## 3 The Gastrointestinal Microbiome in CKD  
The human microbiome consists of different bacteria, archaea and fungi. Almost all microbiota belong to _Firmicutes_, _Bacteroida_, _Proteobacteria_, and _Actinobacteria_[23]. The microbiome in the small intestine mainly comprises facultative anaerobes, while the large intestine hosts obligatory anaerobes [23]. The microbiome enters a symbiotic and complex relationship with the host providing metabolic, protective and trophic functions [23]. It is involved in immunomoddulation, defense mechanisms, synthesizes nutritional factors, such as vitamins and is needed to digest food ingredients not targeted by digestive enzymes [23; 24]. In detail, dietary fibers are metabolized to short-chained fatty acids and gases. Short-chained fatty acids are valuable nutritional factors for the intestinal epithelial cell and mediate peristaltic movement [25]. Experimental data from CKD patients and rodent CKD models revealed a shift in the microbiome towards bacterial families that possess proteolytic enzymes [26; 27; 28]. They play a vital role in the production of gut-derived uremic toxins such as indoxyl-sulfate (IS), p-cresyl sulfate (PCS) and indole 3-acetic acid (IAA) [29; 30; 31]. Physiologically, the kidney excretes these uremic toxins. However, their plasma levels increase during CKD, exerting various adverse effects that contribute to further alterations in the gut-kidney axis. For instance, indole uremic toxins IS and IAA induce ROS production resulting in vascular damage associated with renal anemia, [30] cognitive impairment [32], and potentially cryptosis [33]. Even in patients with mild renal dysfunction, increased production of gut-derived uremic toxins could be observed [31]. In addition, an observational study that recruited pre-dialysis CKD patients found that serum IS and PSC correlate with CKD progression [6]. Experimental studies in rodents also show that adenine-induced CKD goes along with disordered amino acid metabolism that amplifies over time [10]. It has been proposed that targeting gut microbiota or amino acid metabolism might be a way to manage uremic toxin levels as they provide a substitute energy source for the GI microbiome [10; 29]. Nutritional changes associated with dietary intervention, medications, and the secretion of uremic toxins into the gut affect the composition of the microbiome in CKD [27]. In patients with end-stage renal disease (ESRD), analyses of gut microbial DNA revealed an increased abundance of many species, including _Brachybacteria_, _Catenibacteria_, _Enterobacteria_, and _Akkermansia_ (Figure 1A) [28; 34]. Those were generally accompanied by decreases in _Bifidobacteria_ and _Lactobacillus_[28; 35]. In a clinical setting, it is challenging to assess if changes in the microbiome observed during CKD are caused by uremia or due to therapeutic interventions. Fortunately, investigative studies in animal models allow us to focus on isolated uremic effects on the gut microbiome. The composition of the gut microbiome after surgical CKD induction (5/6 nephrectomy) in rats mirrored the state in human CKD patients [28]. Furthermore, systemic inflammation and intestinal bacterial translocation accompanied dysbiosis in a murine model of Alport syndrome-induced CKD [9]. Antibiotic treatment ameliorated inflammatory markers and reduced serum levels of endotoxins, which supports the general notion that dysbiosis could be one of the driving factors behind disease progression and systemic inflammation in CKD [9]. C57 Bl/6 mice are generally considered relatively resistant to CKD development after 5/6 nephrectomy, making them a good model for studying microbial changes over time. Luminal urea concentration was significantly increased after 5/6 nephrectomy, but was not  
Figure 1: Schematic representation of intestinal microbiota in healthy (**left**) and CKD patients (**right**). (**A**) In physiological conditions, intestinal epithelial cells limit interactions between the gut microbiome in the intestinal lumen and the host.