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. 2022 Oct 31;5:2135–2145. doi: 10.1016/j.crfs.2022.10.028

Effects of polysaccharides-riched Prunus mume fruit juice concentrate on uric acid excretion and gut microbiota in mice with adenine-induced chronic kidney disease

Yan Huang 1,1, Chen-Xi Wu 1,1, Lu Guo 1,1, Xiao-Xi Zhang 1, Dao-Zong Xia 1,∗
PMCID: PMC9649360  PMID: 36387593

Abstract

The present study aimed to determine the effects of polysaccharides-riched Prunus mume fruit juice concentrate (PFC) on uric acid (UA) excretion and the gut microbiota in mice with chronic kidney disease (CKD). C57BL/6 mice were randomly allocated to four groups: two that were fed AIN93M diet, one of which was administered 500 mg/kg PFC, and two that were fed AIN93M diet containing 0.2% adenine, one of which was administered 500 mg/kg PFC. PFC promoted UA excretion, which may have been mediated through increases in the protein expression of ATP-binding cassette transporter G2 (ABCG2), organic anion transporter 1 (OAT1), organic carnitine transporter 2 (OCTN2), and reductions in the protein expression of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) in kidneys of CKD mice. ABCG2 expression in the intestine was also increased by PFC administration. Additionally, PFC significantly increased large intestinal short-chain fatty acids (SCFAs) concentrations, and the number of gut microbial species, and reduced the abundance of the genera Bacteroides, Pseudoflavonifractor, Helicobacter, Clostridium_IV and Allobaculum, which have a negative effect on UA excretion. In conclusion, PFC may promote UA excretion in CKD mice by altering the expression of urate transporters and regulating the gut microbiota.

Keywords: Prunus mume, Urate transporters, Gut microbiota, Short-chain fatty acids, Chronic kidney disease

Abbreviations: ABCG2, ATP-binding cassette transporter G2; BUN, blood urea nitrogen; CKD, chronic kidney disease; GAE, gallic acid equivalent; GLUT9, glucose transporter 9; HPIC, high-performance ion chromatography; HPLC, high-performance liquid chromatography; Lefse, linear discriminant analysis effect size; OAT1, organic anion tranporter 1; OCTN2, organic carnitine transporter 2; OTU, operational taxonomic unit; PCoA, principal components analysis; PFC, Prunus mume fruit juice concentrate; PVDF, polyvinylidene fluoride; SCFAs, short-chain fatty acids; UA, uric acid; URAT1, urate transporter 1

Graphical abstract

Image 1

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Highlights

  • •

    PFC promotes uric acid (UA) excretion in adenine-induced chronic kidney disease mice.

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    The UA-lowering mechanisms of PFC rely on ameliorating the expression of urate transporters.

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    PFC increased the large intestinal concentrations of short-chain fatty acids.

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    PFC reduced the gut microbial genera which has a negative effect on UA excretion.

1. Introduction

Uric acid (UA) is the final product of the xanthine dehydrogenase metabolism of purine nucleosides in humans (Yun et al., 2017). The kidney and intestinal tract regulate UA and excessive production or poor excretion of UA results in high serum UA concentration (Abou-Elela, 2017; Singh, 2019; Zhao et al., 2012). Therefore, high UA concentration is common in chronic kidney disease (CKD). Previous studies have demonstrated that high UA concentration and high adenine diet are risk factors for CKD (Nashar and Fried, 2012; Zhu et al., 2014) and that UA-lowering therapy reduces the relative risk of CKD by 55% (Su et al., 2017).

Serum UA concentration is principally controlled by renal and intestinal excretion, which are mediated through urate transporters (Hosomi et al., 2012; Ichida et al., 2012). Approximately 60%–70% of UA is excreted by renal urate transporters, including ATP-binding cassette transporter G2 (ABCG2), organic anion transporter 1 (OAT1), organic carnitine transporter 2 (OCTN2), glucose transporter 9 (GLUT9), and urate transporter 1 (URAT1) (Bhatnagar et al., 2016; Huo and Liu, 2018; Zhang et al., 2018). The remaining 30%–40% of UA is believed to be excreted into the intestinal cavity, principally via ABCG2 (Hosomi et al., 2012). Indeed, the expression level of ABCG2 is higher in the intestine than in the kidney (Kumagai et al., 2017). Taken together, the quoted studies have shown that renal and intestinal urate transporters are crucial for UA excretion.

Diet plays a significant role in the development of CKD. Epidemiological studies have shown that adenine-rich diet increases the risk of CKD (Hou et al., 2020; Metzger et al., 2020; Yang et al., 2018), and it has been shown to have substantial effects on the gut microbiota, thus affecting host metabolism. In recent years, gut microbial dysbiosis has been identified as a major novel risk factor for complications of CKD (Chen. Et al., 2022; Mishima et al., 2017; Ruiz-Andres et al., 2016). Studies have demonstrated that the abundance of particular bacterial taxa, such as Bacteroides and Lactobacillus, could affect the intestinal concentrations of metabolites, such as short-chain fatty acids (SCFAs) and toxins, which may predispose toward CKD (Castillo-Rodriguez et al., 2018). Additionally, the expression of urate transporters is affected by changes in the concentrations of metabolites that result from the effects of feeding adenine diet on the gut microbiota of CKD mice (Mishima et al., 2017). Therefore, the gut microbiota may be involved in the mechanisms whereby particular agents ameliorate CKD.

