Targeting Gut Microbiota as a Promising Therapy for Chronic Kidney Disease

INTRODUCTION Chronic kidney disease (CKD) is a growing public health issue that affects 15%-20% of adults globally.1 Although renin-angiotensin system inhibitors improve renal function, patients still irreversibly progress to uremia, which ultimately requires replacement therapies, including dialysis and kidney transplantation.1 However, renal replacement therapies are costly and not curative. Microbial dysbiosis leads to uremic toxin accumulation and intestinal barrier impairment, thereby triggering renal inflammation and fibrosis Figure 1.2,3 However, the probiotics, such as Lactobacillus johnsonii (L. johnsonii), Bacteroides ovatus (B. ovatus), and Bacteroides fragilis (B. fragilis), inhibit inflammation and renal fibrosis by modulating metabolites.4-6Figure 1.: Crosstalk between chronic kidney disease and microbial dysbiosis. Chronic kidney disease causes microbial dysbiosis, uremic toxin accumulation, and intestinal barrier impairment, which exacerbates renal inflammation and fibrosis. Derived natural products, including traditional Chinese medicines (TCMs), such as resveratrol, neohesperidin, and polysaccharides, have shown potential in regulating gut microbiota, reducing uremic toxin accumulation, increasing short-chain fatty acid production, and improving intestinal barrier integrity Figure 2.4-7 We highlight the pathogenesis of CKD related to microbial dysbiosis and discuss the therapeutic potential of modulating gut microbiota via natural products from the perspective of CKD.Figure 2.: The molecular mechanism of microbial dysbiosis-mediated CKD and the renoprotective effect of natural products by the kidney-gut axis. CKD increases pathogenic bacteria and decreases beneficial bacteria, causing metabolite disorder. Probiotic supplementation ameliorates CKD by regulating metabolite-mediated pathways. Natural products improve CKD in a microbial-dependent manner. 1,5-AG, 1,5-anhydroglucitol; AHR, aryl hydrocarbon receptor; CYP1A1, cytochrome P450 family 1 subfamily A member 1; GLP-1, glucagon-like peptide-1; GLP-1R, glucagon-like peptide-1 receptor; GSH, glutathione; HDCA, hyodeoxycholic acid; IAA, indole-3-acetic acid; IAld, indole-3-aldehyde; IL, interleukin; IS, indoxyl sulphate; Keap1, Kelch-like ECH-associated protein 1; NF-κB, nuclear factor kappa B; NLRP3, NOD-like receptor protein 3; NOX4, nicotinamide adenine dinucleotide phosphate oxidase 4; Nrf2, nuclear factor erythroid 2-related factor 2; pCS, p-cresyl sulphate; ROS, reactive oxygen species; SCFAs, short-chain fatty acids; Smad, suppressor of mothers against decapentaplegic; SOD, superoxide dismutase; TGF-β, transforming growth factor β; TMAO, trimethylamine-N-oxide; TNF-α, tumor necrosis factor α. MICROBIAL DYSBIOSIS IN CKD Microbial dysbiosis correlates with renal function decline Accumulating evidence suggests that microbial dysbiosis plays a critical role in the pathophysiological processes involved in CKD.1,2 Microbial dysbiosis is primarily characterized by alterations in microbial diversity and richness in CKD patients.1,4 Declining kidney function results in uremic toxin accumulation, which mediates local and systemic inflammation and renal fibrosis.2,3 Multiple studies have delineated decreasing Lactobacillus abundance in feces of CKD patients.4,7,8 Membranous nephropathy (MN) is a common immune-mediated glomerular disease in adults.8 The declining renal function was correlated with reduced probiotic abundance in MN patients and rats.8 For instance, L. johnsonii abundance correlated with progressive CKD in patients.4 Lower amounts of L. johnsonii were also observed in adenine-induced CKD rats.4 Moreover, the abundances of B. ovatus and B. fragilis were decreased in CKD patients and unilateral ureteral obstruction (UUO) mice and negatively correlated with serum creatinine and urea levels in CKD patients.5,6 Conversely, a previous study showed that the amounts of pathogenic bacteria, such as Eggerthella lenta (E. lenta) and Fusobacterium nucleatum (F. nucleatum), were increased in patients with end-stage renal disease.3 These findings dictate the dysbiosis of gut microbiota in CKD Figure 2. Probiotic supplementation ameliorates CKD Accumulating evidence has shown that supplementation with Lactobacillus attenuates renal injury.4,7 Supplementation with L. johnsonii improved kidney function and renal fibrosis in adenine-induced CKD