From Gut Homeostasis to Colorectal Cancer: Spatial and Temporal Reprogramming of Microbial Inosine Signaling.

Microbial metabolites are increasingly recognized as critical regulators of gut homeostasis, mediating the interaction among gut microbiota, host tissue, and immune response. Among them, inosine, which was previously considered just a byproduct of the adenosine catabolism, was recently discovered as an important bioactive purine metabolite with distinctive context-dependent signaling function. Indeed, inosine supports intestinal barrier integrity and modulates the immune response under physiological conditions. However, this scenario completely changes when chronic inflammation, dysbiosis, and colorectal cancer (CRC) develop, leading to a profound alteration of its spatial distribution and biological function. This review summarizes the biochemical properties, signaling, and sources of inosine and its role in the maintenance of gut homeostasis. We will also discuss the dynamic regulation of host-microbiota interaction, driven by inosine during CRC development and its progression following its spatial redistribution and temporal reprogramming. In particular, we will describe how inosine can shift from a tumor-supportive role to a trigger of anti-tumor immunity by promoting T cell function and macrophage polarization, becoming a critical modulator of host-microbiota crosstalk in health and disease and a promising therapeutic target for microbiome-based strategies and combined clinical approaches.