Chronic Kidney Disease and Gut Microbiota

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This entry is adapted from the peer-reviewed paper 10.3390/ijms23073954

The gut–kidney interaction implicating chronic kidney disease (CKD) has been the focus of increasing interest. Gut microbiota-targeted therapies could prevent CKD and its comorbidities. Considering that CKD can originate in early life, its treatment and prevention should start in childhood or even earlier in fetal life. Up to 10% of the population worldwide is affected by chronic kidney disease (CKD).

chronic kidney disease developmental origins of health and disease (DOHaD) gut microbiota probiotics prebiotics

1. Gut Microbiota and Kidney Disease

1.1. Early-Life Gut Microbiome

Although microbes colonize the neonatal gut immediately following birth ^[1], microbial colonization continues to develop and vary in species abundance until a typical adult-like gut microbiota is established at the age of 2–3 years ^[2]. A variety of maternal factors and early-life events determine the establishment of the gut microbiome, such as gestational age, type of delivery, maternal conditions, formula feeding, antibiotic exposure, and ecological factors ^[1]^[2]^[3]^[4].

During pregnancy and lactation, the mother gut microbiota can influence offspring gut microbial structure and composition, which highlights the importance of maternal factors in the establishment of early-life gut microbiome ^[4]. Several risk factors related to CKD of developmental origins have also been linked to alterations of gut microbiota, such as gestational diabetes ^[5], maternal obesity ^[6], prematurity ^[7], low birth weight (LBW) ^[8], and maternal malnutrition ^[9]. Additionally, the establishment of the microbiome is highly interconnected with development of the immune system, and CKD has strong immune and inflammatory etiologies ^[10].

Moreover, several environmental chemicals that pregnant mothers are likely to be exposed to are associated with developmental origins of kidney disease ^[11]. Among them, exposure to heavy metals, polycyclic aromatic hydrocarbons, and dioxins also affect the gut microbiome, accompanied with the development of adult diseases ^[12]. All of these studies suggest that the early-life microbial alterations after the CKD-related adverse insults may be involved in the development of kidney disease in later life.

1.2. The Gut–Kidney Axis

The pathogenic interconnection between the gut microbiome and kidney diseases is termed the gut–kidney axis ^[13], which is implicated in CKD and its comorbidities. A paucity of data exists regarding how the gut–kidney axis functions in the pediatric population with CKD and what the impact of the gut microbiota is in this process. However, a great deal of work on the impact of the gut–kidney axis in established CKD has been conducted, including gut barrier dysfunction, inflammation, immune response, alterations of microbiota compositions, dysregulated short-chain fatty acids (SCFA) and their receptors, uremic toxins and so on. Each of them are discussed.

First, CKD can impair the intestinal barrier by disrupting the epithelial tight junction in a 5/6 nephrectomy rat model ^[14]. An apparent reduction of the tight junction proteins was reported in the gut mucosa of CKD animals, possibly attributed to uremic toxins ^[15]. As a result, an increased intestinal permeability and translocation of lipopolysaccharide (LPS) and bacteria across the intestinal barrier were reported. In CKD rats, gut bacteria could activate a T-helper 17 (Th17)/Th1 T-cell response and increase the production of inflammatory cytokines, and LPS could initiate innate immune cells through nuclear factor kappa B (NF-κB) and toll-like receptor 4 (TLR4) pathways, all triggering inflammation and immune response ^[16].

Second, changes in the composition of the gut microbiota are relevant to CKD. Uremia profoundly alters 190 and 175 bacterial operational taxonomic units (OTUs) of the gut microbiome in CKD humans ^[17] and rats ^[18], respectively. Specifically, the presence of aerobic bacteria such as those belonging to the phyla Firmicutes, Actinobacteria, and Proteobacteria in higher numbers, but fewer anaerobic bacteria, such as Sutterellaceae, Bacteroidaceae, and Lactobacillaceae, were observed in end stage kidney disease (ESKD) ^[19]^[20]^[21]. Notably, most has consistently reported that animals and adult patients with CKD had low abundance of genus Lactobacillus, whereas the proportion of family Enterobacteriaceae were increased ^[13]^[17]^[18]^[22]^[23]. A systemic one recruiting 25 studies with 1436 CKD patients revealed that the α-diversity was decreased, and β-diversity of gut microbiota was significantly more distinct in ESKD patients than in healthy controls ^[23].