rats.4 Moreover, supplementation with B. ovatus and B. fragilis alleviated renal fibrosis in UUO- and adenine-induced mice.5,6 In contrast, supplementation with E. lenta and F. nucleatum exacerbated renal functions and fibrosis in CKD rats. However, supplementation with B. animalis reduced the abundance of E. lenta and Fusobacterium spp. and attenuated renal fibrosis and glomerulosclerosis in CKD rats.3 These findings suggest that microbial dysbiosis is involved in CKD and that probiotic supplementation ameliorates renal fibrosis. THE DYSREGULATION OF MICROBIOL-DERIVED METABOLITES IN CKD Altered microbiol-derived metabolites in CKD With the advancement of gut microbiota research, metabolomics is used to identify microbiol-derived metabolites, such as indoxyl sulfate (IS), indole-3-acetic acid and indole-3-aldehyde (IAld), which play a bridge role in gut and various host organs.4-6 Microbial metabolism shifts from carbohydrate to protein metabolism, increasing plasma protein fermentation metabolites and major uremic toxins such as IS, IAld, and indole-3-acetic acid.2 The reduction abundance of probiotics correlated with altering levels of IAld, tryptamine, indole-3-acetic acid and indole-3-lactic acid that correlated with declining renal function in the serum of MN rats and patients.8 Further study demonstrated that IAld levels were negatively correlated with creatinine levels in the serum of UUO- and 5/6 nephrectomized-induced rats and late-stage CKD patients.4 These findings elucidate the dysregulation of microbiol-derived metabolites in CKD Figure 2. Microbial-derived metabolites regulate CKD through diverse signaling pathways Mechanistic studies revealed that MN rats showed increasing intrarenal messenger ribonucleic acid expression of aryl hydrocarbon receptor (AHR) and its target genes cytochrome P450 family 1 subfamily A member 1 (CYP1A1), CYP1A2, and CYP1B1, which were accompanied by protein expression of downregulated cytoplasmic AHR but upregulated nuclear AHR in MN rats and patients.8 IAld attenuated renal injury by inhibiting the AHR pathway in CKD rats and cultured 1-hydroxypyrene-induced human kidney 2 (HK-2) cells. The renoprotective role of IAld was partially abrogated in mice and HK-2 cells with AHR deficiency.4 Similarly, L. johnsonii mitigated renal fibrosis by blocking the AHR pathway via elevating serum IAld levels.4 Moreover, B. ovatus ameliorates renal fibrosis by activating glucagon-like peptide-1 and enhancing its receptor expression via promoting Clostridium scindens-derived hyodeoxycholic acid production,5 and B. fragilis attenuated renal fibrosis by regulating the Kelch like ECH associated protein 1/nuclear factor E2-related factor 2 and transforming growth factor-β1/Smad signaling pathways via upregulating Takeda G protein-coupled receptor 5 expression by increasing 1, 5-anhydroglucitol levels.6 Collectively, these findings suggest that probiotics blunt renal fibrosis by microbial-derived metabolite-mediated signaling pathways Figure 2. TCMS AMELIORATE CKD BY RESHAPING MICROBIAL DYSBIOSIS The renoprotective effect of TCM prescriptions is related to reducing uremic toxin accumulation Ample evidence has verified that TCMs, such as Huangkui capsules, Zhenwu decoctions, and Tangshen formula, hit multiple targets with multiple components and play a critical role in CKD treatment.4-8 Previous studies have shown that TCMs reduce uremic toxin production in patients with CKD. Orally administered Tangshen formula ameliorates diabetic kidney disease by decreasing bacteria that produce IS precursors and serum levels of lipopolysaccharide and IS.7 A recent publication showed that treatment with Moshen granule restored aberrant probiotics and tryptophan-produced indole derivatives in MN rats.8 Treatment with rhubarb enema granule ameliorated tubulointerstitial fibrosis in CKD rats by alleviating circulating trimethylamine N-oxide and IS levels.7 Natural compounds retard CKD by diverse signaling pathways via microbiol-derived metabolites Natural products have been widely recognized as sources of new drugs over the past four decades. TCMs, such as paramylon, isoquercitrin, and alisol B 23-acetate, have been demonstrated to alleviate renal fibrosis by reshaping the gut microbiome.7 Emodin is used for CKD treatment and to decrease uremic toxins. Emodin via colonic irrigation restored microbiol dysbiosis and reduced the levels of urea and IS in CKD rats.7 Zheng et al. showed