## 6 Systemic Inflammation as a Consequence of Impaired Gastrointestinal Barrier in CKD  
Impaired kidney function in CKD is associated with numerous alterations in the bi-directional crosstalk between intestinal hyperpermeability and systemic inflammation. One proposed mechanism to elucidate the aforementioned relationship includes the overproduction and retention of urea and uremic solutes in CKD, shifting to the intestinal tract as the main excretion route [60; 61]. Experimental evidence revealed that gut bacteria is an essential mediator of inflammation as it decomposes urea to ammonia (NH\({}_{3}\)) and ammonium hydroxide (NH\({}_{4}\)OH) [26; 60]. Accumulation of NH\({}_{3}\) and NH\({}_{4}\)OH causes injury to the protective mucosal barrier due to subsequent elevation of luminal pH and activation of pro-inflammatory cytokines [34; 62; 63]. This contributes to increased intestinal permeability and consequent bacterial translocation [26; 57; 62; 63; 64]. Endotoxin, the lipopolysaccharidescharide that constitutes the exterior cell wall of most Gram-negative bacteria, is the key initiator for immune system activation [65]. Elevated plasma levels of translocated endotoxin promote the production of ROS following the activation of the inflammatory NF-kB pathway [66] and local RAAS [8].  
Experimental evidence from laboratory rodents and humans suggests that systemic inflammation is associated with intestinal dysbiosis and barrier dysfunction [9; 55; 57; 65], so it might be tempting to speculate that hyperpermeability and the microbial shift are the leading causes of systemic inflammation in CKD. In CKD rats, nuclear levels of nuclear factor erythroid 2-related factor 2 (Nrf2--a promising target of antioxidant properties) declined, whereas the nuclear fraction of the pro-inflammatory transcription factor NF-kB increased. Treatment with Nrf2 activator dh404 resulted in a diminished level of pro-inflammatory cytokines. Additionally, untreated CKD rats displayed downregulated protein expression of ZO-1, occludin, and claudin-1. Dh404 treatment restored the protein expression of TJ components [66]. Nevertheless, it should be considered that most studies only focused on a few TJ proteins, and there is no data on TJ protein levels in the FAE covering Peyer's patches yet. The main task of the Peyer's patch is the specific presentation of antigen to the underlying cells of the immune system [67]. Impaired barrier function could trigger an unregulated immune response, subsequently leading to detrimental effects on the patient's health. Thus far, there is a lack of experimental evidence linking the relationship between FAE and CKD. The same can be said for the phosphaturic hormone FGF23. FGF23 is negatively associated with the survival of CKD patients and is currently regarded as an early indicator of disease progression [21]. FGF23 is linked to several inflammatory processes in other organs. It directly induces the production of \(c\)-reactive protein and interleukin-6 in murine hepatocytes and tumor necrosis factor-\(\alpha\) (TNF\(\alpha\)) in macrophages [68; 69]. Macrophages also produce FGF23, possibly triggering an autocrine loop of inflammation [69]. Hence, FGF23 can induce inflammatory processes in peripheral organs. It is currently unknown whether FGF23 is only a biomarker for kidney disease progression or actively drives kidney failure, perhaps even through regulation of GI permeability.