In recent years, polysaccharides showed promising candidates for the treatment of hyperuricemia. Water-soluble polysaccharide obtained from Lonicera japonica could significantly reduce the serum UA level in hyperuricemia mice (Yang et al., 2019). Exopolysaccharide produced by Cordyceps militaris showed obvious UA-lowering capacity at a dose of 400 mg/kg against potassium oxonate-induced hyperuricemia (Ma et al., 2014). Furthermore, dietary polysaccharides could regulate gut microbiota in diabetic mice and cyclophosphamide-treated mice (Ding et al., 2019; Wang et al., 2020).

Prunus mume, a natural plant, has been widely cultivated in Japan (named ume), southeastern China (méi), and South Korea (maesil) due to its high ornamental value (colorful corollas, pleasant fragrance, weeping trait) and the culinary, nutritional and medicinal potential of its fruits. Extracts of the fruit of Prunus mume also have been used for a long time in many culinary and medicinal preparations (Bailly, 2020). Previous studies have shown that a methanolic extract of Prunus mume fruit can reduce serum UA concentration in hyperuricemia mice (Yi et al., 2012), an ethanol extract of Prunus mume fruit can stimulate glucose uptake by regulating PPAR-c in C2C12 myotubes and ameliorate glucose intolerance and fat accumulation in mice fed a high-fat diet (Shin et al., 2013), and a concentrated water extract of Prunus mume fruit can suppress adipogenesis in 3T3-L1 adipocytes (Bu et al., 2021). Studies also have reported that Prunus mume leaf extract can reduce blood glucose levels in diabetic mice (Lee et al., 2016), and Prunus mume seed extract can protect against potassium oxonate-induced hyperuricemia (Xia et al., 2013a). Polysaccharides-riched Prunus mume fruit juice concentrate (PFC) is a traditional Japanese product that can improve the circulation (Utsunomiya et al., 2002) and immunity (Lee et al., 2017), and reduce fatigue (Sriwilaijaroen et al., 2011). It was made from fresh fruit that has been boiled for a long time and then repeatedly concentrated. The content of polysaccharides in PFC is about 75.30%. Previous study has reported the number-average and weight-average molecular weights of the polysaccharides were 1.60 kDa and 1.68 kDa and the main monosaccharides were galactose (41.49%), glucose (36.45%), arabinose (9.14%), mannose (4.92%), ribose (4.34%), and xylose (3.23%) (Xiang et al., 2020).

However, the effects of PFC on UA excretion and the gut microbiota have not been investigated to date in a model of CKD. Therefore, we aimed to determine the effects of PFC on adenine diet-induced CKD in mice. To this end, we measured UA excretion, urate transporter expression, and large intestinal short-chain fatty acids concentrations, and determined the effect of PFC on the gut microbiota by 16S rDNA sequencing. The results of this study may provide guidance for the development and use of functional foods containing PFC.

2. Materials and methods

2.1. Chemicals and reagents

PFC (Lot: 20161215) was obtained from Sunactis (Toyama Prefecture, Japan). Acetic acid (>99%, Lot: C0524323), propionic acid (>99%, Lot: C10322064), butyric acid (>99%, Lot: C10201252), isobutyric acid (>99%, Lot: C10201253), and adenine standards (Lot: P03814) were from Sigma-Aldrich (St. Louis, MO, USA). D-(+)-Glucose (Lot: S13J11H107301), Gallic acid (Lot: Y19M8C36143) and rutin (Lot: Y16M9S61523) were from Shanghai yuanye Bio-Technology Co., Ltd. (Shanghai, China). L-Ascorbic acid (Lot: C11491748) was from Macklin (Shanghai, China). Blood urea nitrogen (BUN, Lot: C011) and creatinine (Lot: C013-2-1) texting kits were from Nanjing Jiancheng Bioengineering Institute (Nanjing, China). RIPA lysis buffer (Lot: 10203), protease inhibitor cocktail (Lot: 20215), Bicinchoninic Acid (BCA) Protein Assay Kit and SDS-PAGE loading buffer (Lot: 01411) were from CoWin Biosciences (Beijing, China). Primary antibodies against OAT1 (Lot: GR320240-5), OCTN2 (Lot: GR295095-11) were from Abcam (Cambridge, UK), ABCG2 (Lot: 42078S) was from Cell Signaling Technology (Boston, MA, USA), URAT1 (Lot: 14937-1-AP), GLUT9 (Lot: 67530-1-IG) were from Proteintech Group (Chicago, IL, USA). goat anti-mouse IgG HRP (Lot: 6229), goat anti-rabbit IgG HRP (Lot: 8715) were from Signalway Antibody (College Park, Maryland, USA). Taq DNA Polymerase kit was from Transgenic (Beijing, China). MiSeq Reagent Kit v3 was from Illumina (San Diego, USA). Agencourt AMPure XP PCR purification beads was from Beckman Coulter (USA). All other chemicals and reagents were of analytical grade.

