Obesity and the microbiome in atopic dermatitis: Therapeutic implications for PPAR-γ agonists

Abstract

Atopic dermatitis (AD) is an inflammatory skin disease characterized by epidermal barrier disruption, Th2 immune responses to skin allergens and microbial dysbiosis within affected lesions. Studies within the past decade have revealed genetic and environmental factors contributing to AD in children. Obesity is a metabolic disorder that often manifests early in life and is associated with reduced bacterial diversity, leading to skin colonization with lipophilic bacteria and intestinal colonization with pro-inflammatory species. These changes impair epithelial barriers and promote Th17 responses, which may worsen the severity of AD symptoms. While few studies have examined the contribution of microbiota in obesity-induced allergies, there is emerging evidence that PPAR-γ may be an effective therapeutic target. This review discusses the microbiome in pediatric AD, treatment with probiotics, how disease is altered by obesity and potential therapeutic effects of PPAR-γ agonists. While healthy skin contains diverse species adapted for specific niches, lesional skin is highly colonized with Staphylococcus aureus which perpetuates the inflammatory reaction. Treatments for AD should help to restore microbial diversity in the skin and intestine, as well as epithelial barrier function. Pre-clinical models have shown that PPAR-γ agonists can suppress Th17 responses, IgE production and mast cell function, while improving the epidermal barrier and microbial homeostasis. Overall, PPAR-γ agonists may be effective in a subset of patients with AD, and future studies should distinguish their metabolic and anti-inflammatory effects in order to inform the best therapies.

Keywords: PPAR-γ; allergy; atopic dermatitis; dysbiosis; microbiota; obesity; probiotics.

Figure 1

Interactions between the immune system and microbiome in atopic dermatitis. In healthy individuals, the epidermal barrier is intact and maintained by filaggrin expression, antimicrobial peptides, and other factors. This is associated with a diverse microbiome that colonizes distinct niches on the skin surface. Atopic dermatitis (AD) patients have an impaired skin barrier leading to increased permeability within the keratinocyte layers. This is associated with reduced microbial diversity, including increased colonization with Staphylococcus aureus. These individuals are at increased risk of inflammatory skin injury, leading to the production of cytokines that facilitate Th2 cell differentiation. Allergen-specific Th2 cells then produce cytokines that promote eosinophil recruitment to the skin and IgE production by B cells. Mast cells that are sensitized with IgE release histamine and other inflammatory mediators following subsequent exposures to the skin allergen, while eosinophils mediate skin damage by releasing intracellular granules. Obesity is associated with increased lipid composition on the skin which facilitates dysbiosis, including colonization with lipophilic Corynebacterium species. The chronic inflammatory milieu in obesity promotes Th17 responses on epithelial surfaces including the skin. Cytokines produced by Th17 cells, including IL-17 and IL-22, impact keratinocyte differentiation, epithelial permeability and antimicrobial peptide production. In addition, diet-induced obesity is associated with increased production of IgE and mast cell accumulation in the skin. These effects of obesity are thought to increase the severity of AD in affected patients. PPAR-γ is a transcription factor with anti-inflammatory properties that also regulates lipid metabolism. Medications that target PPAR-γ may treat AD through multiple mechanisms including suppression of Th17 differentiation, mast cell accumulation, IgE production or pro-inflammatory cytokines. PPAR-γ agonists also improve insulin sensitivity, lipid metabolism, epidermal barrier function and microbial diversity, while pro-inflammatory effects include Th2 differentiation and IL-9 production. It is important to ascertain if the efficacy of PPAR-γ agonists in microbiota-dependent allergic diseases is influenced by body mass index, comorbidities or potential pro-inflammatory effects on the immune system in certain patient endotypes.

Figure 2

Microbiome changes in obesity and atopic dermatitis. Skin microbiota in healthy individuals has been well characterized, although more studies are necessary to elucidate developmental changes occurring throughout life. Structural changes associated with atopic dermatitis reduce bacterial diversity and increase colonization with Staphylococcus aureus. Potential probiotics (red font) help to restore diversity and have anti-inflammatory effects. In addition, they may suppress the growth of S. aureus. Obesity results in increased colonization with lipophilic species including Corynebacterium. While intestinal microbiota have been shown to contribute to AD severity in obesity (not shown), the role of skin microbiota in pathophysiology needs to be further studied. Identifying skin species that are unique to atopic dermatitis in the presence or absence of obesity (question marks) may help to guide therapeutic strategies to promote healthy microenvironments colonized with symbiotic microbiota.