Haikun Shenxi Capsule Ameliorates Renal Fibrosis by Modulating Gut Microbiota and Metabolism

Abstract

Objective

To investigate the specific biological mechanisms by which Haikun Shenxi capsule (HKSX) alleviates renal fibrosis (RF), with a particular focus on the interplay between gut microbiota regulation and host metabolic modulation. Methods The therapeutic effects of HKSX were evaluated using a unilateral ureteral obstruction (UUO) mouse model.

Methods

The therapeutic effects of HKSX were evaluated using a unilateral ureteral obstruction (UUO) mouse model. Untargeted metabolomic analyses were performed on serum and fecal samples to identify metabolic changes. Gut microbiota composition was assessed via 16S rRNA sequencing. Renal injury and fibrosis were evaluated by histopathological examination and by measuring the expression of fibrotic markers, including α-smooth muscle actin (α-SMA) and type I collagen (collagen I).

Results

HKSX modulates metabolic homeostasis by regulating the concentrations of pyruvic acid and ornithine in mouse serum and feces. These alterations affect key pathways, including the pentose phosphate pathway, tricarboxylic acid (TCA) cycle, and amino acid metabolism, contributing to the restoration of metabolic equilibrium. Concurrently, 16S rRNA sequencing revealed that HKSX improved the gut microbiota composition by increasing microbial diversity and increasing the abundance of beneficial bacteria, particularly Akkermansia. Moreover, HKSX alleviated UUO-induced renal damage and suppressed the expression of α-SMA and collagen I.

Conclusion

These findings provide strong evidence that HKSX exerts its renoprotective effects through bidirectional regulation of gut microbiota and host metabolism. The integration of traditional Chinese medicine (TCM) with modern systems biology offers fresh perspectives for developing improved natural therapies for RF and related metabolic disorders.

Keywords

Haikun Shenxi capsule / Renal fibrosis / Gut microbiota / Metabolomics / 16S rRNA sequencing / Gut–kidney axis / Traditional Chinese medicine

References

[1] Nørregaard R, Mutsaers HAM, Frøkiær J, et al.. Obstructive nephropathy and molecular pathophysiology of renal interstitial fibrosis. Physiol Rev., 2023, 103(4): 2847-2892

[2] Liu H, Xiang X, Shi C, et al.. Oxidative stress and inflammation in renal fibrosis: novel molecular mechanisms and therapeutic targets. Chem Biol Interact., 2025, 421 111784

[3] Liu Y. Kidney fibrosis: fundamental questions, challenges, and perspectives. Integr Med Nephrol Androl., 2024, 11(4): e24-00027

[4] Wang Y, Chen J, Wang W, et al. The core mechanism of hypertension-linked renal fibrosis: “RAAS-ROS-inflammation-fibrosis” axis. iScience. 2026;29(4):115353.

[5] Huang H, Peng Z, Yuan Q. Research progress in anti-renal fibrosis drugs. Zhong Nan Da Xue Xue Bao Yi Xue Ban (Chinese)., 2024, 49(8): 1353-1362

[6] Chen Y, Mu L, Xing L, et al.. Rhein alleviates renal interstitial fibrosis by inhibiting tubular cell apoptosis in rats. Biol Res., 2019, 52(1): 50

[7] Zhang HW, Lin ZX, Xu C, et al. Astragalus (a traditional Chinese medicine) for treating chronic kidney disease. Cochrane Database Syst Rev. 2014;2014(10):CD008369.

[8] Geng Y, Dong Z, Jia Q, et al. Haikun Shenxi capsule for improving renal function in patients with chronic kidney diseases: a systematic review and meta-analysis. Integr Med Nephrol Androl. 2023;10(2).