Third, the gut microbiota produces diverse metabolites, which are involved in multiple physiological processes, such as immunity and host energy metabolism ^[13]. Following dietary exposures to certain nutrients, particular microbiota-derived metabolites could be altered in ESKD patients ^[24]. Carbohydrates are fermented to generate SCFAs which signal the host to increase energy expenditure, enhance G protein-coupled receptor (GPCR) signaling, and act as an inhibitor for histone deacetylase (HDAC) ^[24]^[25]^[26]. SCFAs are made up of one to six carbon atoms (C1–C6), mainly consisting of acetic acid (C2), propionic acid (C3), and butyric acid (C4) ^[25]. In adult CKD patients, butyrate-producing microbes and butyric acid production reduced with disease severity ^[27].

Indoxyl sulfate (IS) and p-cresyl sulfate (PCS), both end-products of protein fermentation, and trimethylamine-N-oxide (TMAO), an end-product of microbial carnitine/choline metabolism, are well-known microbiota-derived uremic toxins. Urinary excretion of several microbial tryptophan metabolites such as IS and PCS is decreased in patients with CKD. These tryptophan metabolites mainly from the indole metabolic pathway are accumulated as uremic toxins, which are ligands for AHR ^[28]. Activation of AHR is able to trigger inflammation, induce oxidative stress, and modulate the Th17 axis, contributing to CKD progression in vivo and in vitro ^[29]^[30]. The level of another uremic toxin, TMAO, is high in patients with ESKD and associated with increased risk of cardiovascular disease ^[31]^[32]. TMAO generation results from the fermentation by the gut microbiota of dietary carnitine/choline, which is converted to trimethylamine (TMA) and transformed into TMAO by flavin-containing monooxygenase (FMO) in the liver. Conversely, selective targeting of gut-microbiota-dependent TMAO generation has been reported to protect CKD progression in a murine model of CKD ^[33]. Although the uses of prebiotics, probiotics, postbiotics, and synbiotics have shown potential positive effects against uremic toxin generation, their evidence is still limited for the treatment and prevention of human CKD ^[34]^[35]^[36].

Together, the interaction between gut microbiota and CKD is bidirectional: CKD may affect the structure of the gut microbiota and contribute to gut dysbiosis, while dysbiosis in CKD patients may increase uremic toxin levels that in turn contribute to CKD progression. Considering the gut is a potential cause of CKD-related complications, gut microbiota-targeted therapeutic strategies in CKD will have a considerable impact on CKD management.

1.3. Gut Microbiota in Pediatric CKD

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) ^[37]. 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 ^[37]. A similar pattern of gut dysbiosis was reported in adult patients with ESKD ^[23]^[24].

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 ^[38]. These microbes includedClostridium orbiscindens, Faecalibacterium prausnitzii, Eubacterium hallii, E. ramulus, E. rectale, E. ventriosum, Roseburia intestinalis, Eubacteriumspp., and Butyrivibrio spp.

One 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 ^[39]. 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 ^[40]. Additionally, the abundance of phylum Verrucomicrobia, genus Akkermansia, and species Bifidobacterium bifidum were higher in CKD children with congenital anomalies of the kidney and urinary tract (CAKUT) compared to those with non-CAKUT.

In another one, it was recruited 115 children and adolescents with CKD stages 1–4 ^[41]. It was 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 ^[42]^[43], showing that TMAO is increased in CKD and that there is a negative association between circulating TMAO level and renal function. It was 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 ^[44]. 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 ^[45]. Another 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 ^[46]. 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.

2. Gut Microbiota-Targeted Therapy

2.1. Human Evidence in Pediatric CKD

To date, limited data are available to examine whether alterations of gut microbiota by microbiota-targeted therapies can protect against CKD progression and its comorbidities in the pediatric population. For example, Clostridium butyricum is a butyrate-producing bacteria used as a probiotic ^[47]. Oral administration of Clostridium butyricum during remission was reported to reduce the frequency of relapse and the need for immunosuppressive agents in children with INS ^[46]. The protective effect of probiotic therapy was associated with increases in butyrate-producing bacteria and Treg cells. On the other hand, animal studies targeting gut microbiota to prevent the development of CKD and its associated complications have produced some compelling evidence.