2.2. Nutritional characteristic of the mice diet

The control diet (AIN93M) and adenine diet (AIN93MA, which was AIN93M containing 0.2% w/w adenine) were purchased from Shuyishuer Biotechnology Co., Ltd. (Changzhou, Jiangsu, China), and they also provided the carbohydrates, protein, lipids and total ash contents of the mice diet.

2.3. Nutritional and chemical characteristics of PFC

Carbohydrate content was determined by spectrophotometry (Van Wychen and Laurens, 2020). After samples were completely hydrolyzed with 10% hydrochloric acid, it was neutralized with sodium hydroxide. The samples were decolorized with macroporous resin and finally added DNS for color development. The absorbance was measured at 520 nm wavelength, and the carbohydrate content was calculated with glucose as the standard.

Total polysaccharide content was determined by the phenol-sulfuric acid method (Yue et al., 2015). 2 g PFC was dissolved into 80 mL water, 460 mL of 95% ethanol (final ethanol concentration was 80%) was added to precipitate for 12 h, and centrifuged the mixture at 3500 rpm for 20 min at room temperature to obtain the precipitate. The crude polysaccharides were deproteinized by trichloroacetic acid method. Then, the sample was dissolved in distilled water and diluted to 50 mL. Glucose was used as the reference standard for polysaccharide determination.

The reducing sugar was determined by titration approach (copper basic tartrate solution). The protein was obtained using the Kjeldahl nitrogen determination method. The fat was measured gravimetrically after evaporation of the extraction solvent using the Röse-Gottlieb extraction method. The ash was determined by gravimetric difference after ashing following the AOAC method 945.46. The moisture was calculated by gravimetric difference after heating at 105 °C and drying in the dryer (Rombaut et al., 2007).

A series of ascorbic acid standards were used for the determination of vitamin C by high-performance liquid chromatography (HPLC) method (Ma et al., 2020).

Total phenolics and total flavonoids were measured by spectrophotometry, whose contents were expressed as gallic acid equivalents (GAE) (mg/g) and rutin equivalents (mg/g) respectively (Xia et al., 2011b).

The organic acid composition of PFC was analyzed using a Dionex Integration high-performance ion chromatography (HPIC) method (ThermoFisher Scientific, NY, USA) and a gradient system (Supplementary Table 1).

2.4. Animals and experimental design

Male specific pathogen-free C57BL/6 mice were purchased from Shanghai SLAC Laboratory Animals Co., Ltd. and housed at Zhejiang Chinese Medical University Laboratory Animal Research Center (Permit Number: SYXK, 2018-0012). All experimental procedures followed the Guide for the Care and Use of Laboratory Animals (National Institutes of Health (NIH), Bethesda, MD, United States) and approved by Animal Ethical and Welfare Committee of Zhejiang Chinese Medical University (Ethical Approval Number: 20200813-01). Forty mice (7 weeks old, 22.0 ± 2.0 g) were randomly allocated to four groups (n = 10 each): a CNR group (fed AIN93M diet and administered saline), a CNR-P group (fed AIN93M diet and administered PFC 500 mg/kg), a CKD group (fed AIN93MA diet and administered saline), and a CKD-P group (fed AIN93MA diet and administered PFC 500 mg/kg). The dosage of PFC for adults is 2–6 g, equivalently for mice, this dosage is 5.2–15.6 mg for 20 g mice calculated by body surface area method (human dose × conversion factor for 20 g mice). Thus, we used dosage of PFC at 500 mg/kg in this study. Mice in CNR and CNR-P groups were fed the AIN93M diet. PFC or saline was administered by gavage for 4 weeks, and weighed once a week during the period. Urine samples were collected using metabolism cages on the last day of the study. At the end of the study, mice were anesthetized using thiopental and then enucleated for blood collection. The blood samples were incubated at 37 °C for 1 h and then centrifuged at 2500 rpm for 15 min to separate the serum. The kidney tissues, duodenum, ileum, cecum, and colon tissues and content were collected and stored at −80 °C for further analysis.

2.5. Histopathological examination

Kidney tissues were fixed using 4% paraformaldehyde at room temperature for 24 h and embedded in paraffin. Subsequently the tissue sections were cut into 4 μm sections and stained with hematoxylin and eosin (H&E) for histopathological examination according to the standard protocol.

2.6. Biochemical measurements

BUN and serum creatinine concentrations were measured according to manufacturer instructions. The contents of each component of the intestine (duodenum, ileum, cecum, and colon) were homogenized in PBS and centrifuged at 13,000 rpm for 10 min at 4 °C to separate the supernatants. The UA concentrations of the supernatants, serum, and urine were measured using UV spectrophotometry at 700 nm in 96-well plates on a Synergy H1 Multi-mode Microplate Reader (BioTek, VT, USA) (Jiang et al., 2021; Niu et al., 2012).

