Chronic kidney disease (CKD) has become an increasing public health problem with a wide range of complications and high risk of mortality. The worldwide prevalence of CKD (8%–16%) brings a heavy economic burden for middle- and low-income countries in particular (Zhang et al., 2012; Lv and Zhang, 2019). Due to the concealed symptom of early CKD, clinical diagnosis and therapeutic interventions for early CKD patients are lagging (Flagg, 2018); most therapeutic methods for ESRD (end-stage renal disease) patients such as lowering blood pressure, controlling blood glucose, and reducing proteinuria have poor effect in preventing kidney failure (Chen T. K. et al., 2019). As current anti-CKD therapies have limited effectiveness and/or severe adverse effects, alternative treatments like natural products have gained much more attention, especially with current studies implying that gut microbiota is an anti-CKD target.

Gut microbiota are composed of over 1,000 genera of bacteria colonized in the human intestine, which play a crucial role in many important human physiological functions, including maintenance of energy balance, modulation of intestinal homeostasis, and regulation of the immune system (Fan and Pedersen, 2021). The features and functional effect of intestinal flora have been extensively studied in the past few decades, and lots of studies have revealed that dysbiosis of gut microflora is highly associated with the onset and progression of CKD (Jiang et al., 2017; Hu J. et al., 2020; Andrianova et al., 2020; Wang X. et al., 2020; Zhong et al., 2020; Du et al., 2021a). Gut microflora influence the gut–kidney axis, namely, the crosstalk between the intestinal microflora, CKD, and changes in the intestinal environment (Evenepoel et al., 2017), in a bidirectional way; on the one hand, kidney function failure is highly related to the reduced bacterial diversity and biased community constitutions of the gut microflora (Cigarran Guldris et al., 2017; Hobby et al., 2019). Increasing sources of evidence support that altered gut microbiota composition has been reported in patients with different kidney diseases, including those with end-stage renal disease (ESRD), acute kidney injury (AKI), IgA nephropathy, CKD, and diabetic nephropathy (Jiang et al., 2017; Hu J. et al., 2020; Andrianova et al., 2020; Zhong et al., 2020; Du et al., 2021a). CKD patients had lower bacterial diversities than healthy subjects, with an increasing abundance of harmful microbes such as Proteobacteria and Actinobacteria and a decreasing level of beneficial microbes such as Lactobacillaceae (Hu J. et al., 2020; Andrianova et al., 2020; Zhong et al., 2020). Moreover, the change in gut microflora structure and function is highly associated with the severity of CKD (Hu X. et al., 2020). Specific gut microbes producing short-chain fatty acids (SCFAs) are potentially helpful for CKD early diagnosis and prognosis monitoring (Gao B. et al., 2021; Sato et al., 2021). On the other hand, various metabolic pathways including uremic toxin, SCFAs, and bile acid pathway are affected by the altered gut microflora. Experimental and clinical evidence demonstrated that altered gut microflora in CKD patients could accelerate the biosynthesis of uremic toxins, whose concentrations would consequently increase in the blood (Wang X. et al., 2020; Rysz et al., 2021). Also, these resulted in the progression of impairment in the intestinal epithelial barrier and inflammation which intensified the cardiovascular and kidney diseases (Espi et al., 2020; Opdebeeck et al., 2020), suggesting that the gut flora could serve as a novel therapeutic target for CKD and related complications.

In order to clarify the gut microbiota and anti-CKD molecular mechanisms of these natural products, we reviewed the knowledge based on publications in English- and Chinese-language journals. Table 1 summarizes the mechanisms of different natural products from plants and microorganisms, including herbal decoction, crude extracts, polysaccharides from plants and microorganisms, and phytochemicals, in CKD progression through targeting the gut microbial based on these studies, which focus on remodulation of gut microbiota structure, reduction of uremic toxins, enhancement of SCFA production, regulation of intestinal inflammatory signaling, and improvement in intestinal integrity of natural products commonly used in kidney diseases. Meanwhile, the clinical trials of different natural products in CKD clinical practice were also analyzed and discussed (Table 2).

