The major findings of our study are that rats subjected to BNx developed mild gut injury, including decreased intestinal villi height and increased gut permeability. After BNx, bacterial loads in liver and MLN as well as endotoxin in blood increased significantly. Neither the protein expression and the distribution pattern, nor the structure of the TJs was altered in BNx rats.
AKI is a systemic disease and often leads to widespread injury causing multiple organ dysfunctions . Gut is a newly-discovered organ which may be remotely injured after AKI . In mice subjected to BNx, intestinal endothelial and epithelial apoptosis and necrosis develop rapidly with subsequent gut barrier disruption [19–20]. Our study in rats confirms these findings and illustrates the important effects of renal failure on gut, which are independent of renal IR. It is possible that retention of urea as well as other metabolites and hypervolumia related to AKI may impair the gut barrier, resulting in increased permeability.
Inflammation is a prominent component of AKI and patients with AKI frequently suffer from systemic inflammation [21–22]. Currently, our understanding of the mechanisms of AKI-induced systemic inflammation remains incomplete. The gut has long been suspected to play a key role in amplifying the systemic inflammatory response during AKI. In the context of ischemic AKI, emerging evidence indicates that the gut may be an amplifier of systemic inflammation through the translocation of gut bacteria and resultant endotoxinemia [7–8]. Our previously study showed that the gut-derived endotoxin, resulting from an increased gut permeability after severe renal IR, amplifies intrarenal inflammation by activation renal TLR4 signaling . Ding et al. confirmed our findings and demonstrated probiotics can alleviate renal dysfunction caused by renal IR via protecting gut barrier function and preventing endotoxinemia . Of note, data that have been accumulated in ischemic AKI models cannot be expanded to all patients, as ischemia complicates only half of AKI that is encountered in hospitalized patients. Therefore, we used BNx model to test our hypothesis. We show in this study that rats subjected to BNx demonstrated an increased bacterial loads in liver and MLN. We also found a low grade of endotoxinemia in BNx rats. These findings suggest that non-ischemic AKI may share a number of common pictures with ischemic AKI, including gut barrier dysfunction, bacterial/endotoxin translocation and subsequent systemic inflammation. For some patients, BNx is required before renal transplantation due to kidneys that preclude renal allograft placement, high-grade tumor and severe infection [23–24]. In this case, timely and effective improvement of gut dysfunctions following BNx is of great significance to improve prognosis of the patients.
The changes of TJs in gut epithelial cells are one of the major mechanisms which are involved in transmembrane transfer of gut bacteria and their products . Renal IR rats were reported to be associated with diffuse TJs disintegration in gut epithelial cells . In our study, however, BNx and sham operated rats had a similar protein expression and distribution pattern of ZO-1, claudin-1 and occludin in the ileum. Additionally, TEM did not reveal any structural alterations in TJ with BNx rats. Our findings suggest that the translocation of bacterial/endotoxin in non-ischemic AKI was not most likely due to a TJs mediated paracellular pathway. It has reported that apoptosis in intestinal epithelial cells was implicated in bacterial translocation . By using TUNEL method, we demonstrated that apoptosis was increased on ileal intestinal epithelial cells in BNx rats. Thus, as a working hypothesis, at least accelerated apoptosis should promote bacterial/endotoxin translocation, and potentially, the shortening of the villi comes as a cofactor.