2.7. Expression of urate transporters

Kidney tissues were homogenized in RIPA lysis buffer and the protein concentrations of the lysates were determined using a BCA assay kit Proteins were denatured by heating in a metal bath for 10 min. Samples containing 30 μg of total proteins were separated by 8% SDS-PAGE gel and transferred to polyvinylidene fluoride (PVDF) membranes. The membranes were incubated in 5% (w/v) skim milk in tris-buffered saline containing 1% Tween-20 for 1 h at room temperature, then anti-ABCG2, OCTN2, OAT1, URAT1 and GLUT9 antibodies were added overnight at 4 °C. After washing, goat anti-mouse/rabbit IgG was added at 1:10,000 or 1:5000 dilutions and incubated for 2 h. The membranes were scanned using an enhanced chemiluminescence system (Monad, Shanghai, China).

The duodenum, ileum, cecum, and colon tissues were similarly homogenized, and the lysates were separated by 8% SDS-PAGE gel. Total proteins were electrotransferred to PVDF membranes, which were incubated with a rabbit anti-ABCG2 antibody at 4 °C overnight. After washing, goat anti-rabbit IgG was added at 1:5000 dilutions and incubated for 2 h. The membranes were scanned as above.

2.8. SCFAs analysis

One-hundred-milligram aliquots of cecal and colonic contents were suspended in 1.2 mL PBS, homogenized for 2 min, then centrifuged at 13,000 rpm for 10 min. One milliliter of each supernatant was mixed with 2 mL of anhydrous ethanol and another 1 mL was mixed with 1 mL n-hexane, then 100 μL H2SO4 was added. The two mixtures were respectively incubated at room temperature and in a 60°C-water bath for 1 h. The contents were analyzed using gas chromatography (Shimadzu, Kyoto, Japan). The chromatographic conditions were: DB-5 chromatographic column, flame ionization detector, N2 carrier gas at a flow rate of 1 mL/min, split ratio 30:1, starting temperature 30 °C for 10 min, which was raised to 150 °C at a rate of 15 °C/min, sample injector temperature 200 °C, detector temperature 220 °C, and 1 μL sample quantity.

2.9. 16S rDNA extraction from the microbiota and analysis

The genomic DNA from the cecal contents was amplified using a Taq DNA Polymerase kit according to the manufacturer's guidelines. The quality and quantity of genomic DNA were assessed by NanoDrop 2000) (Thermo, Waltham, USA). The 16S V3–V4 region of each sample was amplified using a MiSeq Reagent Kit v3, and purified using Agencourt AMPure XP PCR purification beads. The amplification primers were 5′-CCTACGGGNGGCWGCAG-3′ (forward) and 5′-GACTACHVGGGTATCTAATCC-3′ (reverse), and the quality of the products was assessed using an Agilent 2100 bioanalyzer (Agilent Technologies, CA, USA). The library was sequenced using a two-terminal sequencing strategy on the Miseq platform.

To improve the accuracy of the data, quality control was performed using TrimGalore, Mothur, and Usearch software. Sequences with ≥97% similarity were assigned to the same operational taxonomic units (OTUs). The OTUs were identified using Mothur software and the RDP database (http://rdp.cme.msu.edu/index.jsp). Community bar-plot, alpha and beta diversity analyses, heat mapping, principal components analysis (PCoA), and species identification were performed using the Mothur and R software packages (http://www.R-project.org), and linear discriminant analysis effect size (Lefse) was performed using Lefse (https://galaxyproject.org).

2.10. Statistical analysis

Data analysis were using two-way analysis of variance in SPSS 19.0 software (IBM, Inc., Armonk, NY, USA). When the F ratios were significant, post-hoc comparisons were made using the LSD post-hoc test. Data are expressed as mean ± SEM and P < 0.05 was considered to represent statistical significance.

3. Results

3.1. Nutritional and chemical characteristics of PFC and mice diet

The nutritional content of the PFC and mice diet are shown in Table 1. In the preparation of PFC product, after boiling for up to 6 h, most of the antioxidant compounds in Prunus mume (phenolics, flavonoids, vitamin C, etc) have been decomposed or destroyed. Therefore, PFC is riched in polysaccharides (75.30%, w/w) and organic acids (7.14%, w/w). The main organic acid is citric acid (6.28%, w/w). The moisture of PFC is 10.61% by weight.

Table 1.

Nutritional and chemical characteristics of PFC and mice diet (%, w/w).

Nutrient amount PFC AIN-93M AIN-93MA
Carbohydrates (%) 78.21 73.12 73.12
Reducing sugar (%) 2.75
Polysaccharides (%) 75.30
Protein (%) 2.31 14.20 14.20
Fat (%) 0.18 4.03 4.03
Ash (%) 1.42 3.51 3.51
Adenine (%) 0.20
Citric acid (%) 6.28
Succinic acid (%) 0.37
Tartaric acid (%) 0.29
Malic acid (%) 0.17
Oxalic acid (%) 0.02
Vitamin C (%) 0.01
Total phenolics (%) 0.07
Total flavonoids (%) 0.05
Moisture (%) 10.61
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3.2. Effects of PFC on body weight

Throughout the experimental period, mice in all groups showed normal behavior and activity levels. At the beginning of the study, there were no significant differences in the body weight of mice in different groups (P > 0.05; Table 2). At the end of study, mice in CKD group had significantly lower body weight than those in CNR group (P < 0.05), but there was no significant difference in the body weight of mice in CKD-P and CKD groups. Body weight was not affected by PFC administration in either diet group.

