Aryl hydrocarbon receptor in the kidney regulates metabolic cross-talk with the liver and gut microbiome

Aryl hydrocarbon receptor (AHR) is central to inter-organ and inter-organismal crosstalk along the gut microbiome-liver-kidney axis. Studies in the kidney indicate this is due its regulation of transporter-mediated "remote sensing and signaling" via small molecules derived from the gut microbiome. These include gut microbiome-derived uremic toxins (e.g., indoxyl sulfate) associated with chronic kidney disease (CKD), which are transported by OAT1 and other SLC transporters. However, how kidney AHR regulates gut microbiome-liver-kidney crosstalk is largely unexplored. Here, we applied formal multi-organ metabolic reconstruction to multiomics data from the kidney of AHR knockout mouse and contextualized it with systemic metabolic changes. Consistent with the Remote Sensing and Signaling Theory, the explicit and quantitative multi-organ host and microbe network reconstruction revealed that kidney AHR regulates correlated sets of biochemical reactions at the organ, cellular, and organellar levels. In the absence of kidney AHR, there is up-regulation of polyamine related metabolism and down regulation of pathways involving organic acids (oxalate), thiamine, and amino-, methyl-, and phospho-transferases. Importantly, these AHR-dependent changes in correlated reaction sets occur not only in the kidney but also in the liver and microbiome. The normal inter-organ and inter-organismal (host-microbe) communication via these biochemical pathways between the kidney and other organs is disrupted when AHR function is lost. Thus, the incorporation of tissue and plasma metabolomics with kidney and liver transcriptomics in a biologically coherent framework provides a novel view into the metabolic relationships across the gut microbiome-liver-kidney axis. Through a concordance–discordance assessment of the transcriptome and metabolome, we were able to identify potential metabolic regulatory hubs dependent upon kidney AHR, a uremic toxin sensor and drug target. This included observed up-regulation of urea cycle enzymes with down-regulation of more distant enzymes (that are not directly involved with nitrogen handling). The results show how AHR-dependent remote sensing and signaling can involve interactions via biochemical reaction sub-networks between distinct organellar compartments of the communicating kidney and liver.