Alterations to the Gut Microbiota and Their Correlation With Inflammatory Factors in Chronic Kidney Disease

Renal diseases, especially chronic kidney disease (CKD), have been linked to gut microbiota dysbiosis. Recent studies indicate that there are several factors that alter the gut microbiota in CKD. An influx in urea in intracellular and extracellular fluids leads to an increase of urea in the gastrointestinal tract where it is metabolized to ammonia by urease produced by intestinal bacteria. As a result, ammonia changes the luminal pH, which favors the growth of uremic-toxin-producing microbes, and damages the intestinal epithelial wall leading to systemic inflammation and CKD progression. A balanced gut microbiota is beneficial to the host by providing enzymes that degrade dietary fibers, carbohydrates, and proteins to energy sources for intestinal epithelial cells. Studies have shown alterations in the intestinal microbiota of patients with CKD and their mechanism of inducing systemic inflammation.

This prospective cross-sectional study analyzed and compared the gut microbiota in the feces of patients with CKD and healthy control (HC) subjects via 16S rDNA gene sequencing; and further analyzed the relationships between fecal microbiota and the clinical characteristics of and inflammation in patients with CKD. Thus, the present study aimed to elucidate CKD-associated differences in fecal microbial communities as well as associations among gut dysbiosis, clinical characteristics, and chronic systematic inflammation in patients with CKD.

Between June 2017 and February 2018, 50 patients with CKD and 22 HC subjects were enrolled from the Department of Nephrology and Health Examination of the Shanxi Provincial People's Hospital (Shanxi Medical University, Shanxi, China). 16S ribosomal DNA pyrosequencing using fecal microbiota samples and analyses of the production of serum inflammatory factors were conducted. Serum samples (10 ml) were collected from subjects at the time of the first fecal-sample collection and levels of the inflammatory cytokines IL-6, IL-4, and IL-10 were quantitatively detected.

Previous studies have shown that alterations to the gut microbiota are linked to CKD. This study confirmed that gut microbiota dysbiosis occurs in Chinese patients with CKD and, furthermore, identified differentially expressed bacterial taxa in patients with CKD. The results of the conducted analyses showed that the diversity, overall richness, and structure of the gut microbiota are significantly reduced in Chinese patients with CKD compared to the HC subjects. This finding provides powerful evidence that the gut microbiota is clinically altered in CKD.

Five bacterial phyla are known to be present in the human gut, namely, Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Verrucomicrobia. Of these, and Firmicutes are normally the most predominant. The results of the present study showed that the most abundant phyla in both the CKD and HC groups were Firmicutes and Bacteroidetes, and indeed, their abundance was unchanged; however, the relative abundances of Verrucomicrobia and Actinobacteria were lower and higher in the CKD than in the HC groups, respectively.

The results highlight the correlation between differentially abundant bacteria and inflammatory factors, and the probiotic strain Akkermansia decreased significantly in CKD patients. The abundance of the probiotic strain Akkermansia was reduced, comprising 3.08% and only 0.67% of the microbiota in the HC subjects and patients with CKD, respectively. The abundance of the probiotic Lactobacillus strain was slightly increased in the CKD compared to the HC group, and the abundance of several other bacterial genera, including Parasutterella, Paraprevotella, Clostridium IV, and Alloprevotella, also differed between the patients with CKD and the HC subjects; however, these changes were less significant than those observed for Akkermansia.

This study also showed a clear correlation between the presence of various microbiome genera and well-known clinical indicators of CKD progression, including BUN, SCr, and CysC levels; the CO2CP; and particularly the eGFR (which is known to be a sensitive indicator of renal function in patients with CKD), suggesting that the microbiota may mediate CKD pathogenesis. The findings showed that BUN and SCr levels and eGFR were significantly correlated with the differential abundance of bacteria in individuals with, compared to without CKD.

Chronic systemic inflammation has been shown to be an important factor underlying CKD progression, including the incidence of CKD-associated CVD. The levels of several pro- and anti-inflammatory cytokines, including IL-4, IL-6, IL-8, IL-10, and INF-γ, have been reported in CKD and suggested to contribute to CKD progression and CVD complications. This present study showed that levels of the pro-inflammatory cytokines IL-4 and IL-6 significantly increased in the CKD compared to the HC groups. Moreover, the conducted correlation analysis of the differential abundance of various intestinal genera with these inflammatory factors showed that many bacteria were significantly negatively correlated with IL-4 and/or IL-10 levels, including those of the probiotic Akkermansia (IL-10 only) and Lactobacillus (IL-4 and IL-10) genera. Therefore, it is proposed that Akkermansia bacteria may improve renal function in CKD patients and alleviate the chronic systemic inflammation associated with CKD. However, this requires further in-depth research. The results of the present study revealed that the patients with CKD exhibited a reduced abundance of intestinal probiotics and elevated levels of inflammatory factors, and furthermore, that levels of these probiotics and inflammatory factors were negatively correlated. The role of Akkermansia and IL-10 in CKD needs further in-depth study.

In conclusion, the results show that that gut microbiome components are significantly different in HC subjects and patients with CKD and that the differential abundance of some genera is correlated with CKD clinical characteristics and the production of inflammatory factors. Further research is needed to elucidate the mechanism(s) by which Akkermansia and IL-10 interact to mediate CKD disease progression.