Table 2.

Effects of PFC on body weight of mice with adenine-induced CKD.

0 Week 1 Week 2 Week 3 Week 4 Week
CNR 22.20 ± 0.28a 22.71 ± 0.22a 23.22 ± 0.34a 23.99 ± 0.46a 24.30 ± 0.40a
CNR-P 22.49 ± 0.39a 23.24 ± 0.51a 23.43 ± 0.43a 24.06 ± 0.36a 24.54 ± 0.29a
CKD 22.46 ± 0.33a 18.48 ± 0.44b 17.38 ± 0.40b 16.93 ± 0.44b 16.86 ± 0.42b
CKD-P 22.19 ± 0.33a 18.61 ± 0.50b 18.00 ± 0.35b 17.68 ± 0.34b 17.37 ± 0.28b
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Means in a column without a common superscript letter differ, P < 0.05. Data are mean ± SEM (n = 9–10). CNR: AIN93M diet + saline; CNR-P: AIN93M diet + PFC 500 mg/kg; CKD: AIN93M diet containing 0.2% adenine + saline; CKD-P group: AIN93M diet containing 0.2% adenine + PFC 500 mg/kg.

3.3. Effects of PFC on histopathological examination

H&E-staining showed that kidney tissue morphology was normal in CNR and CNR-P mice, while CKD mice exhibited several characterized histologic alterations, including inconspicuous boundary between adjacent proximal tubule cells, glomerular atrophy and tubular swelling. However, the above effects of CKD-P mice were improved (Fig. 1).

Fig. 1.

Fig. 1

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Representative H&E-staining showing in mice kidneys.

3.4. Effects of PFC on biochemical indicators

BUN and serum creatinine concentrations were significantly higher in CKD group than CNR group, but significantly lower in CKD-P group than CKD group (Fig. 3). As shown in Fig. 2, after induction with adenine diet, the serum UA concentration was significantly increased, while the UA concentrations of 24 h urine, duodenum, ileum, cecum, and colon contents were markedly reduced (P < 0.05), which shows that the excretion of UA was lower in CKD mice. However, PFC significantly reduced serum UA concentration in mice with CKD (P < 0.05) and markedly up-regulated UA concentrations in the duodenum, ileum, and cecum contents in CKD group (P < 0.05).

Fig. 3.

Fig. 3

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Effects of PFC on serum creatinine (A) and BUN (B) with adenine-induced CKD. Different letters mean significant difference (P < 0.05). Data are mean ± SEM (n = 9–10).

Fig. 2.

Fig. 2

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Effects of PFC on UA levels of serum (A), urine (B), duodenum (C), ileum (D), cecum (E), and colon contents (F) in mice with adenine-induced CKD. Different letters mean a significant difference (P < 0.05). Data are mean ± SEM (n = 9–10).

3.5. Effects of PFC on the expression of urate transporters in the kidney and intestine

As shown in Fig. 4, there was no difference in the protein expression of urate transporters between the CNR and CNR-P groups. However, PFC reduced the protein expression of URTA1 and GLUT9, while increased the protein expression of ABCG2, OCTN2 and OAT1 in CKD-P group compared to CKD group (P < 0.05), which implies facilitation of UA excretion. The adenine diet significantly reduced the expression of ABCG2 protein in the duodenum, ileum, cecum, and colon of mice (Fig. 5), but PFC markedly ameliorated this change in the ileum, cecum, and colon, which is consistent with greater UA excretion. These findings were similar to those in the kidney (Fig. 5B–D), but there was no significant effect of PFC on the protein expression of ABCG2 in the duodenum (Fig. 5A).

Fig. 4.

Fig. 4

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Effects of PFC on renal urate transporters protein expression in mice with adenine-induced CKD. Different letters mean a significant difference (P < 0.05). Data are mean ± SEM (n = 3).

Fig. 5.

Fig. 5

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Effects of PFC on intestinal transporter ABCG2 expression in mice with adenine-induced CKD. Different letters mean a significant difference (P < 0.05). Data are mean ± SEM (n = 3).

3.6. Effects of PFC on SCFAs concentrations in the cecal and colonic contents

SCFAs are products of the microbial fermentation of carbohydrates in the gut and are important for intestinal health. The concentrations of the major SCFAs (acetic acid, propionic acid, and butyric acid) in the cecal and colonic contents of mice in the various groups are shown in Fig. 6. The concentrations of acetic acid, propionic acid, n-butyric acid, and i-butyric acid (Fig. 6A–D) in the cecum of mice in CKD group were significantly lower than those in CNR group (P < 0.05). Additionally, the concentration of propionic acid in the colon of mice in CKD group was significantly lower than that in the CNR group (P < 0.05). However, PFC significantly increased the SCFAs concentrations in the cecal and colonic contents. In particular, the concentrations of acetic acid, propionic acid, and butyric acid were significantly higher in the cecal contents of CKD-P group than in those of CKD group (P < 0.05).