that piceatannol reduced the synthesis of uremic toxin precursors in Bacillus, thereby decreasing IS and p-cresyl sulphate in CKD mice.7 Miao et al. demonstrated that treatment with natural compounds such as barleriside A and 5,6,7,8,3ʹ,4ʹ-hexamethoxyflavone increased L. johnsonii abundance in CKD rats.4 Moreover, treatment with natural compounds such as polyphenol neohesperidin and pentacyclic triterpenoid madecassoside improved renal function, reduced serum creatinine and urea levels, and increased relative abundances of B. ovatus and B. fragilis in mice with renal fibrosis, indicating that these compounds counteract renal fibrosis in a microbial-dependent manner.5,6 Wang et al. revealed that flavonoid isoquercitrin suppressed the establishment of H proton potential by modulating the gut microbiota electron transport chain, thereby blocking tryptophan transportion and further decreasing indole biosynthesis in adenine-induced CKD mice.9 Natural polysaccharides improve CKD by restoring microbiol balance Accumulating evidence has also indicated that natural polysaccharides play a significant role in maintaining the intestinal barrier and modulating the dysbiosis of gut microbiota in CKD.7,10 Polysaccharides from Bupleurum, Astragalus, and Armillariella tabescens mycelia maintained the intestinal barrier by upregulating protein expression of claudin-1 and occludin in the colonic tissues of rats with diabetic kidney disease.7 Moutan Cortex polysaccharides abolished hyperglycemia and renal injury by reshaping microbial dysbiosis, restoring intestinal barrier function, inhibiting proinflammation, and increasing short-chain fatty acid levels in diabetic kidney disease rats.10 Collectively, these findings indicate that natural products blunt CKD by modulating microbiol dysbiosis microbial-derived metabolite-mediated signaling pathways Figure 2. CONCLUSION AND PERSPECTIVE In summary, the progression of CKD correlates with the dysbiosis of gut microbiota and the dysregulation of microbial-derived metabolites. The literature highlights the physiological functions of gut microbiota and pathologic consequences of microbiol dysbiosis. The presence or absence of certain microbiota species modulates intestinal immune responses and opens inspiring possibilities by regulating these responses via restoring microbial-derived metabolite-mediated signaling pathways. Several seminal publications have highlighted that supplementation with probiotics inhibit inflammation and renal fibrosis. Further studies uncovered that natural compounds improve CKD by increasing probiotics, indicating that natural products alleviate CKD and renal fibrosis in a microbial-dependent manner. Therefore, targeting gut microbiota might be an effective and promising therapeutic strategy for CKD treatment. Targeting gut microbiota using natural products is a promising therapy for CKD treatment, but it still faces a series of novel challenges. First, significantly altered bacteria species in feces and their corresponding metabolites in serum should be identified by combining metagenomic and metabolomic techniques. Increasing evidence highlights that gut microbiota alters adaptively early in CKD but later leads to uremic toxin accumulation. Second, more research needs to be done on understanding the pharmacological effects of significantly altered bacteria species and their corresponding metabolites in CKD. Third, it is critical to understand underlying microbiol dysbiosis-associated molecular mechanisms mediated by microbial-derived metabolites in CKD. The causal relevance of CKD, microbiol dysbiosis, and microbial-derived metabolites should be further clarified using new microbial technologies, such as germ-free animals, genomic sequencing, and antibiotic treatments. Advances in sequencing techniques, untargeted metabolomics, and bioinformatics have elucidated the role of gut microbiota in health and disease. Combining these techniques can help improve our understanding of the physiological roles of gut microbiota and elucidate the etiology and pathophysiology of CKD. An integrative multiomics strategy can offer a new perspective on dissecting and improving the diagnosis and prevention of CKD. Future research must explore how natural products reshape gut microbiota in CKD patients and intervention of CKD. The publishing studies offer new perspectives on the exploration of gut microbiota-related therapeutic targets in CKD.