Besides animal experiment, accumulating clinical trials have shown that natural products from plant and microorganism have an effect on the reduction of proteinuria and improvement of renal function by modifying the gut microbiota (Table 2). The first benefit of administering natural products during CKD is recovery of the dysbiosis of gut microflora. The Jian Pi Qu Shi Formula, made of Astragalus membranaceus Bge., Codonopsis pilosula, and other eight herbal medicines, was shown to regulate intestinal flora in the pilot trial of patients with idiopathic membranous nephropathy (Lang et al., 2020). A cohort study of 160 diabetic kidney patients suggested that Modified Shenqi Dihuang decoction has good curative effect on reducing proteinuria, protecting renal function, restoring the balance of intestinal flora by increasing the numbers of Bacteroides, Bifidobacteria, and Lactobacillus, but decreasing the numbers of Enterobacter, Enterococcus, and yeast (Du et al., 2021b). Zicuiyin decoction, which had better efficacy in improving and protecting kidney function in diabetic kidney disease (DKD) patients, could decline eGFR and ameliorate gut microbiota dysbiosis in a multicenter, parallel-control, open-label, randomized clinical trial (Liu et al., 2022). Fushen Granule (FSG) ameliorated BUN and Scr and improved albumin (ALB) by enriching beneficial bacteria associated with metabolism in patients with peritoneal dialysis-related peritonitis (PDRP) in a randomized controlled trial (Lin W. et al., 2021). Supplementation of amylose resistant starch HAM-RS2 (20 g/d resistant starch) led to an improvement of constipation severity and renal function, elevation in Faecalibacterium, and a decrease in serum urea, IL-6, TNF-α, and Malondialdehyde (MDA) of systemic inflammation in hemodialysis (HD) patients (Tayebi Khosroshahi et al., 2018; Laffin et al., 2019; Jia et al., 2021). Long-term synbiotic supplementation for 12 months, consisted of high-resistant starch fiber supplement HI-MAIZE 260 (20 g/d, 50% resistant starch) and the probiotic components of nine strains from Bifidobacteria, Lactobacillus, and Streptococcus genera, could reduce eGFR and increase Scr concentration by altering the gut microbiome with an enrichment of Bifidobacterium and Blautia spp. in stage 3–4 CKD patients (McFarlane et al., 2021). While short-term treatment of synbiotic (Nutrihealth®), containing a mix of probiotics and a prebiotic fiber, omega-3 fatty acids, and vitamins, could increase Bifidobacterium counts and maintain the intestinal microbial balance in Mexican patients with ESRD(Cruz-Mora et al., 2014).