Fig. 6.

Fig. 6

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Effects of PFC on intestinal SCFAs contents in mice with adenine-induced CKD. Different letters mean significant difference (P < 0.05), capital letters mean cecum and lowercase letters mean colon. Data are mean ± SEM (n = 3).

3.7. Effects of PFC on the microbial structure of the cecal contents

To explore the richness and diversity of the cecal microbiota, alpha diversity analyzed by Chao 1, ACE, Shannon, and Simpson indices were calculated. As shown in Table 3, the richness (Chao 1 and ACE indices) of the microbiota in the CNR-P group was higher than that of the CNR group (P < 0.05) and CKD-P group was also much higher than that of CKD group (P < 0.05). Additionally, PFC administration increased the level of diversity (Shannon and Simpson indices) in the control diet-fed mice, but there was no difference in diversity between CKD-P and CKD groups. PCoA was used to characterize the overall structure of the microbial community in each group. Beta-diversity analysis, based on Bray-Curtis distances in PCoA score plots, showed that the intestinal microbiota in CNR, CNR-P, CKD, and CKD-P groups were highly distinct. There were four clusters that corresponded to the four groups, but the distribution in CKD-P group was more similar to those of the CNR and CNR-P groups than that of CKD group (Fig. 7). A total of 326 bacterial species were found across all groups, but the numbers of microbial species in the cecal contents of CNR-P and CKD-P groups were significantly higher than in CNR and CKD groups, respectively (Fig. 8).

Table 3.

Richness and α-diversity of cecal microbiota from mice of each group.

Chao 1 ACE Shannon Simpson
CNR 283.37 ± 7.73c 278.46 ± 7.14c 3.62 ± 0.06c 0.07 ± 0.01a
CNR-P 331.81 ± 9.54a 321.90 ± 9.50a 4.05 ± 0.04a 0.05 ± 0.01b
CKD 280.66 ± 5.43c 270.36 ± 5.17c 3.84 ± 0.04b 0.04 ± 0.00b
CKD-P 303.37 ± 3.37b 294.73 ± 3.89b 3.81 ± 0.07b 0.05 ± 0.01b
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Means in a column without a common superscript letter differ, P < 0.05. Data are mean ± SEM (n = 9–10). CNR: AIN93M diet + saline; CNR-P: AIN93M diet + PFC 500 mg/kg; CKD: AIN93M diet containing 0.2% adenine + saline; CKD-P group: AIN93M diet containing 0.2% adenine + PFC 500 mg/kg.

Fig. 7.

Fig. 7

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Effects of PFC on the cecal microbiota structure PCoA score in mice with adenine-induced CKD. The red represents CKD group, purple represents CNR group, blue represents CNR-P group, yellow represents CKD-P group. Data are mean ± SEM (n = 9–10). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 8.

Fig. 8

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Venn diagram illustrating the overlap of OTUs for cecal microbiota in mice with different treatments. The red represents CNR group, yellow represents CNR-P group, purple represents CKD group, blue represents CKD-P group. Data are mean ± SEM (n = 9–10). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

At the phylum level, adenine diet-feeding reduced the sizes of the Proteobacteria and Firmicutes populations and increased the abundance of Bacteroidetes in mice (Fig. 9A). The abundance of the Proteobacteria was lower in CNR-P group, but not in CKD-P group. Additionally, the abundances of the genera Bacteroides, Helicobacter, Lactobacillus, Parabacteroides, Allobaculum, and Romboutsi were higher in CKD group than in CNR group, but PFC administration significantly reduced the abundance of Bacteroides, Pseudoflavonifractor, Helicobacter, Clostridium_IV, Lactobacillus, and Allobaculum, but not of Parabacteroides (Fig. 9B). However, the genus Lactobacillus, which includes the probiotic species Lactobacillus_johnsonii_FI9785 and Lactobacillus_animalis, was significantly more abundant in CKD-P group (Fig. 9C).

Fig. 9.

Fig. 9

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Relative abundance of cecal microbiota at phylum (A), genus (B) and species (C) level in mice with different treatments. Data are mean ± SEM (n = 9–10).

A heatmap of the cecal microbial genera is shown in Fig. 10, which demonstrates patterns consistent with the above expression data. LEfSe was performed to identify the microbial taxa that were differentially represented among the groups. Each layer node represents a phylum, class, order, family, genus, and species from inside to out, and the differences induced by PFC are shown in Fig. 11. At the phylum level, the gut microbiota of mice in CKD-P group showed a higher abundance of Bacteroidetes than the other groups. At the class level, PFC reduced the relative abundance of the Epsilonproteobacteria and increased the relative abundance of the Porphyromonadaceae. At the family level, the abundances of the Helicobacteraceae, Clostridiaceae_1, Catabacteriaceae, Bacteroidaceae, Rikenellaceae, Ruminococcaceae, and Lactobacillaceae were reduced, whereas those of the Erysipelotrichaceae, Prevotellaceae, and Porphyromonadaceae were increased by PFC.