[9] Wang J, Geng L, Yue Y, et al.. Use of fucoidan to treat renal diseases: a review of 15 years of clinic studies. Prog Mol Biol Transl Sci., 2019, 163: 95-111

[10] Chen CH, Sue YM, Cheng CY, et al.. Oligo-fucoidan prevents renal tubulointerstitial fibrosis by inhibiting the CD44 signal pathway. Sci Rep., 2017, 7: 40183

[11] Zhao X, Liu Z, Wu C. Gut microbiota and membranous nephropathy: novel molecular mechanisms and natural product therapeutic strategies. Integr Med Nephrol Androl., 2025, 12(4): e24-00062

[12] He X, Guo Y, Zhao Y. Targeting gut microbiota as a promising therapy for chronic kidney disease. Integr Med Nephrol Androl., 2025, 12(3): e25-00026

[13] Jin Y, Zhang SJ, Zhuang S, et al.. Microbiota-gut-kidney axis in health and renal disease. Int J Biol Sci., 2026, 22(2): 750-770

[14] Corradi V, Caprara C, Barzon E, et al. A possible role of P-cresyl sulfate and indoxyl sulfate as biomarkers in the prediction of renal function according to the GFR (G) categories. Integr Med Nephrol Androl. 2024;11(3).

[15] Si ZL, Wang HY, Wang T, et al.. Gut bacteroides ovatus ameliorates renal fibrosis by promoting the production of HDCA through upregulation of Clostridium scindens. Cell Rep., 2024, 43(10 114830

[16] Zhang Y, Xu D, Cai X, et al.. Gut commensal barnesiella intestinihominis ameliorates hyperglycemia and liver metabolic disorders. Adv Sci., 2025, 12(8): 2411181

[17] Feng YL, Cao G, Chen DQ, et al.. Microbiome-metabolomics reveals gut microbiota associated with glycine-conjugated metabolites and polyamine metabolism in chronic kidney disease. Cell Mol Life Sci., 2019, 76(24): 4961-4978

[18] Zeisberg M, Soubasakos MA, Kalluri RVarga J, Brenner DA, Phan SH. Animal models of renal fibrosis. Fibrosis research, 2005, Totowa, NJ, Humana Press, 261-272

[19] Xue M, Tian Y, Sui Y, et al.. Protective effect of fucoidan against iron overload and ferroptosis-induced liver injury in rats exposed to alcohol. Biomed Pharmacother., 2022, 153 113402

[20] Shen ZH, Zhu CX, Quan YS, et al.. Relationship between intestinal microbiota and ulcerative colitis: mechanisms and clinical application of probiotics and fecal microbiota transplantation. World J Gastroenterol., 2018, 24(1): 5-14

[21] Petakh P, Oksenych V, Kamyshnyi A. The F/B ratio as a biomarker for inflammation in COVID-19 and T2D: Impact of metformin. Biomed Pharmacother., 2023, 163 114892

[22] Han N, Peng X, Zhang T, et al.. Strain-level dynamics of Akkermansia muciniphila in the human gut microbiota. AMB Express., 2025, 16(1): 2

[23] Zhang H, Liu C, Huang Y, et al.. Inactivated Akkermansia muciniphila AKK PROBIO preserves intestinal homeostasis and ameliorates DSS-induced colitis in mice. Foods., 2025, 14(23): 4063

[24] Dong X, Lin L, Liu L, et al.. Oral administration of Clostridium butyricum alleviates high-fat diet-induced obesity in mice by modulating gut Akkermansia muciniphila abundance via direct growth promotion. J Microbiol Biotechnol., 2025, 35 e2509005

[25] Liu P, Hu P, Jin M, et al.. Compound probiotics alleviate hyperuricemia-induced renal injury via restoring gut microbiota and metabolism. BMC Microbiol., 2025, 25(1): 280

[26] Yamashita N, Kusaba T, Nakata T, et al.. Intratubular epithelial-mesenchymal transition and tubular atrophy after kidney injury in mice. Am J Physiol Renal Physiol., 2020, 319(4): F579-F591

[27] Xing J, Tian XJ. Investigating epithelial-to-mesenchymal transition with integrated computational and experimental approaches. Phys Biol., 2019, 16(3 031001

[28] Zager RA, Johnson AC, Becker K. Renal cortical pyruvate depletion during AKI. J Am Soc Nephrol., 2014, 25(5): 998-1012

[29] Onodera T, Wang MY, Rutkowski JM, et al.. Endogenous renal adiponectin drives gluconeogenesis through enhancing pyruvate and fatty acid utilization. Nat Commun., 2023, 14(1): 6531

[30] Jin ES, Wen X, Malloy CR. Isotopomer analyses with the tricarboxylic acid cycle intermediates and exchanging metabolites from the rat kidney. NMR Biomed., 2023, 36(10 e4994

