Pharmaceutically Active Microbial AhR Agonists as Innovative Biodrugs in Inflammation

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 15; no. 3; p. 336
• Main Authors: Puccetti, Matteo, Pariano, Marilena, Costantini, Claudio, Giovagnoli, Stefano, Ricci, Maurizio
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 10.03.2022; MDPI
• Subjects: Amino acids; aryl hydrocarbon receptor; Autoimmune diseases; Bacteria; Disease; drug delivery; Enzymes; Health risk assessment; Homeostasis; Hydrocarbons; Immune system; indole-3-aldehyde; Inflammation; Inflammatory bowel disease; Ligands; Metabolism; Metabolites; Microbiota; Microorganisms; Mortality; Pathogenesis; Pathogens; Pathophysiology; Physiology; Review; Systems development; Transplants & implants; indole-3-aldehyde; drug delivery; aryl hydrocarbon receptor
• ISSN: 1424-8247; 1424-8247
• 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.