Dynamic gut microbiome-metabolome in cationic bovine serum albumin induced experimental immune-complex glomerulonephritis and effect of losartan and mycophenolate mofetil on microbiota modulation

Wenying Shi; Zhaojun Li; Weida Wang; Xikun Liu; Haijie Wu; Xiaoguang Chen; Xunrong Zhou; Sen Zhang

doi:10.1016/j.jpha.2023.12.021

Volume 14 Issue 4

Apr. 2024

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Wenying Shi, Zhaojun Li, Weida Wang, Xikun Liu, Haijie Wu, Xiaoguang Chen, Xunrong Zhou, Sen Zhang. Dynamic gut microbiome-metabolome in cationic bovine serum albumin induced experimental immune-complex glomerulonephritis and effect of losartan and mycophenolate mofetil on microbiota modulation[J]. Journal of Pharmaceutical Analysis, 2024, 14(4): 100931. doi: 10.1016/j.jpha.2023.12.021

Citation:

Wenying Shi, Zhaojun Li, Weida Wang, Xikun Liu, Haijie Wu, Xiaoguang Chen, Xunrong Zhou, Sen Zhang. Dynamic gut microbiome-metabolome in cationic bovine serum albumin induced experimental immune-complex glomerulonephritis and effect of losartan and mycophenolate mofetil on microbiota modulation[J]. Journal of Pharmaceutical Analysis, 2024, 14(4): 100931. doi: 10.1016/j.jpha.2023.12.021

Citation:

Wenying Shi, Zhaojun Li, Weida Wang, Xikun Liu, Haijie Wu, Xiaoguang Chen, Xunrong Zhou, Sen Zhang. Dynamic gut microbiome-metabolome in cationic bovine serum albumin induced experimental immune-complex glomerulonephritis and effect of losartan and mycophenolate mofetil on microbiota modulation[J]. Journal of Pharmaceutical Analysis, 2024, 14(4): 100931. doi: 10.1016/j.jpha.2023.12.021

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Dynamic gut microbiome-metabolome in cationic bovine serum albumin induced experimental immune-complex glomerulonephritis and effect of losartan and mycophenolate mofetil on microbiota modulation

doi: 10.1016/j.jpha.2023.12.021

a. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China;
b. State Key Laboratory of Functions and Applications of Medicinal Plants, College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China;
c. Department of Medicine Solna, Center for Molecular Medicine, Karolinska University Hospital and Karolinska Institute, Stockholm, 17176, Sweden;
d. Department of Pharmacy, The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, China

Funds:

The authors acknowledge the funds by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS), China (Grant No.: 2022-I2M-1-014), the National Natural Science Foundation of China (Grant No.: 82293684), Beijing Natural Science Foundation, China (Grant No.: L232084), and the National Key R&

D Program of China (Grant No.: 2022YFA0806400).

Received Date: Aug. 14, 2023
Accepted Date: Dec. 28, 2023
Rev Recd Date: Dec. 14, 2023
Publish Date: Dec. 30, 2023

Abstract

Abstract

Dynamic changes in gut dysbiosis and metabolomic dysregulation are associated with immune-complex glomerulonephritis (ICGN). However, an in-depth study on this topic is currently lacking. Herein, we report an ICGN model to address this gap. ICGN was induced via the intravenous injection of cationized bovine serum albumin (c-BSA) into Sprague-Dawley (SD) rats for two weeks, after which mycophenolate mofetil (MMF) and losartan were administered orally. Two and six weeks after ICGN establishment, fecal samples were collected and 16S ribosomal DNA (rDNA) sequencing and untargeted metabolomic were conducted. Fecal microbiota transplantation (FMT) was conducted to determine whether gut normalization caused by MMF and losartan contributed to their renal protective effects. A gradual decline in microbial diversity and richness was accompanied by a loss of renal function. Approximately 18 genera were found to have significantly different relative abundances between the early and later stages, and Marvinbryantia and Allobaculum were markedly upregulated in both stages. Untargeted metabolomics indicated that the tryptophan metabolism was enhanced in ICGN, characterized by the overproduction of indole and kynurenic acid, while the serotonin pathway was reduced. Administration of losartan and MMF ameliorated microbial dysbiosis and reduced the accumulation of indoxyl conjugates in feces. FMT using feces from animals administered MMF and losartan improved gut dysbiosis by decreasing the Firmicutes/Bacteroidetes (F/B) ratio but did not improve renal function. These findings indicate that ICGN induces serous gut dysbiosis, wherein an altered tryptophan metabolism may contribute to its progression. MMF and losartan significantly reversed the gut microbial and metabolomic dysbiosis, which partially contributed to their renoprotective effects.
- Immune-complex glomerulonephritis,
- Gut microbiome,
- Metabolomics,
- Fecal microbiota transplant,
- Tryptophan metabolism

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References(57)

