Acne treatments: future trajectories.

Current acne treatments present several limitations, posing the need for new effective therapies for long-term administration for recalcitrant or relapsing acne. Key players in acne that may emerge as targets for future acne treatments include the cutaneous loss of diversity of Cutibacterium (formerly Propionibacterium) acnes phylotypes and the insulin-like growth factor-1 signalling pathway. New data about the loss of diversity of microbiota in acne provides the rationale for the potential use of oral or topical probiotics. Another therapeutic approach to modulate the microbiota could be topical formulation of C. acnes bacteriophages to target specifically the pathogenic 'acnegenic' C. acnes phylotypes. Insulin-sensitizing agents such as metformin, myo-inositol and d-chiro-inositol represent promising agents, but to date there have been only limited studies and much heterogeneity in the methods of assessing acne efficacy outcomes. Moving towards a holistic approach for patients with acne is the future, by taking into account both internal and external factors, such as pollution, stress, acne family history, age, smoking habits and diet, and addressing quality of life and the psychological impact of acne.

Clonal diversity of Cutibacterium acnes (formerly Propionibacterium acnes) in prosthetic joint infections.

Prosthetic joint infections (PJIs) are rare but feared complications following joint replacement surgery. Cutibacterium acnes is a skin commensal that is best known for its role in acne vulgaris but can also cause invasive infections such as PJIs. Some phylotypes might be associated with specific diseases, and recently, a plasmid was detected that might harbour important virulence genes. In this study, we characterized C. acnes isolates from 63 patients with PJIs (n = 140 isolates) and from the skin of 56 healthy individuals (n = 56 isolates), using molecular methods to determine the phylotype and investigate the presence of the plasmid. Single-locus sequence typing and a polymerase chain reaction designed to detect the plasmid were performed on all 196 isolates. No statistically significant differences in sequence types were seen between the two study groups indicating that the C. acnes that causes PJIs originates from the patients own normal skin microbiota. Of the 27 patients with multiple tissue samples, 19 displayed the same sequence types among all their samples. Single-locus sequence typing identified different genotypes among consecutive C. acnes isolates from four patients with recurrent infections. The plasmid was found among 17 isolates distributed in both groups, indicating that it might not be a marker for virulence regarding PJIs. Patients presenting multiple sequence types in tissue samples may represent contamination or a true polyclonal infection due to C. acnes.

A metabolic engineering strategy for producing conjugated linoleic acids using the oleaginous yeast Yarrowia lipolytica.

Conjugated linoleic acids (CLAs) have been found to have beneficial effects on human health when used as dietary supplements. However, their availability is limited because pure, chemistry-based production is expensive, and biology-based fermentation methods can only create small quantities. In an effort to enhance microbial production of CLAs, four genetically modified strains of the oleaginous yeast Yarrowia lipolytica were generated. These mutants presented various genetic modifications, including the elimination of ß-oxidation (pox1-6∆), the inability to store lipids as triglycerides (dga1∆ dga2∆ are1∆ lro1∆), and the overexpression of the Y. lipolytica ∆12-desaturase gene (YlFAD2) under the control of the constitutive pTEF promoter. All strains received two copies of the pTEF-oPAI or pPOX-oPAI expression cassettes; PAI encodes linoleic acid isomerase in Propionibacterium acnes. The strains were cultured in neosynthesis or bioconversion medium in flasks or a bioreactor. The strain combining the three modifications mentioned above showed the best results: when it was grown in neosynthesis medium in a flask, CLAs represented 6.5% of total fatty acids and in bioconversion medium in a bioreactor, and CLA content reached 302 mg/L. In a previous study, a CLA degradation rate of 117 mg/L/h was observed in bioconversion medium. Here, by eliminating ß-oxidation, we achieved a much lower rate of 1.8 mg/L/h.

Vitamin B12 modulates the transcriptome of the skin microbiota in acne pathogenesis.

