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Cited by 126Gut microbiota and healthSodium Intake and HealthGastrointestinal motility and disorders

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Enteric dysbiosis-linked gut barrier disruption triggers early renal injury induced by chronic high salt feeding in mice

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Hu, Jingjuan, Luo, Haihua, Wang, Jieyan, Tang, Wenli, Lu, Junqi, Wu, Shan, Xiong, Zhi, Yang, Guizhi, Chen, Zhenguo, Lan, Tian, Zhou, Hongwei, Nie, Jing, Jiang, Yong, Chen, Peng·2017·Experimental & Molecular Medicine
DOI 10.1038/emm.2017.122PMC PMC5579512
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Abstract

Chronic high-salt diet-associated renal injury is a key risk factor for the development of hypertension. However, the mechanism by which salt triggers kidney damage is poorly understood. Our study investigated how high salt (HS) intake triggers early renal injury by considering the ‘gut-kidney axis’. We fed mice 2% NaCl in drinking water continuously for 8 weeks to induce early renal injury. We found that the ‘quantitative’ and ‘qualitative’ levels of the intestinal microflora were significantly altered after chronic HS feeding, which indicated the occurrence of enteric dysbiosis. In addition, intestinal immunological gene expression was impaired in mice with HS intake. Gut permeability elevation and enteric bacterial translocation into the kidney were detected after chronic HS feeding. Gut bacteria depletion by non-absorbable antibiotic administration restored HS loading-induced gut leakiness, renal injury and systolic blood pressure elevation. The fecal microbiota from mice fed chronic HS could independently cause gut leakiness and renal injury. Our current work provides a novel insight into the mechanism of HS-induced renal injury by investigating the role of the intestine with enteric bacteria and gut permeability and clearly illustrates that chronic HS loading elicited renal injury and dysfunction that was dependent on the intestine. Kidney damage caused by high salt intake is triggered by microbial imbalances and impaired inflammatory responses in the gut. Peng Chen at the Southern Medical University in Guangzhou, China, and co-workers investigated how high salt intake triggers early-stage kidney damage, a key factor in the development of high blood pressure. Chen's team fed mice with high salt levels for eight weeks and found that the diversity and amount of microbial flora in the intestines changed considerably as a result. This imbalance led to the break-down of the gut barrier, the cell layer lining the gut that prevents material passing into other organs, meaning that bacteria entered the kidneys. High salt also impaired inflammatory responses and disrupted immune system gene expression. The findings may inform future treatments for high blood pressure and kidney dysfunction.