[31] Manteuffel-Cymborowska M, Chmurzyńska W, Peska M, et al.. Arginine and ornithine metabolizing enzymes in testosterone-induced hypertrophic mouse kidney. Int J Biochem Cell Biol., 1995, 27(3): 287-295

[32] Manteuffel-Cymborowska M, Chmurzyńska W, Grzelakowska-Sztabert B. Ornithine decarboxylase induction in mouse kidney as indicator of renal damage. Differential nephrotoxic effect of anticancer antifolate drugs. Cancer Lett. 1991;59(3):237–241.

[33] Nakano Y, Otani S, Terazawa M, et al. Rebound hyperammonemia triggered by interruption of renal replacement therapy in adolescent ornithine transcarbamylase deficiency. J Med Invest. 2025;72(3.4):443–446.

[34] Wang Z, Tian L, Jiang Y, et al.. Synergistic role of gut-microbial L-ornithine in enhancing ustekinumab efficacy for Crohn’s disease. Cell Metab., 2025, 37(5): 1089-1102.e7

[35] Hosomi K, Saito M, Park J, et al.. Oral administration of Blautia wexlerae ameliorates obesity and type 2 diabetes via metabolic remodeling of the gut microbiota. Nat Commun., 2022, 13(1): 4477

[36] Cani PD. Human gut microbiome: hopes, threats and promises. Gut., 2018, 67(9): 1716-1725

[37] Weersma RK, Zhernakova A, Fu J. Interaction between drugs and the gut microbiome. Gut., 2020, 69(8): 1510-1519

[38] Van Hul M, Cani PD, Petitfils C, et al.. What defines a healthy gut microbiome?. Gut., 2024, 73(11): 1893-1908

[39] Zhai Q, Feng S, Arjan N, et al.. A next generation probiotic, Akkermansia muciniphila. Crit Rev Food Sci Nutr., 2019, 59(19): 3227-3236

[40] Zheng M, Han R, Yuan Y, et al.. The role of Akkermansia muciniphila in inflammatory bowel disease: Current knowledge and perspectives. Front Immunol., 2023, 13: 1089600

[41] Patial V, Katoch S, Chhimwal J, et al.. Catechins prevent obesity-induced kidney damage by modulating PPARγ/CD36 pathway and gut-kidney axis in rats. Life Sci., 2023, 316 121437

[42] Bian X, Wu W, Yang L, et al.. Administration of Akkermansia muciniphila ameliorates dextran sulfate sodium-induced ulcerative colitis in mice. Front Microbiol., 2019, 10: 2259

[43] Reichardt N, Duncan SH, Young P, et al.. Phylogenetic distribution of three pathways for propionate production within the human gut microbiota. ISME J., 2014, 8(6): 1323-1335

[44] Vital M, Karch A, Pieper DH. Colonic butyrate-producing communities in humans: an overview using omics data. MSystems., 2017, 2(6): e00130-e117

[45] Kim MJ, Lee H, Chanda D, et al.. The role of pyruvate metabolism in mitochondrial quality control and inflammation. Mol Cells., 2023, 46(5): 259-267

[46] Heller JS, Chen KY, Kyriakidis DA, et al.. The modulation of the induction of ornithine decarboxylase by spermine, spermidine and diamines. J Cell Physiol., 1978, 96(2): 225-234

[47] Sivashanmugam M, Jaidev J, Umashankar V, et al.. Ornithine and its role in metabolic diseases: an appraisal. Biomed Pharmacother., 2017, 86: 185-194

Funding

China Association of Chinese Medicine(2023DYPLHGG-07)

National Natural Science Foundation(82504996)

Postdoctoral Fellowship Program of CPSF(GZC20252608)

Ningbo Top Medical and Health Research Program(2022030309)

Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(LBZ24H270001)

Pioneer and Leading Goose R&D Program of Zhejiang(2023C03038)

Fundamental Research Funds for Central Universities of the Central South University(2632026TD06)

Medical Science and Technology Project of Zhejiang Province(No. 2024ZL142)

Science and Technology Program of Zhejiang Province(GZY-ZJ-KJ-24048)

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