*Gut Microbiota and SCFAs in CKD*

The complex functions of the gut microbiota are related to other organs and result in the formation of an '-axis' between them [79]. The gut microbiota plays an important role in kidney homeostasis, regulating the gut-kidney axis [80], and intestinal dysbiosis is implicated in the pathogenesis of various renal disorders, including urinary tract infections (UTIs) that are also related to the "intestinal bloom of uropathogens" with a prevalence of the uropathogenic *Escherichia coli* [81,82]. These infections can also evolve into pyelonephritis as a complication of an ascending urinary tract infection that spreads from the bladder to the kidneys and their collecting systems, which still results in the significant morbidity and mortality associated with the severe cases of this disease [83]. A marked gut dysbiosis is also commonly observed in CKD patients and results from qualitative and quantitative changes in the composition and metabolic activities of the gut microbiota [84]. This may be due to both the use of antibiotics and drugs (e.g., iron-containing or resin-based phosphate binders) and changes in diet, including a decrease in resistant starch and/or fibre content or restriction of fruits and vegetables, as well as a decrease in colonic transit time in patients with uremia [85,86]. Furthermore, during CKD, the colon becomes the main route for uric acid and oxalate secretion. The influx of urea, uric acid, and oxalate into the colon affects the composition and metabolism of the gut microbiota, promoting the overgrowth of ureaseproducing bacteria and changes in the growth of the bacterial communities themselves [23]. Thus, an increase in Phyla *Actinobacteria*, *Firmicutes* and *Proteobacteria* microbes and a decrease in *Bifidobacteria* and *Lactobacilli* and SCFA levels have been reported in the course of CKD and in patients with end-stage renal disease [4,87]. These aspects reflect the evidence that SCFA levels progressively decrease during the different stages of CKD and, ultimately, in dialysis patients [88]. SCFAs produced by bacteria in the kidney protect tubular cells from oxidative stress and mitochondria biogenesis, reduce renal ischaemia-reperfusion injury, inflammation, reactive molecules, and immune and apoptotic cell infiltration in damaged kidneys [89]. Thus, the dysbiotic microbiota produces both a large amount of NH3/NH4OH that influences the pH of the intestinal lumen and toxic metabolites such as indoles and phenols that are further metabolised in the liver and intestine into pCS, IS, and

TMO. Generally, pCS accumulates in tubular cells and binds to OAT receptors located on the basolateral membrane of renal proximal tubular cells and generates reactive oxygen species, whereas IS binds to OAT receptors and activates NF-κB and AP-1-dependent gene transcription, inducing inflammation and nephrotoxicity [90]. Thus, these toxic metabolites may lead to accelerated renal damage by both promoting the progression of oxidative stress and inflammation and by promoting the alteration of the gut microbiota, which, by further producing gut-derived toxins, also alters the function of the intestinal epithelial barrier. At the same time, these toxic metabolites are absorbed through the damaged intestinal barrier and released into the systemic circulation. Indeed, there is considerable evidence to suggest that gut dysbiosis may contribute to the progression of some of the events that occur over the course of CKD, such as oxidative stress, endotoxemia, inflammation, and an increased prevalence of comorbidities [91–94]. Thus, it seems clear that there is a close relationship between the gut microbiota and renal function that is implicated in renal physiology and disease conditions.