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Figure 1 Chronic high salt feeding reduced the bacterial load in the intestine. C57BL/6 mice were fed normal or high salt drinking water for 8 weeks (n=6–9). (a) Total bacterial load in the cecum; (b) bacterial load in the lumen, mucus layer and epithelium in the jejunum, ileum and colon. HS, high salt. The results are expressed as the mean±s.e.m. *P<0.05.
Figure 1 Chronic high salt feeding reduced the bacterial load in the intestine. C57BL/6 mice were fed normal or high salt drinking water for 8 weeks (n=6–9). (a) Total bacterial load in the cecum; (b) bacterial load in the lumen, mucus layer and epithelium in the jejunum, ileum and colon. HS, high salt. The results are expressed as the mean±s.e.m. *P<0.05.CC BY-NC-ND · PubMed Central
Figure 2 Chronic high salt feeding caused enteric dysbiosis. C57BL/6 mice were fed normal or high salt drinking water for 8 weeks (n=6–10). (a) Relative amounts of Firmicutes and Bacteroidetes in the cecum; (b–d) scatter plot of 3D PCoA for the microbiota in the cecal content, ileal mucus layer and colonic mucus layer. HS, high salt. The results are expressed as the mean±s.e.m. *P<0.05. 3D, three-dimensional; PCoA, principal coordinate analysis.
Figure 2 Chronic high salt feeding caused enteric dysbiosis. C57BL/6 mice were fed normal or high salt drinking water for 8 weeks (n=6–10). (a) Relative amounts of Firmicutes and Bacteroidetes in the cecum; (b–d) scatter plot of 3D PCoA for the microbiota in the cecal content, ileal mucus layer and colonic mucus layer. HS, high salt. The results are expressed as the mean±s.e.m. *P<0.05. 3D, three-dimensional; PCoA, principal coordinate analysis.CC BY-NC-ND · PubMed Central
Figure 3 Chronic high salt feeding was associated with gut inflammatory response disruption. C57BL/6 mice were fed normal or high salt drinking water for 8 weeks (n=6–12). (a) HE, TUNEL and ki67 staining; (b) mRNA levels of key cytokines and chemokines in the ileum; (c) IFN-γ immunohistochemistry in the ileum and the quantification analysis (n=3); (d) mRNA levels of TLRs in the ileum; (e) mRNA levels of genes involved in the Nf-κB signaling pathway in the ileum; (f) CD expression in the ileum. Scale bar, 100 μm. HS, high salt. The results are expressed as the mean±s.e.m. *P<0.05.
Figure 3 Chronic high salt feeding was associated with gut inflammatory response disruption. C57BL/6 mice were fed normal or high salt drinking water for 8 weeks (n=6–12). (a) HE, TUNEL and ki67 staining; (b) mRNA levels of key cytokines and chemokines in the ileum; (c) IFN-γ immunohistochemistry in the ileum and the quantification analysis (n=3); (d) mRNA levels of TLRs in the ileum; (e) mRNA levels of genes involved in the Nf-κB signaling pathway in the ileum; (f) CD expression in the ileum. Scale bar, 100 μm. HS, high salt. The results are expressed as the mean±s.e.m. *P<0.05.CC BY-NC-ND · PubMed Central
Figure 4 Chronic high salt feeding led to gut barrier dysfunction and promoted bacterial translocation into the kidney. C57BL/6 mice were fed normal or high salt drinking water for 8 weeks (n=6–7). (a) Fecal albumin content; (b) tight junction mRNA levels in the colon; (c) ZO-1 and Claudin-2 protein levels in the ileum; (d) occludin, ZO-1 and Claudin-2 protein levels in the colon; (e) bacterial translocation indicated by the relative 16S/18S ratio in the kidney, liver and spleen; (f) LDA along with effect size measurements was applied to show the enriched bacteria in the high salt kidney (n=3). HS, high salt. The results are expressed as the mean±s.e.m. *P<0.05. LDA, linear discriminant analysis.
Figure 4 Chronic high salt feeding led to gut barrier dysfunction and promoted bacterial translocation into the kidney. C57BL/6 mice were fed normal or high salt drinking water for 8 weeks (n=6–7). (a) Fecal albumin content; (b) tight junction mRNA levels in the colon; (c) ZO-1 and Claudin-2 protein levels in the ileum; (d) occludin, ZO-1 and Claudin-2 protein levels in the colon; (e) bacterial translocation indicated by the relative 16S/18S ratio in the kidney, liver and spleen; (f) LDA along with effect size measurements was applied to show the enriched bacteria in the high salt kidney (n=3). HS, high salt. The results are expressed as the mean±s.e.m. *P<0.05. LDA, linear discriminant analysis.CC BY-NC-ND · PubMed Central
Figure 5 Antibiotics restored gut leakiness induced by chronic high salt feeding. C57BL/6 mice were fed normal water, high salt drinking water and antibiotics (polymyxin B and neomycin) contained in high salt drinking water for 8 weeks (n=6–15). (a) Ileal Ifn-γ mRNA levels; (b) fecal albumin content; (c) FITC-Dextran (4 kDa, FD-4) level in the plasma; (d) relative plasma endotoxin level; (e) relative 16S/18S ratio in the kidney. ABX, antibiotics; HS, high salt. The results are expressed as the mean±s.e.m. *P<0.05.
Figure 5 Antibiotics restored gut leakiness induced by chronic high salt feeding. C57BL/6 mice were fed normal water, high salt drinking water and antibiotics (polymyxin B and neomycin) contained in high salt drinking water for 8 weeks (n=6–15). (a) Ileal Ifn-γ mRNA levels; (b) fecal albumin content; (c) FITC-Dextran (4 kDa, FD-4) level in the plasma; (d) relative plasma endotoxin level; (e) relative 16S/18S ratio in the kidney. ABX, antibiotics; HS, high salt. The results are expressed as the mean±s.e.m. *P<0.05.CC BY-NC-ND · PubMed Central
Figure 6 Antibiotics ameliorated early renal injury induced by chronic high salt feeding. C57BL/6 mice were fed normal water, high salt drinking water and antibiotics (polymyxin B and neomycin) contained in high salt drinking water for 8 weeks (n=6–8). (a) Na+ concentration in the urine and plasma; (b) renal col1a1 mRNA level; (c) plasma creatinine level; (d) urine albumin/creatinine ratio; (e, f) TUNEL staining in the kidney and the quantification analysis. Scale bar, 100 μm. ABX, antibiotics; HS, high salt. The results are expressed as the mean±s.e.m. *P<0.05.
Figure 6 Antibiotics ameliorated early renal injury induced by chronic high salt feeding. C57BL/6 mice were fed normal water, high salt drinking water and antibiotics (polymyxin B and neomycin) contained in high salt drinking water for 8 weeks (n=6–8). (a) Na+ concentration in the urine and plasma; (b) renal col1a1 mRNA level; (c) plasma creatinine level; (d) urine albumin/creatinine ratio; (e, f) TUNEL staining in the kidney and the quantification analysis. Scale bar, 100 μm. ABX, antibiotics; HS, high salt. The results are expressed as the mean±s.e.m. *P<0.05.CC BY-NC-ND · PubMed Central
Figure 7 Antibiotics restored the blood pressure elevation induced by chronic high salt feeding. C57BL/6 mice were fed normal water, high salt drinking water and antibiotics (polymyxin B and neomycin) contained in high salt drinking water for 8 weeks (n=8–9). (a) The SBP; (b) MBP; and (c) DBP in each group. ABX, antibiotics; HS, high salt; MBP, mean blood pressure. The results are expressed as the mean±s.e.m. *P<0.05.
Figure 7 Antibiotics restored the blood pressure elevation induced by chronic high salt feeding. C57BL/6 mice were fed normal water, high salt drinking water and antibiotics (polymyxin B and neomycin) contained in high salt drinking water for 8 weeks (n=8–9). (a) The SBP; (b) MBP; and (c) DBP in each group. ABX, antibiotics; HS, high salt; MBP, mean blood pressure. The results are expressed as the mean±s.e.m. *P<0.05.CC BY-NC-ND · PubMed Central
Figure 8 Gut leakiness and renal injury were transferrable via gut microbiota. C57BL/6 mice were intragastrically administered with feces from control mice and chronic high-salt-treated mice for the indicated weeks (n=5–9). (a) The Firmicutes/Bacteroidetes ratio in the cecal content 8 weeks after transplantation. (b) Relative fecal albumin content and (c) relative urine albumin/creatinine ratio. (d, e) TUNEL staining in the kidney and the quantification analysis 8 weeks after transplantation. Scale bar, 100 μm. HS, high salt. The results are expressed as the mean±s.e.m. *P<0.05.
Figure 8 Gut leakiness and renal injury were transferrable via gut microbiota. C57BL/6 mice were intragastrically administered with feces from control mice and chronic high-salt-treated mice for the indicated weeks (n=5–9). (a) The Firmicutes/Bacteroidetes ratio in the cecal content 8 weeks after transplantation. (b) Relative fecal albumin content and (c) relative urine albumin/creatinine ratio. (d, e) TUNEL staining in the kidney and the quantification analysis 8 weeks after transplantation. Scale bar, 100 μm. HS, high salt. The results are expressed as the mean±s.e.m. *P<0.05.CC BY-NC-ND · PubMed Central