The second benefit of supplementation with natural products is uremic toxin removal in the clinical application of CKD treatment. The curcumin supplementation showed a significant decrease in PCS plasma levels in HD patients (Salarolli et al., 2021) and reduced the inflammatory response by modifying the gut microbiota structure of CKD patients after 3-month administration (Pivari et al., 2022). In a clinical trial of 60 peritoneal dialysis patients, Shen-Shuai-Ning granules could decrease IS serum concentration after 12 weeks of treatment (Chen et al., 2018). Supplementation with the functional food HI-MAIZE^® 260 cookies (16 g/d resistant starch) could increase fiber intake, reduce IL-6 and IS plasma levels (Esgalhado et al., 2018), decrease different growth factors (De Paiva et al., 2020), and alter the SCFA-producing microbiota in HD patients (Kemp et al., 2021), but no indole-3-acetic acid (IAA) levels or aryl hydrocarbon receptor (AhR) expression in patients with end-stage CKD (Azevedo et al., 2020). However, the unripe banana flour (21 g/d, 48% resistant starch) only decreased IS in the subgroup of participants undergoing peritoneal dialysis (PD) (De Andrade et al., 2021). The prebiotic fructo-oligosaccharide (FOS) decreased the serum total ΔPCS and serum-free Δ%PCS, but not IS and IAA in non-diabetic- and non-dialysis-dependent CKD patients (Ramos et al., 2019). The prebiotic inulin-type fructans restricted the increase in gut-derived indole in PD patients (Li L. et al., 2020). The ß-glucan prebiotic (50% ß-glucan) significantly altered the levels of total and free p-cresyl glucuronide (pCG) and lowered the beta diversity of the gut microbiome in stage 3–5 CKD predialysis participants (Ebrahim et al., 2022). The prebiotic oligofructose-inulin significantly increased intraparticipant microbiome diversity and reduced serum PCS concentrations in HD patients (Meijers et al., 2010; Raj et al., 2021). Inulin with low-protein diet modified gut microbiota and reduced inflammatory factors (TNF-α and NOX2) and metabolic parameters (serum uric acid (SUA) and C-reactive protein (CRP)) in the plasma of CKD patients (Lai et al., 2019). A synbiotic Probinul-Neutro lowered total plasma PC concentrations in non-dialyzed CKD patients with stage 3–4 CKD (Guida et al., 2014). Two-month administration of the synbiotic NatuREN G^® resulted in the amelioration of the abdominal pain and constipation symptoms and a decrease in free IS in the stage 3b–4 CKD group (Cosola et al., 2021). The synbiotic capsules (GeriLact brand, Iran) supplementation containing a mix of probiotics and FOS as prebiotic might increase IS and parathyroid hormone levels in HD patients (Mirzaeian et al., 2020). A low-protein diet plus a new formulation of probiotics (Bifidobacterium longum and Lactobacillus reuteri) was effective in reducing IS in patients affected by advanced CKD (De Mauri et al., 2022). Synbiotic therapy, which consisted of a combination of high-molecular weight inulin, FOS, and galacto-oligosaccharides (GOSs) and the probiotic component including nine strains from the Lactobacillus, Bifidobacteria, and Streptococcus genera, decreased serum PCS of CKD patients with enrichment of Bifidobacterium and depletion of Ruminococcaceae after 6 weeks (4-week washout) in a randomized, double-blind, placebo-controlled, crossover trial (Rossi et al., 2016). However, supplementation with trans-resveratrol (Alvarenga et al., 2022) and cranberry dry extract (Teixeira et al., 2022) did not reduce the plasma levels of uremic toxins IS, PCS, and IAA produced by the intestinal microflora in patients with stage 3–4 CKD. In brief, natural products from plants and microorganisms may be a promising treatment for CKD patients in clinical practices.

The studies summarized in this review provide correlative insights into how host–gut microbiota–natural products from plant and microorganism interactions can contribute to CKD management. Advances in constantly updated sequencing technologies let investigators determine the change in microorganisms in experiments with CKD animals treated with different traditional Chinese formulas, crude extracts, natural polymers, and phytochemicals (Table 1). Abnormal changes in the gut microbiota of CKD animals make the pathogenic bacteria-producing urinary toxin accumulate in the blood and fail to be eliminated by the impaired kidney. Simultaneously, the damage to the intestinal epithelial barrier increases the permeability of the intestinal mucosa, which allows pathogenic bacteria and enterogenous endotoxins to translocate into the blood circulation and activates the immune system of the intestinal mucosa. All of these contribute to the imbalance in intestinal microecology, the inducement of systemic inflammatory response, and the impairment of kidney tissue and function. The aforementioned intestinal events are not mutually exclusive. Natural products from plants and microorganisms may act on the dysbiosis of intestinal microecology in CKD through a variety of channels; for example, a natural polysaccharide may modulate the structure of gut microflora, fortify the intestinal mucosa barrier, and reduce the inflammatory reaction in the colon tissue. Even components from the same herb may have different targets. For instance, ethanol extract from S. miltiorrhiza could increase the diversity of intestinal microflora and regulate the amount of SCFAs, which display the multi-target characteristics of natural products. Interestingly, herbal medicine plus probiotics or synbiotics appeared to strengthen their effectiveness on the dysbiosis of gut microbiota.

