From microbial metabolites to inflammation pharmacology via targeted delivery technology

Up to 350 words. No references allowed. Abstracts may be submitted at a later date.Despite the fact that the association between inflammation and chronic disease is now widely recognized, how to translate the body of knowledge into effective strategies for prevention and treatment of pathologic inflammation to improve human health is lagging behind. An important issue in the development of anti-inflammatory drugs is to maintain an equilibrium between resolving the inflammatory pathology without compromising the ability of the immune system to respond to pathogens. Current standard immunosuppressant regimens are limited by their systemic administration, which promotes off-target effects and dosing toxicities, and lack of specificity in regard to their mechanism of action. Therefore, local drug delivery strategies, which target anti-inflammatory cargo at specific sites for immunomodulation, are emerging as viable platforms to address these limitations. The appreciation that symbiotic microorganisms inhabiting the gastrointestinal tract promote health via bacterial metabolites that impact disease pathology has greatly impacted in areas of fundamental importance to both the conceptualization of host–microbiota interactions and its translation to clinical applications. Indeed, metabolites are not only ideally suited as biomarkers for disease development, but also their causal involvement in the molecular etiology of human disease offers untapped opportunities for drug discovery and development of new patient-tailored therapies. In this regard, L-tryptophan (Trp) metabolites, of both host and microbial origin, act as important regulators of host-microbial symbiosis and immune homeostasis 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 that has substantial implications for health even beyond the mucosal site. A number of studies have highlighted the capacity of AhR to respond to Trp-derived metabolites of microbial origin, such as indoles and indolyl metabolites thus positioning AhR as a candidate indole receptor. However, the context-and ligand-dependent activity of AhR requires the resorting to suitable biopharmaceutical formulations to enable site-specific drug delivery in order to achieve therapeutic effectiveness, decrease unwanted toxicities and prevent off-target effects. I will highlight how our studies have provided proof-of-concept demonstration that pharmaceutically active indole metabolites, such as indole-3-aldehyde, could be of therapeutic value in chronic inflammatory conditions in which the epithelial barrier disruption and microbial dysbiosis are causally linked. This required the resorting to suitable biopharmaceutical formulations to develop more localized and specific immunomodulatory approaches, decrease unwanted toxicities and prevent off-target effects.

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