Fig. 10.

Fig. 10

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Heatmap analysis of cecal microbiota at the genus level in mice with different treatments. 1 means CNR group, 2 means CNR-P group, 3 means CKD group, 4 means CKD-P group. Data are mean ± SEM (n = 9–10).

Fig. 11.

Fig. 11

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LEfSe comparison of cecal microbiota among mice with different treatments. Data are mean ± SEM (n = 9–10).

In summary, PFC administration increased the richness, diversity, and number of microbial species in the cecum, thereby reducing the gut microbial dysbiosis induced by adenine diet-feeding.

4. Discussion

CKD is characterized by a slow and progressive decline in renal function. UA is believed to play a role in the development of CKD (Su et al., 2017). UA undergoes glomerular filtration, tubular reabsorption, secretion, and post-secretory reabsorption in the kidney, which is mediated by several transporter proteins (Hosomi et al., 2012). URAT1 is responsible for urate reabsorption from the kidney tubular lumen into the blood to maintain blood urate homeostasis (Eraly et al., 2008). Conversely, OAT1 mediates urate secretion from the blood into the tubular lumen and is expressed on the basolateral membranes of renal proximal tubules (Su et al., 2014; Wang et al., 2019). OCTN2 is expressed in the proximal tubule of the kidney and is known to transport organic cations (Ding et al., 2013). GLUT9 is expressed on basolateral membranes and is also capable of transporting UA from renal tubules into the circulation (Cui et al., 2020). Finally, ABCG2 is a high-capacity urate exporter that plays an important role in both renal and extra-renal UA excretion (Wang et al., 2019). A previous study showed that ABCG2 is abundantly expressed on the apical membrane of intestinal epithelial cells, where it transports UA from the circulation to the enteric cavity (Chen et al., 2018).

Some natural active compounds have been verified for their protective effects on CKD, such as Alisma orientale Juzepzuk (Dou et al., 2018). In recent years, studies have shown that natural active polysaccharide is a kind of promising candidates for the treatment of adenine-induced chronic renal failure, which can be developed as UA lowering agents for the treatment of CKD, such as soybean soluble polysaccharide (Hou et al., 2020), Lonicera japonica polysaccharides, Cordyceps militaris polysaccharides (Ma et al., 2014), and Pleurotus eryngii polysaccharide (Niu et al., 2012). PFC is a commercial product in Japan and China, riched in polysaccharides (75.30%, w/w). In the present study, the serum CRE, BUN, and UA concentrations were significantly increased by adenine diet-feeding of mice (Figs. 2, 3), and the intestinal and urinary excretion of UA were reduced (Fig. 2). A high serum UA concentration is thought to be an important contributor to the progression of CKD (Shchelochkov et al., 2019). This study showed that PFC significantly changed the serum and urinary UA concentrations. Also, we found that adenine diet-feeding reduced the expression of ABCG2, OCTN2, and OAT1 and increased the expression of URAT1 and GLUT9 in the kidney, which is consistent with the results of previous studies (Liu et al., 2018). PFC has obvious regulatory effects on the expression of urate transporters mentioned above (Fig. 4). Therefore, the UA-lowering role of PFC is probably via effects on the expression of urate transporters.

Moreover, the UA concentration in the intestinal contents and the intestinal expression of ABCG2 were reduced by the consumption of adenine diet (Figs. 2, 5). Recently, other studies have shown that several uremic toxins (such as indoxyl sulfate, p-cresyl sulfate, and hippuric acid) are generated by the gut microbiota in mice with adenine diet-induced CKD and can inhibit substrate-specific transportation mediated by ABCG2 (Lowenstein and Nigam, 2021). Butyric acid produced by the gut microbiota is the substrate of ABCG2 in the colon, and the expression of ABCG2 increases alongside an increase in the butyric acid concentration (Gill and Dudeja, 2011). To build on the results of the present study, it will be necessary to conduct further analyses on the effect of changes in microbial composition on UA excretion by the intestine and to identify the microbial species implicated. Moreover, studied showed that dietary polysaccharide could regulate gut microbiota in some abnormal conditions (Ding et al., 2019; Wang et al., 2020). Thus, the capacity of polysaccharides to reduce UA and treat CKD could be linked with gut microbiota.

The composition of the gut microbiota in patients with advanced renal injury is significantly different from that of healthy people (Li et al., 2019; Ng et al., 2005). Therefore, 16S rDNA sequencing was performed on the cecal contents of each group of mice in the present study. The results show that the gut microbial composition of mice with CKD significantly differs from that of control mice (Fig. 9). A previous study found that the genus Lactobacillus was less abundant in patients with CKD and slowed the progression of kidney disease by improving the intestinal environment (Yoshifuji et al., 2016). However, we found that Lactobacillus was more abundant in CKD group at the genus level. Since PFC may have positive effect on the excretion of UA, it is therefore encouraged to further study whether this is associated with changes in the abundance of Lactobacillus in the gut. The species Lactobacillus_johnsonii_FI9785 and Lactobacillus_animalis are known to have probiotic effects in animals (Karunasena et al., 2013; Mayer et al., 2020), and we found that the abundances of these particular species were significantly greater in CKD-P group, which implies that PFC may promote the multiplication of probiotic Lactobacillus species.

