by the gut microbiota on the development of atopic dermatitis (AD). Probiotics and prebiotics balance the microbiota and promote the generation of bacterial metabolites, such as short-chain fatty acids and tryptophan derivates, which promote the regulation of the exacerbated AD immune response through regulatory T cells and IL-10 and TGF-β cytokines. Metabolites also have a direct action on keratinocytes once they reach the bloodstream. Besides, probiotics decrease the levels of metabolites associated with AD onset, such as phenols. Understanding all these crosstalk processes between the gut and the skin reveals a number of possibilities, mainly through the manipulation of the gut microbiome, which may represent therapeutic strategies that can contribute to the standard treatments of AD patients to improve their quality of life.

Keywords: Atopic dermatitis; gut microbiome; gut-skin axis; phenols; prebiotics; probiotics; short-chain fatty acids; tryptophan metabolites.

Figure 1.

Physiopathology of AD. A defective skin barrier activates keratinocytes (KC) to produce thymic stromal lymphopoietin (TSLP), IL-25, and IL-33. Under these inflammatory stimuli, dendritic cells (DC) uptake penetrating antigen and migrate to skin lymph nodes (LN) to activate and differentiate T cells into Th2 and Th22 profiles. Th2 lymphocytes then promote IgE production by activated B cells (BC). Chemokines produced by keratinocytes (TARC, MDC) attract Th2 cells to dermis. Activated innate lymphoid cells (ILC)2 and Th2 cells release IL-4, IL-5 and IL-13 that trigger mast cells (MC) and eosinophils (Eo) recruitment. These inflammatory cells release factors that contribute to edema, erythema, and pruritus. IL-31 and Th2 cytokines contribute to pruritus, which induces scratching and perpetuates skin barrier disruption. Th2 cytokines disrupt the expression of skin structural proteins, such as filaggrin, enhancing dysfunctional cutaneous barrier and producing transepidermal water loss (TEWL). This inflammatory environment is associated with cutaneous dysbiosis characterized by Staphylococcus aureus colonization. In chronic lesions, Th1 and Th22 responses are enhanced, contributing to epidermal hyperplasia, keratinocyte apoptosis and barrier damage. IFN, interferon; TNF, tumor necrosis factor; AMP, antimicrobial peptides; TARC, thymus and activation regulated chemokine; MDC, macrophage derived chemokine. Created with BioRender.com.

Figure 2.

SCFAs produced through fiber fermentation by gut microbiota exert beneficial effects on AD skin. Short chain fatty acids (SCFAs) generated by microbial fermentation of non-digested fiber are transported into colonic epithelial cells and partly transferred to portal circulation to be systemically distributed. SCFAs induce: i) regulatory T (Treg) lymphocytes in gut-associated lymphoid tissue (GALT) that can migrate to the skin; ii) increased expression of transforming growth factor (TGF)-β in colonic cells; and iii) increased expression of Foxp3 in the skin. In the skin, SCFAs and Treg cells modulate the damage and inflammation associated with AD lesions. Keratinocytes (KC) express free fatty acid receptor (FFAR)2, FFAR3 and hydroxy-carboxylic acid receptor (HCA)2 receptors that in response to SCFAs promote epigenetic changes that elicit gene expression related to immunity, barrier function and keratinocyte differentiation. TEWL, transepidermal water loss; HAT, histone acetyltransferase; SCORAD, SCORing for AD; GPCR, G protein coupled receptors; MCT, H⁺-dependent monocarboxylate transporters; SMCT, Na⁺-dependent monocarboxylate transporters; HDAC, histone deacetylases. Created with BioRender.com.

Figure 3.

Effects of tryptophan and tyrosine catabolism by gut microbiota on AD. a) Indol derivates (Indol(d)) generated by microbes during tryptophan metabolism display benefits on atopic dermatitis (AD), through regulation of keratinocyte (KC) gene expression which is reflected in an improvement of AD signs and symptoms. b) Phenol derivates produced by Clostridioides difficile induce changes in the skin that are associated with barrier dysfunction and AD onset. Probiotic administration decreases serum p-cresol and improves cutaneous barrier function. ILA, indole-lactate; IPA, indole-propionate; I3C, indole-3-carbaldehyde; SCORAD, SCORing for AD; PAR-2, proteinase-activated receptor-2; AhR, aryl hydrocarbon receptor. Created with BioRender.com.

Figure 4.

Modulatory effects of prebiotics and probiotics on Treg cells and cytokines are beneficial in AD. Probiotics and prebiotics decrease levels of gut and systemic inflammatory mediators and increase anti-inflammatory cytokines and Treg cell differentiation. Peripherical Treg (pTreg) Foxp3 cells express molecules of skin recruitment (CLA, CCR4/8), and retention (CD103), and upon arriving in the dermis, are able to modulate atopic dermatitis (AD) inflammation. As result, there is an improvement in the cutaneous barrier and SCORing for AD (SCORAD) index. TNF, tumor necrosis factor; TGF, transforming growth factor; CLA, cutaneous lymphocyte-associated antigen; TEWL, transepidermal water loss. Created with BioRender.com.