Enteric delivery of indole-3-carboxylic acid unlocks therapeutic potential of postbiotic metabolite cascade

Indole-3-carboxaldehyde (I3A), a microbial tryptophan metabolite, exhibits significant immunomodulatory activity at the host-microbial interface. However, its rapid transformation into metabolites like indole-3-carboxylic acid (I3CA) raises questions about their therapeutic potential. This study aimed to evaluate the pharmacological contributions of I3CA through the development of a proper delivery strategy. I3CA was formulated into enteric microparticles to enhance stability and targeted release. The formulations were characterized for size, morphology, drug content, encapsulation efficiency, and in vitro release profiles. Pharmacokinetic studies in mice assessed absorption, distribution, and half-lives of I3CA. In vitro assays evaluated AhR-dependent immunomodulatory activity, while murine models of intestinal and pulmonary inflammation tested therapeutic efficacy. Although not gastro-resistant, the obtained I3CA-MP formulation showed acceptable enteric behavior, releasing I3CA completely within 6–8 h in vitro. I3CA exhibited additive AhR-dependent immunomodulatory effects and showed rapid absorption and distribution in mice, with half-lives comparable to I3A. In murine models, I3CA mirrored the therapeutic benefits of I3A, reducing inflammation in colitis and aspergillosis, and enhancing epithelial barrier function. This study highlights I3CA as a key contributor to the pharmacological effects of I3A, emphasizing the importance of metabolite cascades in postbiotic therapeutics. The developed enteric delivery system effectively harnesses the therapeutic potential of I3CA, offering new insights into host-microbe metabolic interactions and paving the way for innovative postbiotic-based treatments.