## 5 Gastrointestinal Barrier Function in CKD  
The surface of the GI tract is lined with epithelial cells connected by tight junction (TJ) proteins. There are two ways of crossing this cellular barrier. The transcellular route is mediated by substrate-specific receptors and involves diffusion through the cell and -basedal release [47], while the TJ restricts the paracellular route [48; 49]. The TJ is a multiprotein complex constituted of structural proteins, such as occludin, tricellulin and zonula occludens-1 (ZO-1), and functional proteins, which belong to the family of claudins [48; 49]. The expression and localization of claudin family members vary along the vertical axis of the GI tract [50]. Claudins that mediate ion and small molecule transport (e.g., claudin-2, \(-\)12) are predominately present in the small intestine [50]. Claudin-2-mediated pore pathway arbitrates the transition of small uncharged ions up to a radius of 4 A, [49; 51] whereas occludin appears to play a central role in the formation of the leak pathway for larger ion transition across the barrier [52]. Transepithelial leakage and flux of particles of any size through the membrane via the unrestricted permeability pathway is a result of damage to the epithelial cells (Figure 1B) [48]. In contrast, claudins that restrict transport (e.g., claudin-4, \(-\)5) are increasingly expressed in the large intestine [50]. Protein production levels are usually stable within singular anatomical segments. An exception is the follicle-associated epithelium (FAE) that covers Peyer's Patches in the distal small intestine. Here, sealing claudins dominate to prevent accidental contact between antigens and the underlying cells of the immune system [53; 54]. Dysfunctions in the intestinal epithelium that propagate bacterial, uremic and endotoxin cross-over to the bloodstream are defined as intestinal hyperpermeability or \"leaky gut\" syndrome (LGS). Hyperpermeability in the intestine subsequently leads to alterations in the GI microbiome, thus promoting inflammation [55]. Precise interplay between persistent systemic inflammatory response observed during intestinal barrier dysfunction and disease progression in CKD remains to be explored. As CKD progresses, a decline of the glomerular filtration of sodium and activation of the RAAS signaling pathway occurs, causing increased sodium retention. Consequently, osmolarity rises, triggering a negative feedback mechanism that results in fluid retention [56]. Hypervolemia independently correlates with renal and cardiovascular outcomes in patients with stage 3 to 5 CKD [56]. Despite suggested pathophysiological mechanisms of how an edematous bowel wall increases gut permeability in CKD patients leading to sepsis and elevated levels of endotoxins exacerbating the progression, the relative contribution of volume overload to poor outcomes is still unknown. In 2012, [PERSON] et al. highlighted morphological changes in the colonic TJ structure of 5/6 nephrectomy rats. Claudin-1, occludin, and ZO-1 production was markedly reduced [57]. mRNA levels of the above-mentioned proteins remained similar between control and CKD groups, suggesting the changes observed at the protein level were due to post-transcriptional or post-translational modifications [57]. Histological analysis displayed an increase in GI wall thickness and lymphocytic infiltration in rats with CKD [57]. Furthermore, in hemodialysis (HD) patients with ischemic bowel disease, significantly declined expression of claudin-1, occludin, and ZO-1 was marked compared to patients with advanced CKD without ischemic bowel disease [7]. In mice subjected to unilateral ureteral obstruction, depletion of gut microbiota induced by broad-spectrum antibiotics was followed by elevated occludin and ZO-1 gene expression [58]. Therefore, alterations of TJ proteins play a key role in the underlying molecular mechanism of the impaired GI barrier in CKD. Beneficial gut bacteria _Akkermansia_ is a prominent example of direct interaction between the microbiome and the GI TJ.