2.2. Animal Models of Early-Life Gut Microbiota-Targeted Therapy

Rats are the dominant species used by experiments, and hypertension is the most commonly studied CKD-related comorbidity. A variety of early-life insults can lead to structural and functional changes in the developing kidney by the so-called renal programming ^[48]. Unlike in humans, kidney development in rats continues up to postnatal week 1–2. According to DOHaD theory, adverse environmental insults during pregnancy and lactation period can interrupt kidney development, resulting in renal programming and adult kidney disease. Several models of renal programming have been used to examine gut microbiota-targeted interventions in CKD of developmental origins, such as maternal high-fructose diet ^[49]^[50], perinatal high-fat diet ^[51]^[52]^[53], perinatal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure ^[54], maternal adenine-induced CKD ^[55], maternal TMAO and ADMA exposure ^[56], and maternal high-fructose diet and TCDD exposure ^[57].

Taking the example of the maternal high-fructose diet model, high-fructose intake during pregnancy and lactation modified over 200 renal transcripts from nephrogenesis stage to adulthood ^[58]. Using whole-genome RNA next-generation sequencing (NGS), high-fructose-induced alterations of the renal transcriptome were reported in kidneys from 1-day-, 3-week-, and 3-month-old male offspring. NGS identified genes in arachidonic acid metabolism (Cyp2c23, Hpgds, Ptgds and Ptges) that contribute to renal programming and hypertension. Notably, this renal programming model has been used to examine the reprogramming effects of gut microbiota-targeted therapy on fructose-induced developmental programming ^[59]. Since the above-mentioned renal programming models have been established and linked to adverse renal outcomes in adult offspring, readers are referred to original references. There was only one conducting an adenine-induced pediatric CKD model to determine the effects of probiotic resveratrol on CKD progression ^[60].

Elsewhere showed that several probiotic microorganisms and prebiotics have benefits on adult CKD ^[35]^[36], while there was only very limited evidence regarding their role on CKD of developmental origins. Supplementation with Lactobacillus casei rhamnosus from pregnancy through lactation protected adult male rat progeny against hypertension programmed by a maternal high-fructose diet ^[49] or perinatal high-fat diet ^[51].

Additionally, inulin as a prebiotic has been examined for its protective effect in hypertension of developmental origins ^[49]^[51]. In a high-fat model ^[51], it was previously demonstrated that inulin treatment protected against hypertension in adult rat offspring coinciding with alterations of the gut microbiota, particularly increasing the abundance of Lactobacillus, a well-known probiotic strain. Likewise, perinatal supplementing to rat dams with inulin protected adult offspring against maternal high-fructose diet-induced hypertension, which coincided with an increased plasma level of propionic acid ^[51].

Resveratrol can modulate gut microbiota composition, undergo biotransformation to activate metabolites via the intestinal microbiota, affect gut barrier function, modify the Firmicutes to Bacteroidetes (F/B) ratio, and reverse the gut microbial dysbiosis ^[61]^[62]^[63]^[64]. With a prebiotic effect for gut microbes, increasing evidence supports the beneficial effects of resveratrol on many diseases, including CKD ^[65]^[66]. One was revealed that perinatal resveratrol therapy could protect adult offspring against hypertension and CKD of developmental origins ^[67]. Studies using a maternal TCDD exposure rat model showed TCDD-induced renal hypertrophy and hypertension in adult progeny, and both are key features of early CKD. TCDD-induced hypertension is associated with activation of AHR signaling, induction of TH17-dependent renal inflammation, and alterations of gut microbiota compositions ^[54]. Conversely, the induction of AHR- and TH17-mediated renal inflammation could be counterbalanced by perinatal resveratrol supplementation. The beneficial effects of resveratrol are associated with reshaping the gut microbiome by augmenting microbes that can inhibit TH17 responses and reduce the F/B ratio, a microbial marker of hypertension ^[13]. In a maternal CKD model, adult offspring developed renal hypertrophy and hypertension ^[55]. Perinatal resveratrol therapy protected hypertension, coinciding with the restoration of microbial richness and diversity and an increase in Lactobacillus and Bifidobacterium ^[55]. Similar to TMAO, asymmetric dimethylarginine (ADMA) is a well-known uremic toxin ^[68]. Another one using a maternal TMAO plus ADMA exposure model demonstrated that adult offspring born to dams exposed to uremic toxins had renal dysfunction and hypertension ^[56]. Conversely, maternal treatment with resveratrol rescued hypertension induced by TMAO plus ADMA exposure, accompanied by increased butyrate-producing microbes and fecal butyric acid level.