In CKD patients, the absorption of protein in the small intestine is impaired, which might contribute to protein malnutrition, a well-known problem in CKD patients. When the absorption of protein in the small intestine is impaired and carbohydrate availability is lower, proteolytic bacteria, such as Bacteroides, increasingly ferment proteins to produce energy, which also generates potentially toxic metabolites, such as phenols and indoles (Bammens et al., 2003; Gryp et al., 2017). Phenolic substances have been shown to inhibit the activity of human urate transporters, such as ABCG2 (Evenepoel et al., 2009). Li et al. showed that the genus Bacteroides is enriched in the colon of CKD patients (Eraly et al., 2008), and our results are consistent with this finding (Fig. 9). The predominant proteolytic bacterial genus in feces was shown to be Bacteroides in 1986, but Romboutsia, Parabacteroides, and Clostridium can also produce toxic metabolites (Evenepoel et al., 2009). However, in the present study, the abundances of Bacteroides and Clostridium_IV were reduced, while those of Romboutsia and Parabacteroides were unaffected by PFC administration. The resulting reduction in the production of potential toxins may explain the observed increase in the expression of ABCG2, and therefore the increase in intestinal UA excretion induced by PFC. Additionally, the abundance of Helicobacter was also significantly reduced by PFC in adenine diet-induced CKD mice, which is consistent with the findings of a previous study, in which it was shown that Prunus mume juice reduced the Helicobacter population (Nakajima et al., 2006).

SCFAs are the principal sources of energy in the colon and are generated by metabolism of unabsorbed carbohydrates in the small intestine. The production of SCFAs in the large intestine occurs through carbohydrate fermentation (Furuse et al., 2014). They include acetic acid, propionic acid, and butyric acid, which are typically produced in a ratio of about 60:25:15 and play a significant role in the colon and cecum (Gill and Dudeja, 2011). Previous studies have shown that butyric acid and propionic acid can play anti-inflammatory and protective roles in the kidney. Additionally, butyric acid produced by gut microbiota is a substrate for ABCG2 in the colon, and the expression of ABCG2 increases as the concentration of butyric acid increases. Therefore, we measured the SCFAs concentrations in the cecal and colon contents of mice in the present study and found that PFC increases these concentrations. This implies that PFC is metabolized by gut microbiota to generate SCFAs, which may increase the expression of ABCG2 and UA excretion. The cecal concentrations of SCFAs were higher than the colonic concentrations, probably because they were predominantly absorbed in the colon. Furthermore, the SCFAs concentrations in the intestinal contents of CKD group were significantly lower than those of CNR group (Fig. 6), which was consistent with the results of a previous study (Castillo-Rodriguez et al., 2018). Certainly, the accurate impact of SCFAs from PFC on gut microbiota and more detailed mechanisms of PFC in UA excretion and gut microbiota are not clear. It also remains unclear importance of gut microbiota in the onset and development of CKD in spite of some cumulative of studies showing that CKD is closely associated with disturbances in the composition of gut microbiota. In the future, we plan to study the changes in gut microbial metabolites induced by PFC and further explore the relationship between the gut microbiota and UA excretion.

5. Conclusions

In conclusion, PFC intake could improve kidney damage caused by CKD, and promote the excretion of UA by reversing the abnormal protein expressions of renal and intestinal urate transporters. It also increases the large intestinal concentrations of SCFAs and reduces the abundance of the microbial genera Bacteroides, Pseudoflavonifractor, Helicobacter, Clostridium_IV, and Allobaculum. These findings may help guide the development and use of functional foods containing PFC.

Data availability

All data is available within the article or its supplementary materials.

Ethics approval

The animal experiment protocol was approved by the Animal Ethical and Welfare Committee of Zhejiang Chinese Medical University (Ethics Approval Number: 20200813-01).

CRediT authorship contribution statement

Yan Huang: Methodology, Data curation, Writing – original draft. Chen-Xi Wu: Formal analysis, Resources. Lu Guo: Software, Investigation. Xiao-Xi Zhang: Validation. Dao-Zong Xia: Conceptualization, Writing – review & editing, Supervision, Funding acquisition.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was funded by the National Natural Science Foundation of China (82074085, 81673656), the Opening Project of Zhejiang Provincial Preponderant and Characteristic Subject of Key University (Traditional Chinese Pharmacology), Zhejiang Chinese Medical University (ZYAOXZD2019002).

Footnotes

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.crfs.2022.10.028.

Appendix A. Supplementary data

The following is the Supplementary data to this article:

Multimedia component 1
mmc1.doc (31KB, doc)

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