Human skin forms a protective barrier against the external environment and is our first line of defense against toxic, solar, and pathogenic insults. Our skin also defines our outward appearance, protects our internal tissues and organs, acts as a sensory interface, and prevents dehydration. Crucial to the skin’s barrier function is the colonizing microbiota, which provides protection against pathogens, tunes immune responses, and fortifies the epithelium. Here we highlight recent advances in our understanding of how the microbiota mediates multiple facets of skin barrier function. We discuss recent insights into pathological host–microbiota interactions and implications for disorders of the skin and distant organs. Finally, we examine how microbiota-based mechanisms can be targeted to prevent or manage skin disorders and impaired wound healing.

Significance: The mammalian gastrointestinal tract is home to diverse communities of bacteria that contribute to the metabolic health of their hosts. The epithelial lining of the intestine produces a diverse repertoire of antimicrobial proteins that limit the ability of these microorganisms to enter host tissues and cause disease. We have discovered that resistin-like molecule β (RELMβ) is a previously unknown member of the intestine's antibacterial arsenal. RELMβ is secreted from the intestinal surface and kills Gram-negative bacteria by damaging their membranes, thereby preventing these bacteria from coming into close contact with host tissues. Our findings reveal a new family of endogenous antibiotic proteins and contribute to the understanding of how mammals maintain mutually beneficial relationships with complex communities of intestinal bacteria.

AMPlifying type 2 immunity: Antimicrobial proteins (AMPs) are a frontline defense against pathogenic microorganisms at mucosal surfaces. These cationic molecules inactivate their targets primarily by disrupting cell walls and membranes. Hu et al . found that small proline-rich protein 2A (SPRR2A) is a bactericidal protein produced in the gut that targets Gram-positive bacteria and is phylogenetically distinct from all other known AMPs (see the Perspective by Harris and Wickramasinghe). SPRR2A production is selectively enhanced by type 2 cytokines such as interleukin-4 and -13 that are elicited by helminth infection. Mice lacking SPRR2A are unable to prevent intestinal bacteria from invading the intestinal barrier after helminths damage the intestinal epithelium. SPRR2A is thus a critical component of type 2 immunity that protects against the bacterial invasion and dissemination that follow helminth infection. —STS

Vitamin A is a dietary component that is essential for the development of intestinal immunity. Vitamin A is absorbed and converted to its bioactive derivatives retinol and retinoic acid by the intestinal epithelium, yet little is known about how epithelial cells regulate vitamin A-dependent intestinal immunity. Here we show that epithelial cell expression of the transcription factor retinoic acid receptor β (RARβ) is essential for vitamin A-dependent intestinal immunity. Epithelial RARβ activated vitamin A-dependent expression of serum amyloid A (SAA) proteins by binding directly to Saa promoters. In accordance with the known role of SAAs in regulating Th17 cell effector function, epithelial RARβ promoted IL-17 production by intestinal Th17 cells. More broadly, epithelial RARβ was required for the development of key vitamin A-dependent adaptive immune responses, including CD4 ⁺ T-cell homing to the intestine and the development of IgA-producing intestinal B cells. Our findings provide insight into how the intestinal epithelium senses dietary vitamin A status to regulate adaptive immunity, and highlight the role of epithelial cells in regulating intestinal immunity in response to diet.