Of note is that the low bioavailability of resveratrol diminishes its efficacy and clinical translation ^[69]. Accordingly, it was produced resveratrol butyrate ester (RBE) via the esterification of resveratrol with the SCFA butyrate to improve the efficacy ^[70]. Using a pediatric CKD model ^[39], it was recently found low-dose RBE (25 mg/L) is as effective as resveratrol (50 mg/L) in protecting against hypertension and renal dysfunction. The beneficial effects of RBE include regulation of SCFA receptors, decreased AHR signaling, and increased abundance of the beneficial microbes Blautia and Enterococcus.

Although there are many prebiotic foods, only garlic oil has shown beneficial effects against high-fat diet-induced hypertension in adult progeny ^[60]. These effects include increased α-diversity, increased plasma levels of acetic acid, butyric acid, and propionic acid, and increased beneficial bacteria Lactobacillus and Bifidobacterium.

In addition to probiotics and prebiotics, postbiotics is another gut microbiota-targeted therapy. Postbiotics include various components, such as microbial cell fractions, extracellular polysaccharides, functional proteins, cell lysates, extracellular vesicles, cell-wall-derived muropeptides and so on. ^[71]. Nevertheless, very limited information exists regarding the use of postbiotics in CKD. Acetate supplementation within gestation and lactation was reported to protect offspring against high-fructose-diet-induced hypertension, a major complication of CKD ^[50]. However, its protective effects on other complications of CKD are still waiting for clarification. Another example of postbiotic use in hypertension of developmental origins is conjugated linoleic acid ^[53]. Linoleic acid is a gut microbial metabolite derived from dietary polyunsaturated fatty acids (PUFA) ^[72]. Several gut microbes have been identified as producing PUFA-derived intermediate metabolites ^[73]. Administration of PUFA-derived bacterial metabolites such as linoleic acid has been shown to provoke anti-obesity and anti-inflammatory effects ^[74]. However, unlike probiotics and prebiotics ^[75]^[76], currently there is a lack of a clear definition for postbiotics. Considering the complex nature of postbiotics ^[71], a clear definition is important for future from a regulatory perspective.

Moreover, there are other microbiota-related therapies applied for preventing CKD and its comorbidities. Microbe-dependent TMA and TMAO formation can be inhibited by 3,3-dimethyl-1-butanol (DMB), a structural analogue of choline ^[77]. Recently, two studies reported that maternal oral administration of DMB protected hypertension in adult rat progeny exposed to a maternal high-fructose diet ^[45] or high-fructose diet plus TCDD exposure ^[57]. This was accompanied by affecting the metabolic pathway of TMA-TMAO and reshaping gut microbiota ^[57].

As far as the multifaceted relationship between the gut and kidney, there might be other potential approaches by which the gut microbiota might prevent CKD and its associated complications. For example, RAS blockers are currently the most common therapies used for renoprotection and antihypertension ^[78]. Considering drug-mediated alterations in the gut microbiota compositions can have beneficial effects on the host ^[79], a greater understanding of mechanisms driving drug–gut microbiota interactions might aid in guiding the development of microbiota-targeted pharmacological interventions. Together, early microbiota-targeted therapies, in the long term, may enable the capacity to prevent the development of CKD and its comorbidities in a desired favorable direction. However, there is an urgent need to identify and fill the knowledge gaps on gut microbiota-targeted therapies between established CKD and CKD of developmental origins.

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You-Lin Tain

Chien-Ning Hsu

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