Various diseases have been linked to the human microbiota, but the underlying molecular mechanisms of the microbiota in disease pathogenesis are often poorly understood. Using acne as a disease model, we aimed to understand the molecular response of the skin microbiota to host metabolite signaling in disease pathogenesis. Metatranscriptomic analysis revealed that the transcriptional profiles of the skin microbiota separated acne patients from healthy individuals. The vitamin B12 biosynthesis pathway in the skin bacterium Propionibacterium acnes was significantly down-regulated in acne patients. We hypothesized that host vitamin B12 modulates the activities of the skin microbiota and contributes to acne pathogenesis. To test this hypothesis, we analyzed the skin microbiota in healthy subjects supplemented with vitamin B12. We found that the supplementation repressed the expression of vitamin B12 biosynthesis genes in P. acnes and altered the transcriptome of the skin microbiota. One of the 10 subjects studied developed acne 1 week after vitamin B12 supplementation. To further understand the molecular mechanism, we revealed that vitamin B12 supplementation in P. acnes cultures promoted the production of porphyrins, which have been shown to induce inflammation in acne. Our findings suggest a new bacterial pathogenesis pathway in acne and provide one molecular explanation for the long-standing clinical observation that vitamin B12 supplementation leads to acne development in a subset of individuals. Our study discovered that vitamin B12, an essential nutrient in humans, modulates the transcriptional activities of skin bacteria, and provided evidence that metabolite-mediated interactions between the host and the skin microbiota play essential roles in disease development.

A honey trap for the treatment of acne: manipulating the follicular microenvironment to control Propionibacterium acnes.

Today, as 40 years ago, we still rely on a limited number of antibiotics and benzoyl peroxide to treat inflammatory acne. An alternative way of suppressing the growth of Propionibacterium acnes is to target the environment in which it thrives. We conjecture that P. acnes colonises a relatively "extreme" habitat especially in relation to the availability of water and possibly related factors such as ionic strength and osmolarity. We hypothesise that the limiting "nutrient" within pilosebaceous follicles is water since native sebum as secreted by the sebaceous gland contains none. An aqueous component must be available within colonised follicles, and water may be a major factor determining which follicles can sustain microbial populations. One way of preventing microbial growth is to reduce the water activity (a w ) of this component with a biocompatible solute of very high water solubility. For the method to work effectively, the solute must be small, easily diffusible, and minimally soluble in sebaceous lipids. Xylose and sucrose, which fulfil these criteria, are nonfermentable by P. acnes and have been used to reduce water activity and hence bacterial colonisation of wounds. A new follicularly targeted topical treatment for acne based on this approach should be well tolerated and highly effective.

Assessment of the bacterial diversity of human colostrum and screening of staphylococcal and enterococcal populations for potential virulence factors.

In contrast to breast milk, little is known about the bacterial composition of human colostrum. The objective of this work was to analyze the bacterial diversity of colostrum obtained from healthy women and to characterize the dominant bacterial species for the presence of possible virulence factors. Samples of colostrum obtained from 36 healthy women were inoculated into different culture media. Several isolates from each medium were selected and identified. Staphylococcal and enterococcal isolates were submitted to genetic profiling. One representative of each profile was included in a genetic and phenotypic characterization scheme, including detection of potential virulence traits/genes and sensitivity to antibiotics. Staphylococcus epidermidis and Enterococcus faecalis were the dominant species, followed by Streptococcus mitis, Propionibacterium acnes and Staphylococcus lugdunensis. Among the 48 S. epidermidis isolates selected on the basis of their genetic profiles, the biofilm-related icaD gene and the mecA gene were detected in only 11 and six isolates, respectively. In parallel, 10 enterococcal isolates were also characterized and none of them contained the cylA, vanA, vanB, vanD, vanE and vanG genes. All of them were sensitive to vancomycin. There were no indications that the colostrum samples contained harmful bacteria.

Clinical considerations in the treatment of acne vulgaris and other inflammatory skin disorders: focus on antibiotic resistance.

Propionibacterium acnes is an anaerobic bacterium that plays an important role in the pathogenesis of acne. Certain antibiotics that can inhibit P acnes colonization also have demonstrated anti-inflammatory activities in the treatment of acne, rosacea, and other noninfectious diseases. Decreased sensitivity of P acnes to antibiotics, such as erythromycin and tetracycline, has developed and may be associated with therapeutic failure. Benzoyl peroxide (BPO) is a nonantibiotic antibacterial agent that is highly effective against P acnes and for which no resistance against it has been detected to date. Retinoids are important components in combination therapy for acne, including use with antibiotics, and can serve as an alternative to these agents in maintenance therapy. By increasing our understanding of the multifaceted actions of antibiotics and the known clinical implications of antibiotic resistance, physicians can improve their decision making in prescribing these agents.