Inhibiting Intestinal Krüppel-Like Factor 5 Impairs the Beneficial Role of Renal Denervation in Gut Microbiota in Rats with Heart Failure

ABSTRACT Krüppel-like factor 5 (KLF5) is critical in maintaining intestinal barrier function, and renal denervation (RDN) mitigates gut microbiota aberrations in rats with heart failure (HF). It is unclear whether intestinal KLF5 can be regulated by RDN and whether inhibiting intestinal KLF5 weakens the beneficial role of RDN on gut microbiota. Sprague-Dawley rats were distributed into a CG (sham transverse aortic constriction [TAC] and sham RDN), HF (induced by TAC), or RDN (underwent RDN after TAC) group or a CG.M, HF.M, or RDN.M group, which included the administration of the KLF5 inhibitor to the CG, HF, or RDN group, respectively. Transmission electron microscopy, mRNA, and protein expression of KLF5 and desmoglein 2 (DSG2) in jejunum and sequencing of the 16S rRNA gene in fecal samples were evaluated. KLF5 expression was lower in the RDN group than in the HF group (P < 0.001). The microvillus length, density, length-to-width ratio, and DSG2 expression were lower in the RDN.M group than in the RDN group, and the same trend was observed between the HF.M and HF groups (all P < 0.05). The gut bacterial community structure was altered after administration of a KLF5 inhibitor. The abundances of Proteobacteria, Gammaproteobacteria, Sutterella, and Prevotellaceae were higher, and the abundance of Firmicutes was lower in the RDN.M group than in the RDN group (all P < 0.05). These findings indicated that RDN suppressed intestinal KLF5 expression, and inhibiting intestinal KLF5 expression exacerbated the gut microbiota by impairing the intestinal barrier function in HF rats following RDN, which weakened the beneficial role of RDN on gut microbiota. IMPORTANCE Krüppel-like factor 5 (KLF5) is critical for the maintenance of intestinal barrier function. It is unclear whether intestinal KLF5 expression can be affected by renal denervation (RDN) in heart failure (HF) and whether inhibiting intestinal KLF5 expression exacerbates the gut microbiome and weakens the role of RDN in mitigating gut microbiome aberrations in HF rats after RDN. We demonstrated that RDN significantly suppressed intestinal KLF5 expression and that inhibiting intestinal expression of KLF5 exacerbated the gut microbiota and weakened the role of RDN in mitigating microbiota aberrations by impairing intestinal barrier function, resulting in an increase in bacteria harmful to cardiac function and a decrease in beneficial bacteria in HF rats following RDN. This study highlighted the important roles of intestinal KLF5 in modulating gut microbiota in HF and suggested that the influence of RDN on intestinal KLF5 was another possible role of RDN in HF besides downregulating the sympathetic nerve.