Puccetti Matteo, Pariano Marilena, Costantini Claudio, Giovagnoli Stefano, Ricci Maurizio
Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy.
Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy.
Pharmaceuticals (Basel). 2022 Mar 10;15(3):336. doi: 10.3390/ph15030336.
Alterations of the microbiome occur in inflammatory and autoimmune diseases, a finding consistent with the role of the microbiome in the maintenance of the immune system homeostasis. In this regard, L-tryptophan (Trp) metabolites, of both host and microbial origin, act as important regulators of host-microbial symbiosis by acting as aryl hydrocarbon receptor (AhR) ligands. The intestinal and respiratory barriers are very sensitive to AhR activity, suggesting that AhR modulation could be a therapeutic option to maintain the integrity of the epithelial barrier, which has substantial implications for health even beyond the mucosal site. A number of studies have highlighted the capacity of AhR to respond to indoles and indolyl metabolites, thus positioning AhR as a candidate indole receptor. However, the context-and ligand-dependent activity of AhR requires one to resort to suitable biopharmaceutical formulations to enable site-specific drug delivery in order to achieve therapeutic effectiveness, decrease unwanted toxicities and prevent off-target effects. In this review, we highlight the dual activity of the microbial metabolite indole-3-aldehyde at the host-microbe interface and its ability to orchestrate host pathophysiology and microbial symbiosis and discuss how its proper clinical development may turn into a valuable therapeutic strategy in local and distant inflammatory diseases.
微生物群的改变发生在炎症性和自身免疫性疾病中，这一发现与微生物群在维持免疫系统稳态中的作用一致。在这方面，宿主和微生物来源的L-色氨酸（Trp）代谢产物通过作为芳烃受体（AhR）配体，充当宿主-微生物共生的重要调节因子。肠道和呼吸道屏障对AhR活性非常敏感，这表明调节AhR可能是维持上皮屏障完整性的一种治疗选择，这对健康的影响甚至超出了粘膜部位。许多研究强调了AhR对吲哚和吲哚代谢产物作出反应的能力，从而将AhR定位为候选吲哚受体。然而，AhR的背景和配体依赖性活性要求人们采用合适的生物制药制剂，以实现位点特异性药物递送，从而达到治疗效果，降低不良毒性并防止脱靶效应。在这篇综述中，我们强调了微生物代谢产物吲哚-3-醛在宿主-微生物界面的双重活性及其协调宿主病理生理学和微生物共生的能力，并讨论了其合理的临床开发如何可能转化为治疗局部和远处炎症性疾病的有价值的治疗策略。
