UC San Diego

The Remote Sensing and Signaling Theory predicts inter-organ and inter-organismal small-molecule communication mediated by a network of “drug” transporters. Organic Anion Transporter 1 (OAT1), SLC22A6, is a multi-specific transporter localized to the proximal tubule of the kidney and serves as a member of this sensing network. Here we demonstrate OAT1 in mice is an important regulator of systemic levels of several gut-derived compounds. Genetic deletion of OAT1 leads to elevation of 40 gut-derived compounds in the serum. Following 16S and whole genome sequencing of the gut bacteria we find that loss of OAT1 leads to compositional shifts in the microbiome, favoring members of Prevotellaceae and Lactobacillus. Functional pathway analysis of the gut-microbiome shows enrichment of long chain fatty acid synthesis, tyrosine and tryptophan degradation, which are all pathways associated with OAT1 function. We find that functional enrichment in the gut bacteria explain serum metabolomic changes of gut-derived compounds. These results demonstrate remote communication between host and gut via small molecule communication mediated by OAT1. We believe other drug-transporters handling gut-derived compounds may also have a similar effect on microbiome composition.