*3.3. Gut Microbiota in Pediatric CKD*

Table 1 summarizes the alterations of gut microbiota and its related metabolites in pediatric kidney disease, as reported in the literature [83–89]. The study of the gut microbiome in children with kidney disease mainly focused on three types of dysbiosis: loss of diversity, shifts in keystone taxa, and alterations of microbial metabolites.

**Table 1.** Summary of studies investigated links between gut microbiota and pediatric chronic kidney disease.


Data on age are presented as mean ± standard deviation or median (interquartile range); PD = peritoneal dialysis; HD = hemodialysis; CKD = chronic kidney disease; INS = idiopathic nephrotic syndrome; CAKUT = congenital anomalies of the kidney and urinary tract; DMA = dimethylamine; TMA = trimethylamine; TMAO = trimethylamine-N-oxide; ABPM = 24 h ambulatory blood pressure monitoring.

The pediatric gut microbiome in a uremic milieu has been evaluated in a small group of ESKD children who underwent hemodialysis (HD, *n* = 8), peritoneal dialysis (PD, *n* = 8), or kidney transplant (*n* = 10) [83]. Alpha diversity was decreased in children undergoing PD or transplant. ESKD children undergoing HD had increased abundance of phylum *Bacteroidetes*. Children on PD had an increase in the abundance of phyla *Firmicutes* and *Actinobacteria* but a decrease in abundance of family *Enterobacteriaceae*. Additionally, children on HD or PD had increased plasma levels of microbiota-derived uremic toxins, IS, and PCS [83]. A similar pattern of gut dysbiosis was reported in adult patients with ESKD [69,70].

In another small group of children (*n* = 12) with idiopathic nephrotic syndrome (INS), butyric acid level in the feces was decreased in relapsing INS children coinciding with decreased abundance of butyrate-producing bacteria belonging to *Clostridium* clusters IV and XIVa [84]. These microbes included *Clostridium orbiscindens*, *Faecalibacterium prausnitzii*, *Eubacterium hallii*, *E. ramulus*, *E. rectale*, *E. ventriosum*, *Roseburia intestinalis*, *Eubacterium* spp., and *Butyrivibrio* spp.

One study recruiting 60 children diagnosed with CKD stage 1 and 26 stage 2–3 children showed that urinary levels of TMAO and dimethylamine (DMA, a metabolite of TMAO) were lower in children with CKD stages 2–3 than CKD stage 1 [85]. Additionally, the proportion of genus *Prevotella* was decreased in CKD children with blood pressure (BP) abnormalities.

In 78 children and adolescents with CKD stage 1–4 and a median age of 11.2 years, BP determined using 24 h ambulatory blood pressure monitoring (ABPM) was defined out of range, and BP was related to increased plasma levels of propionic acid and butyric acid [86]. Additionally, the abundance of phylum *Verrucomicrobia*, genus *Akkermansia*, and species *Bifidobacterium bifidum* were higher in CKD children with CAKUT compared to those with non-CAKUT.

In another study from our group, we recruited 115 children and adolescents with CKD stages 1–4 [88]. We found plasma levels of DMA, trimethylamine (TMA), and TMAO higher in children with CKD stage 2–4 vs. CKD stage 1. These data are consistent with previous studies in CKD adults [90,91], showing that TMAO is increased in CKD and that there is a negative association between circulating TMAO level and renal function. We also observed that phylum *Cyanobacteria*, genera *Subdoligranulum*, *Faecalibacterium*, *Ruminococcus*, and *Akkermansia* were decreased in CKD children stools with an abnormal ABPM profile.

CKD children with abnormal ABPM had a decreased proportion of genera *Gemella*, *Providencia*, and *Peptosreptoccocus*. Of note is that these genera of bacteria are involved in TMA production [92]. Accordingly, whether these microbes play a key role on the development of hypertension via the TMA−TMAO metabolic pathway in CKD children deserves further clarification.

In 20 children with INS who received oral prednisone therapy, abundance of genera *Romboutsia*, *Stomatobaculum*, and *Cloacibacillus* was increased after a 4-week initial therapy [87]. Another study recruited 20 children with INS and showed that probiotic treatment protected against relapse and coincided with increases in butyrate-producing bacteria and blood regulatory T cell (Treg) counts [89]. Considering gut microbiota shapes, the Th17/Treg balance, and Th17 involved in renal inflammation, probiotic treatment may have beneficial effects impacting the gut–kidney axis via immune regulation.
