Genetic and Functional Analyses of Cutibacterium Acnes Isolates Reveal the Association of a Linear Plasmid with Skin Inflammation.

Cutibacterium acnes is a commensal bacterium on the skin that is generally well-tolerated, but different strain types have been hypothesized to contribute to the disease acne vulgaris. To understand how some strain types might contribute to skin inflammation, we generated a repository of C. acnes isolates from skin swabs of healthy subjects and subjects with acne and assessed their strain-level identity and capacity to stimulate cytokine release. Phylotype II K-type strains were more frequent on healthy and nonlesional skin of subjects with acne than those isolated from lesions. Phylotype IA-1 C-type strains were increased on lesional skin compared with those on healthy skin. The capacity to induce cytokines from cultured monocyte-derived dendritic cells was opposite to this action on sebocytes and keratinocytes and did not correlate with the strain types associated with the disease. Whole-genome sequencing revealed a linear plasmid in high-inflammatory isolates within similar strain types that had different proinflammatory responses. Single-cell RNA sequencing of mouse skin after intradermal injection showed that strains containing this plasmid induced a higher inflammatory response in dermal fibroblasts. These findings revealed that C. acnes strain type is insufficient to predict inflammation and that carriage of a plasmid could contribute to disease.

Competition between skin antimicrobial peptides and commensal bacteria in type 2 inflammation enables survival of S. aureus.

During inflammation, the skin deploys antimicrobial peptides (AMPs) yet during allergic inflammation it becomes more susceptible to Staphylococcus aureus. To understand this contradiction, single-cell sequencing of Il4ra-/- mice combined with skin microbiome analysis reveals that lower production of AMPs from interleukin-4 receptor α (IL-4Rα) activation selectively inhibits survival of antibiotic-producing strains of coagulase-negative Staphylococcus (CoNS). Diminished AMPs under conditions of T helper type 2 (Th2) inflammation enable expansion of CoNS strains without antibiotic activity and increase Staphylococcus aureus (S. aureus), recapitulating the microbiome on humans with atopic dermatitis. This response is rescued in Camp-/- mice or after topical steroids, since further inhibition of AMPs enables survival of antibiotic-producing CoNS strains. In conditions of Th17 inflammation, a higher expression of host AMPs is sufficient to directly inhibit S. aureus survival. These results show that antimicrobials produced by the host and commensal bacteria each act to control S. aureus on the skin.

Development of a human skin commensal microbe for bacteriotherapy of atopic dermatitis and use in a phase 1 randomized clinical trial.

Staphylococcus aureus colonizes patients with atopic dermatitis (AD) and exacerbates disease by promoting inflammation. The present study investigated the safety and mechanisms of action of Staphylococcus hominis A9 (ShA9), a bacterium isolated from healthy human skin, as a topical therapy for AD. ShA9 killed S. aureus on the skin of mice and inhibited expression of a toxin from S. aureus (psmα) that promotes inflammation. A first-in-human, phase 1, double-blinded, randomized 1-week trial of topical ShA9 or vehicle on the forearm skin of 54 adults with S. aureus-positive AD (NCT03151148) met its primary endpoint of safety, and participants receiving ShA9 had fewer adverse events associated with AD. Eczema severity was not significantly different when evaluated in all participants treated with ShA9 but a significant decrease in S. aureus and increased ShA9 DNA were seen and met secondary endpoints. Some S. aureus strains on participants were not directly killed by ShA9, but expression of mRNA for psmα was inhibited in all strains. Improvement in local eczema severity was suggested by post-hoc analysis of participants with S. aureus directly killed by ShA9. These observations demonstrate the safety and potential benefits of bacteriotherapy for AD.