Previous studies on the human microbiome have identified correlative microorganisms associated with CKD patients. Transferring the CKD patients’ microbiome into germ-free mice aggravated CKD-associated phenotypes, which proved the causality between gut microflora and the pathogenesis of CKD (Wang X. et al., 2020). Gut microflora is thought to be the most potential therapeutic target for CKD treatment. Accumulating studies have demonstrated that an ancient classic herbal formula, natural polysaccharide, or bioactive compound could alter the diversity of the intestinal microbiota and the production of uremic toxins in CKD patients (Table 2). However, different kinds of natural active products from plants and microorganisms have different mechanisms and limits that need to be distinguished, though they are similar adjuvant treatments via targeting gut microbiota. Fermentable dietary fibers, such as inulin, FOS, galacto-oligosaccharides (GOSs), and resistant starch, are utilized as prebiotics that are selectively digested by host microorganisms, which could stimulate the growth of one or a limited number of beneficial bacteria and reduce the uremic toxin released in the colon. However, common side effects including mild diarrhea and gassiness were often accompanied with administration of these fibers (Sanctuary et al., 2019); Moreover, FOS and GOS were reported to have harmful effects on the glucose metabolism by reducing butyrate-producing microbes (Liu et al., 2017). Therefore, whether they have potential adverse effects and became intolerant, especially in long-term interventions, need to be further researched. The administration of probiotic supplementation only failed to reduce uremic toxins and inflammatory markers in CKD patients (Borges et al., 2018), and the combination of probiotics with healthy components like prebiotics and bioactive compounds, called synbiotics, could benefit the gut ecosystem and host life. Many cohort studies of synbiotics listed in the review are short-term RCTs with small-scale participants, and we are unable to rule out the bioactive components or a specific bacterium that mainly contribute to the efficacy, not to mention the best dosage and proportion of prebiotics, route of administration, and duration of intervention. The variation of a single element in the study may result in different outcomes.

Herbal medicine has been one of the most widely used alternative methods for the prevention and treatment of CKD in China and other Asian countries for hundreds of years. Our review demonstrated that different proportions of traditional herbal formulas or different herbal ingredients have different focuses on the intestinal dysbacteriosis and abnormal immune system of CKD, which presented the great advantage of herbal medicine in CKD treatment. The synergistic effects of multiple ingredients of herbal medicine on the gut microbiota of patients with CKD are reflected in two aspects: on the one hand, the bioactive ingredients have multi-target characteristics. The discrepancy in the regulatory objectives of gut microbiota makes them supplement each other. Taking Astragali Radix as an example, where Astragalus polysaccharide and astragaloside IV are the most important bioactive ingredients purified from Astragali Radix, both of which have to be biotransformed by gut microbiota to get better potency (Wang and Chen, 2017; Hong et al., 2021). Astragalus polysaccharide can modify the gut flora structure and fortify the intestinal mucosa barrier of the colon tissue, while astragaloside IV can protect against kidney injury by alleviating oxidative stress, attenuating mitochondrial dysfunction, and reducing inflammatory reactions in the kidney tissue (Zhang et al., 2020). On the other hand, the different proportions or bioactive ingredients cooperate with each other to improve the therapeutic effects by regulating the structure and metabolites of gut microbiota. Moreover, the synergistic effect can also reduce the possible toxic and side effects during the treatment process. Taking RR and CF as examples, they have been used together to treat CKD for thousands of years. The relative abundance of probiotic genera Ruminococcaceae and Lachnospiraceae was decreased in CKD rats, which could not be significantly recovered by the treatment of RR or CF, respectively, but they are notably increased in the RR + CF treatment groups (Zhang et al., 2021d). However, there are still some problems that need to be solved. First of all, even though many bioactive components from herbal medicine were identified through modern technology including standardized phytochemistry, pharmacology, pharmacokinetics, pharmacodynamics, and toxicology research procedures (Lin T. L. et al., 2021), the bottleneck barrier of herbal medicine development i.e., investigating how the complex ingredients in herbal medicines work together in a synergistic pattern is still not fully elucidated. Second, herbal medicine can avoid the adverse therapeutic effect caused by Western medicine treatment in the clinical practices of CKD treatment (Zhao et al., 2021), but most studies of these herbal medicines are focused on animal experiments. There are few clinical trials about herbal medicine plus first-line Western medicine for CKD treatment except for the multicenter clinical trial of Abelmoschus manihot and irbesartan (Zhao et al., 2022). High-quality interventional trials of well-studied, high-quality RCTs investigating herbal medicine treatment in CKD are still lacking. Third, though a variety of active substances identified from the herbal medicines, such as alkaloids, polysaccharides, glycosides, lipids, and vitamins, provide material basics for the multi-level and multi-target characteristic of herbal medicine, side effects and safety validations of herbal medicine on CKD patients need further large size and long duration clinical trials.

