Kidney dysfunction regulates gut transporters

BACKGROUND: The gut-kidney axis is crucial in chronic kidney disease (CKD). As kidney function declines, uremic toxins accumulate in plasma, and gut dysbiosis, oxidative stress, and inflammation arise, potentially affecting the expression of proteins involved in absorption, distribution, metabolism, and excretion (ADME). We aimed to determine the colonic expression of ADME proteins in CKD and explore modulatory mechanisms. METHODS: RNA and protein expression of key gut transporters, enzymes and receptors were determined in colon biopsies from 17 patients with CKD and 12 healthy volunteers using RNA sequencing and targeted mass spectrometry. In parallel, we induced CKD in rats by 5/6th nephrectomy, and we administered an antibiotic cocktail to assess differences when depleting the gut microbiome. Caco-2 cells exposed to human serum or fecal water derived from CKD patients were used to elucidate modulatory mechanisms. RESULTS: CKD downregulated the colon efflux transporter proteins P-gp (apical), MRP3 (basolateral) and BCRP (apical) (BCRP only in patients not undergoing hemodialysis). P-gp downregulation was mediated by aromatic gut microbiome-derived uremic toxins in patients, consistently with in vitro observation that P-gp was downregulated in Caco-2 cells exposed to CKD serum. In CKD rats' colon, Mdr1a was downregulated, and Bcrp was upregulated only when antibiotics were administered, indicating the gut microbiome influences P-gp and BCRP in CKD. CONCLUSIONS: We confirmed kidney-gut crosstalk, highlighting how uremic environment and gut dysbiosis consequent to CKD impact gut transport physiology. P-gp and BCRP can be downregulated via gut microbiome metabolites, thus shedding light on the importance of therapies targeting microbial activity.