视黄醇是维生素A的一种，它能够促进皮肤角质细胞的增殖，调节皮肤细胞胶原蛋白的表达，因而作为一种抗衰老活性成分被广泛添加在护肤品中。皮肤是人体最大的器官，也是大量皮肤共生菌的栖息场所。然而，人们视黄醇对皮肤微生物组的影响，皮肤微生物组是否参与，以及如何参与视黄醇介导的皮肤抗衰过程仍然知之甚少。因此，本论文招募了九名志愿者，开展了为期28天的纵向研究。受试者连续使用0.15%的视黄醇乳液，每七天测量一次皮肤表型数据，并采集皮肤表皮拭子样本，用于后续的宏基因组和代谢组分析。 表型数据分析显示，视黄醇乳液能明显改善受试者皮肤状况，包括提高皮肤的保水能力，在表皮形成酸性环境，增强皮肤屏障功能，减少皱纹的数量和体积，具有显著的抗衰功效。 宏基因组和代谢组测序数据表明，视黄醇乳液的使用重塑了皮肤微生态，不仅改变了皮肤微生物组的结构和功能，也对宿主和微生物代谢物产生了影响。使用视黄醇乳液后，多种条件致病菌的相对丰度显著下降，微生物组细菌分泌系统和抗原合成基因通路相对于基线富集，证明了视黄醇乳液具有抗菌效果。此外，视黄醇乳液会促进皮肤微生物分泌具有潜在益生作用的代谢物，如缅茄素、奎宁酸、原儿茶酸、松脂醇、亚麻木酚素等，有待进一步研究这些微生物代谢物的皮肤抗衰功效。视黄醇乳液的使用会在皮肤表面形成酸性环境，这一变化与多种条件致病菌丰度的降低有关，这表明视黄醇乳液具有抗菌和消炎作用，而皮肤微生物可能通过分泌酸性物质，如扁桃酸、苯乙酮酸、香草酸等代谢物使皮肤pH降低。 与基线相比，使用视黄醇乳液后观察到视黄醇代谢通路的显著富集。视黄醇水溶性代谢产物1-O-全反式视黄酰葡萄糖醛苷(RAG)的丰度在第7天达到峰值。通过构建基因组尺度的代谢模型(GEM)，研究发现皮肤微生物Sericytochromatia sp.和Corynebacterium kefirresidentii具有将视黄醇氧化为视黄醛的能力，十余种皮肤微生物可以利用UDP-葡萄糖作为碳源。进一步推测，微生物可能通过将UDP-葡萄糖作为碳源，增加葡萄糖醛酸的消耗，从而加速RAG水解。而RAG水解产生的视黄酸和视黄醇会被皮肤细胞和皮肤微生物重新利用。因此皮肤微生物组加快了视黄醇代谢速度，提高其利用率，延长了视黄醇在人体内的有效作用时间，改善了它的代谢动力学。
Retinol, as an anti-aging active ingredient, has been widely added to skincare products due to its ability to promote the proliferation of skin keratinocytes and regulate skin cell collagen expression. The skin, being the largest organ of the human body, harbors a myriad of skin commensal bacteria. However, the impact of retinol on the skin microbiome, as well as the role of the skin microbiome in mediating the anti-aging properties of retinol, remains poorly understood. Therefore, a cohort of 9 participants was recruited to undergo a consecutive 28-day regimen of using 0.15% retinol lotion. Skin phenotype data was measured and epidermal swab samples were collected for subsequent metagenomic and metabolomic analysis every 7 days. Phenotypic data analysis revealed that retinol lotion significantly improved skin conditions, including enhancing skin hydration, acidifying the epidermis, strengthening the skin barrier function, and reducing the number and volume of wrinkles, exhibiting remarkable anti-aging effects.Metagenomic and metabolomic sequencing demonstrated that the application of the retinol lotion reshaped the skin microecology, not only altering the structure and function of the skin microbiome but also affecting the host and microbial metabolites. Following the use of the retinol lotion, the relative abundance of various opportunistic pathogens significantly decreased, with microbial pathways related to bacterial secretion systems and antigen synthesis enriched compared to the baseline, demonstrating the antibacterial effect of retinol. Additionally, the retinol lotion promoted the secretion of potentially beneficial metabolites by skin microbes, such as maesopsin, quinic acid, protocatechuic acid, pinoresinol, and secoisolariciresinol, warranting further investigation into the anti-aging effects of these microbial metabolites. The use of the retinol lotion resulted in the formation of an acidic environment on the skin surface, which was associated with the decreased relative abundance of various opportunistic pathogens, indicating the antibacterial and anti-inflammatory effects of the retinol lotion. Meanwhile, skin microbes may lower the skin pH by secreting acidic substances such as mandelic acid, phenylglyoxylic acid, and vanillic acid. Compared to the baseline, significant enrichment of the retinol metabolism pathway was observed following the use of the retinol lotion, with the abundance of a water-soluble retinol metabolite, 1-O-All-Trans-Retinoyl-Beta-Glucuronic Acid, peaked on day 7. Through GEM construction, we identified 2 skin microorganism, Sericytochromatia sp. and Corynebacterium kefirresidentii having the ability to oxidize retinol to retinal, while over 10 skin microbes can utilize uridine diphosphate glucose (UDP-glucose) as a carbon source. We hypothesized that skin microbes may accelerate RAG hydrolysis by utilizing UDP-glucose as a carbon source, and increasing the consumption of glucuronic acid. The retinoic acid and retinol generated by RAG hydrolysis were then reused by skin cells and skin microbes. Thus, the skin microbiome accelerates retinol metabolism, increases its utilization rate, prolongs the effective time of action of retinol in the human body, and improves its metabolic kinetics.
