Abstract
Alterations to the gut microbiota have been previously suggested to be tightly linked to chronic systemic inflammation, which is a major contributing factor to complications and disease progression in chronic kidney disease (CKD). Nevertheless, the effect of gut dysbiosis on the pathogenesis and/or production of inflammatory factors in CKD has not been extensively studied to date. In the present study, we conducted 16S ribosomal DNA pyrosequencing using fecal microbiota samples and analyzed the production of serum inflammatory factors in 50 patients with CKD and 22 healthy control (HC) subjects. The results revealed that compared to the HC subjects, patients with CKD exhibited a significant reduction in the richness and structure of their fecal microbiota. At the phylum level, compared to the HC group, patients with CKD also presented reduced abundance of Actinobacteria but increased abundance of Verrucomicrobia. Moreover, the genera Lactobacillus, Clostridium IV, Paraprevotella, Clostridium sensu stricto, Desulfovibrio, and Alloprevotella were enriched in the fecal samples of patients with CKD, while Akkermansia and Parasutterella were enriched in those of the HC subjects. The abundance of Akkermansia in the CKD group was significantly lower than that in the HC group (3.08 vs. 0.67%); this decrease in the abundance of Akkermansia, an important probiotic, in patients with CKD is a striking discovery as it has not been previously reported. Finally, we analyzed whether these changes to the fecal microbiota correlated with CKD clinical characteristics and/or the production of known inflammatory factors. Altered levels of the microbiota genera Parasutterella, Lactobacillus, Paraprevotella, Clostridium sensu stricto, and Desulfovibrio were shown to be correlated with CKD disease-severity indicators, including the estimated glomerular filtration rate. Most notably, Akkermansia was significantly negatively correlated with the production of interleukin-10. The results of the present study suggest that microbiota dysbiosis may promote chronic systemic inflammation in CKD. Furthermore, they support that modifying the gut microbiota, especially Akkermansia, may be a promising potential therapeutic strategy to attenuate the progression of, and/or systemic inflammation in, CKD.
Highlights
Chronic kidney disease (CKD) is a major public health problem that affects an estimated 350 million people worldwide and results in 0.5–1 million deaths annually
Persistent immune activation is a major risk factor for both CKD progression and cardiovascular complications (Darisipudi and Knauf, 2016); identifying bacteria associated with chronic systemic inflammation and elucidating the role and mechanisms by which the altered gut microbiota contributes to chronic systematic inflammation are of urgent importance to improve current CKD therapies
The results of this analysis showed that the subjects in the CKD group had significantly higher blood urea-nitrogen (BUN) (P < 0.0001), serum creatinine (SCr) (P < 0.0001), and Cystatin-C (CysC) (P < 0.0001) levels than those in the healthy control (HC) group
Summary
Chronic kidney disease (CKD) is a major public health problem that affects an estimated 350 million people worldwide and results in 0.5–1 million deaths annually. When the gut microbiota becomes dysbiotic, pathogenic bacteria overgrow and secrete increased amounts of bacterial products such as lipopolysaccharides, peptidoglycans, and bacterial DNA and/or outer-membrane proteins into the host circulatory system, thereby causing chronic immune activation. These harmful substances destroy intestinal permeability (Anders et al, 2013; Sabatino et al, 2015) and activate the intestinalmucosa immune system (Hand et al, 2016), thereby promoting the generation of inflammatory factors such as interleukin (IL)- 6, interferon γ (IFN-γ), and tumor necrosis factor α (TNF-α) (Rossi et al, 2014). Persistent immune activation is a major risk factor for both CKD progression and cardiovascular complications (Darisipudi and Knauf, 2016); identifying bacteria associated with chronic systemic inflammation and elucidating the role and mechanisms by which the altered gut microbiota contributes to chronic systematic inflammation are of urgent importance to improve current CKD therapies
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