Enteric formulated indole-3-carboxaldehyde targets the aryl hydrocarbon receptor for protection in a murine model of metabolic syndrome

The metabolic syndrome (MetSyn) is a disorder characterized by a cluster of diseases where the regulation of the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor endowed with ligand- and context-dependent activities, can have a major therapeutic relevance. We have recently discovered a tryptophan metabolite of microbial origin, indole-3-carboxaldehyde (3-IAld), able to regulate intestinal mucosal homeostasis by acting as a ligand of AhR. This makes 3-IAld a potential candidate to treat MetSyn related ailments. Herein, we provide a proof of concept on the efficacy and safety of 3-IAld encapsulated in enteric microparticles (MP) in vivo in a MetSyn murine model. In particular, we showed that 3-IAld: i) is released from MPs in the intestine and potentially metabolized; ii) is able to activate AhR locally; iii) prevents the metabolic complications and the intestinal epithelial barrier dysfunction; iv) is not associated with toxic events. This study does not only extend the biological activity of 3-IAld in vivo, but also provides hints on the therapeutic potential of 3-IAld delivered by enteric MP in MetSyn related diseases.