Analysis of organized relationship between the gut microbiota, uremic metabolites known to be produced in the gut, and kidney function impairment, of the patients in various stages of Chronic Kidney Disease.

Uremia of chronic kidney disease (CKD) has been known to aggravate gut dysbiosis, and vice versa. However, few studies have examined the microbiota and their metabolites, uremic toxins, according to the CKD severity, thus the alteration of gut microbiota in mild to moderate CKD patients are not clearly understood. We enrolled 103 CKD patients and 46 controls. CKD patients were divided according to their CKD stages as follows: mild CKD, stage 1 or 2; moderate to severe CKD, stage 3 to 5 without dialysis; ESRD, stage 5 on dialysis. We analyzed the fecal microbiota using the MiSeq system and measured the concentrations of 4 uremic toxins including p-cresyl sulfate, indoxyl sulfate, p-cresol glucuronide, and trimethylamine N-oxide in the sera of all participants by liquid chromatography tandem mass spectrometry. The mean age of the patients was 49.2 ± 12.5 years old, 46.3% were males, and 10.1% had diabetes mellitus. The concentrations of 4 serum uremic toxins increased significantly as the kidney function deteriorated. Microbial diversity was not significantly different among all groups. The proportions of Lachnospira, Veillonella, and Dialister decreased, whereas those of Alistipes and Oscillibacter increased as kidney function deteriorated. Oscillibacter showed positive interaction with other genera of microbiota in moderate or higher stage CKD groups. In addition, Oscillibacter was positively correlated with all of the measured uremic toxin levels. In predicted functional analysis, the contribution of microbiota on the pyruvate metabolism was significantly increased with CKD progression. The contributions of Oscillibacter and Veillonella on pyruvate metabolism were significantly different according to the CKD groups. Especially, the contribution of Oscillibacter to lactate dehydrogenase increased and the contribution of Oscillibacter to pyruvate dehydrogenase decreased as the renal function deteriorated. A specific gut microbe, Oscillibacter showed a significant correlation with serum uremic metabolites as well as kidney function. Contribution of Oscillibacter on pyruvate metabolism change in CKD by interacting other genera in gut microbiota could be an important clue for gut environmental change according to the kidney function, resulting in dysbiosis concomitant to uremic toxin production.