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Authors
Hu, J., Luo, H., Wang, J., Tang, W., Lu, J., Wu, S., Xiong, Z., Yang, G., Chen, Z., Lan, T., Zhou, H., Nie, J., Jiang, Y., & Chen, P.
Affiliations
  • Southern Medical University (CN)
  • Guangdong Pharmaceutical University (CN)
Corresponding author
Chen, Peng
ORCID
Venue
Experimental & Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2017-08
Volume
49
Issue
8
Pages
e370-e370
ISSN
  • 1226-3613 (ISSN-L)
  • 2092-6413
DOI
10.1038/emm.2017.122
PMC
PMC5579512
OpenAlex
W2749268425
Cited by
126
References
41
Citations by year
2026: 11 · 2025: 16 · 2024: 24 · 2023: 15 · 2022: 18 · 2021: 16 · 2020: 12 · 2019: 9 · 2018: 5
FWCI
2.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Experimental & Molecular Medicine (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Brigham and Women's Hospital
  • National Natural Science Foundation of China (31500952)
  • Southern Medical University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Nursing › Nutrition and Dietetics › Sodium Intake and Health
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
Keywords
kidney injury, gut dysbiosis, gut-kidney axis, intestinal permeability, bacterial translocation, gut barrier disruption, fecal microbiota, hypertension, non-absorbable antibiotics, intestinal inflammation, immune gene expression
MeSH terms
Bacillota, Gastrointestinal Microbiome, Animals, Blood Pressure, Feces, Male, Mice, Inbred C57BL, Permeability, RNA, Time Factors, Sodium Chloride, Dietary, Gene Expression Profiling, Bacteroidetes, Gastrointestinal Tract, Mice, Acute Kidney Injury, Dysbiosis

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