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Magnesium lithospermate B improves the gut microbiome and bile acid metabolic profiles in a mouse model of diabetic nephropathy

Abstract

Magnesium lithospermate B (MLB) is a new drug marketed in China to treat angina, but its low oral bioavailability limits its clinical application to the intravenous route. Paradoxically, orally administered low-dose MLB was found to alleviate kidney injury in diabetic nephropathy (DN) rats, but its mechanism of action remains unknown. In recent years, the kidney-gut axis has been suspected to be involved in kidney damage pathogenesis, potentially representing a non-classical pathway for pharmacologic intervention. To ascertain whether MLB targets the kidney-gut axis, streptozotocin (STZ)-treated mice were prepared as a mouse model of DN. The STZ mice were treated with MLB (50 mg kg−1 d−1, p.o.) for 8 weeks. Twenty-four-hour urinary albumin was detected to mirror kidney function. At week 4, 6, 8, feces were collected; bile acids (BAs) were quantified to examine the alterations in the BA metabolic profiles, and bacterial 16S rRNA gene fragments were sequenced to identify alterations in gut microbial composition. In STZ mice, 24-h urinary albumin levels and total fecal BAs, especially cholic acids (CAs) and deoxycholic acids (DCAs) were greatly increased, and the gut microbiome was dramatically shifted compared with control mice. Oral administration of MLB significantly decreased 24-h urinary albumin levels and total BAs, CAs and DCAs, and reversed CA:TCA (taurocholic acid) and DCA:CA ratios. It also changed the microbiome composition in STZ mice based on operational units. Thus the therapeutic effect of MLB on kidney injury might be attributed (at least partially) to its ability to modulate the disordered gut microbiome and BA metabolism.

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Acknowledgements

This work was supported by grants from the Youth Innovation Promotion Association CAS, the State Key Laboratory of Drug Research (SIMM1403ZZ-03), the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDA12050306), and the National Natural Science Foundation of China (81673302).

Author contributions

J-hS, KW, JL, and JZ design the study. JZ and Q-lZ performed the experiments. JZ wrote the paper. J-hS, KW, and JL reviewed and edited the manuscript.

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Correspondence to Kai Wang or Jia Liu.

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Keywords

  • magnesium lithospermate B
  • diabetic nephropathy
  • intestinal microbiota
  • bile acid.
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