Another important aspect that has to be considered is that the ingredients of natural products may be metabolized by gut microflora and affect their structures and efficacy. Accumulating evidence showed that the bioactive compounds from herbal medicines like Astragali Radix and S. miltiorrhiza were effective in ameliorating kidney injury via gut microbiota biotransformation (Wang and Chen, 2017; Cai et al., 2019). It was reported that APS could be fermented by intestinal microorganisms Desulfovibrio vulgaris to produce acetic acids (Hong et al., 2021). Astragaloside IV (ASIV) is the most abundant saponin purified from Astragali Radix. It is gradually deglycosylated by human intestinal flora and transformed into cycloastragenol (Wang and Chen, 2017), which is the effective form with better permeability and absorptivity to improve the bioavailability in vivo (Zhai et al., 2016). Tanshinones and salvianolic acid from S. miltiorrhiza would exert effect after being metabolized through methylation, demethylation, dehydrogenation, hydrogenation, and hydroxylation by intestinal bacteria (Cai et al., 2019).

Identifying gut microbiota as the alternative target of natural products from plants and microorganisms in the treatment of CKD still face more challenges. These associative studies should spur further causal investigations by using modern microbial technology, such as genomic sequencing, germ-free (GF) animals, and antibiotic treatments. Additionally, to understand how natural products from plants and microorganisms affect the gut microbiota in CKD patients and to develop new alternative therapies for CKD treatment, the strain- and molecular-level connections between the gut microbiome, natural products from plants and microorganisms, and host CKD phenotype should be established in future research based on the hypotheses developed from these correlative studies (Chaudhari et al., 2021). The systematic research on functional compounds from natural products metabolized by gut microbiota might seek out a new approach to uncover these problems. Identification and functional testing of gut microbiota metabolites related to natural product components would deepen the understanding of how the natural products modulate CKD patients’ physiology via targeting gut microbiota by using cutting-edge omics platforms including next-generation sequencing (NGS), proteomics, metabolomics, and cultureomics. These strategies have pushed the development of novel disease-related probiotics, prebiotics, and functional proteins for the treatment of CKD by targeting the dysbiosis of the gut microbiota in recent years (Lobel et al., 2020; Zhu et al., 2021). The synergistic effect of multiple methods such as herbal medicine and these disease-related probiotics or prebiotics would provide a novel therapeutic method for CKD patients.

In summary, the literature analyzed in this review suggests a great advantage in the adoption of natural products from plants and microorganisms to treat CKD via targeting gut microbiota. These natural products from plants and microorganisms have an impact on the biogenesis and progression of CKD and its relative metabolic complications through alteration of the diversity and composition of the gut microbiota. More research should be carried out to prove the causal role of intestinal microflora in the treatment of CKD by natural products from plants and microorganisms based on these associative studies.