References

[1]	C. Meyer-Schwesinger, S. Dehde, P. Klug, et al., Nephrotic syndrome and subepithelial deposits in a mouse model of immune-mediated anti-podocyte glomerulonephritis, J. Immunol. 187 (2011) 3218-3229.
[2]	J.M. Thurman, M. Le Quintrec, Targeting the complement cascade: Novel treatments coming down the Pike, Kidney Int. 90 (2016) 746-752.
[3]	G.R. Valiente, A. Munir, M.L. Hart, et al., Gut dysbiosis is associated with acceleration of lupus nephritis, Sci. Rep. 12 (2022), 152.
[4]	Q. Mu, H. Zhang, X. Liao, et al., Control of lupus nephritis by changes of gut microbiota, Microbiome 5 (2017), 73.
[5]	S. Zhang, W. Wang, L. Yan, et al., Nicousamide attenuates renal dysfunction and glomerular injury in remnant kidneys by inhibiting TGF-β1 internalisation and renin activity, Eur. J. Pharmacol. 845 (2019) 74-84.
[6]	I.W. Wu, C. Lin, L.C. Chang, et al., Gut microbiota as diagnostic tools for mirroring disease progression and circulating nephrotoxin levels in chronic kidney disease: Discovery and validation study, Int. J. Biol. Sci. 16 (2020) 420-434.
[7]	T. Gryp, K. De Paepe, R. Vanholder, et al., Gut microbiota generation of protein-bound uremic toxins and related metabolites is not altered at different stages of chronic kidney disease, Kidney Int. 97 (2020) 1230-1242.
[8]	A.M. Madella, J. van Bergenhenegouwen, J. Garssen, et al., Microbial-derived tryptophan catabolites, kidney disease and gut inflammation, Toxins 14 (2022), 645.
[9]	R. Yacoub, G.N. Nadkarni, D.I. McSkimming, et al., Fecal microbiota analysis of polycystic kidney disease patients according to renal function: A pilot study, Exp. Biol. Med. (Maywood) 244 (2019) 505-513.
[10]	D. Azzouz, A. Omarbekova, A. Heguy, et al., Lupus nephritis is linked to disease-activity associated expansions and immunity to a gut commensal, Ann. Rheum. Dis. 78 (2019) 947-956.
[11]	H. Wu, B. Jia, X. Zhao, et al., Pathophysiology and system biology of rat c-BSA induced immune complex glomerulonephritis and pathway comparison with human gene sequencing data, Int. Immunopharmacol. 109 (2022), 108891.
[12]	P.N. Furness, D.R. Turner, Chronic serum sickness glomerulonephritis: Passive immunisation inhibits the removal of glomerular antigen and electron dense deposits, Virchows Arch. A Pathol. Anat. Histopathol. 413 (1988) 551-553.
[13]	K. Joh, S. Aizawa, K. Ohkawa, et al., Selective planting of cationized, haptenized ovalbumin on the rat tubular basement membrane, Virchows Arch. 424 (1994) 587-591.
[14]	M.C. Villarroel, M. Hidalgo, A. Jimeno, Mycophenolate mofetil: An update, Drugs Today 45 (2009) 521-532.
[15]	P. Li, H. Lin, Z. Ni, et al., Efficacy and safety of Abelmoschus manihot for IgA nephropathy: A multicenter randomized clinical trial, Phytomedicine 76 (2020), 153231.
[16]	V. Sepe, C. Libetta, M.G. Giuliano, et al., Mycophenolate mofetil in primary glomerulopathies, Kidney Int. 73 (2008) 154-162.
[17]	M. Platten, E.A.A. Nollen, U.F. Rohrig, et al., Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond, Nat. Rev. Drug Discov. 18 (2019) 379-401.
[18]	J. Zou, X. Zhou, Y. Ma, et al., Losartan ameliorates renal interstitial fibrosis through metabolic pathway and Smurfs-TGF-β/Smad, Biomed. Pharmacother. 149 (2022), 112931.
[19]	H. Wang, W. Fu, Z. Jin, et al., Advanced IgA nephropathy with impaired renal function benefits from losartan treatment in rats, Ren. Fail. 35 (2013) 812-818.
[20]	I. Robles-Vera, M. Toral, N. de la Visitacion, et al., Changes to the gut microbiota induced by losartan contributes to its antihypertensive effects, Br. J. Pharmacol. 177 (2020) 2006-2023.
[21]	S. Zhang, H. Xin, Y. Li, et al., Skimmin, a coumarin from Hydrangea paniculata, slows down the progression of membranous glomerulonephritis by anti-inflammatory effects and inhibiting immune complex deposition, Evid. Based Complement. Alternat. Med. 2013 (2013), 819296.
[22]	S. Zhang, J. Ma, L. Sheng, et al., Total coumarins from Hydrangea paniculata show renal protective effects in lipopolysaccharide-induced acute kidney injury via anti-inflammatory and antioxidant activities, Front. Pharmacol. 8 (2017), 872.
[23]	W. Wang, Z. Li, Y. Chen, et al., Prediction value of serum NGAL in the diagnosis and prognosis of experimental acute and chronic kidney injuries, Biomolecules 10 (2020), 981.
[24]	M. Eddouks, D. Chattopadhyay, V. De Feo, et al., Medicinal plants in the prevention and treatment of chronic diseases 2013, Evid. Based Complement. Alternat. Med. 2014 (2014), 180981.
[25]	C. Huang, J. Dong, X. Jin, et al., Intestinal anti-inflammatory effects of fuzi-Ganjiang herb pair against DSS-induced ulcerative colitis in mice, J. Ethnopharmacol. 261 (2020), 112951.
[26]	S. Zhang, W. Wang, J. Ma, et al., Coumarin glycosides from Hydrangea paniculata slow down the progression of diabetic nephropathy by targeting Nrf2 anti-oxidation and smad2/3-mediated profibrosis, Phytomedicine 57 (2019) 385-395.
[27]	S. Zhang, D. Wang, N. Xue, et al., Nicousamide protects kidney podocyte by inhibiting the TGFβ receptor II phosphorylation and AGE-RAGE signaling, Am. J. Transl. Res. 9 (2017) 115-125.
[28]	L.F. Gomez-Arango, H.L. Barrett, S.A. Wilkinson, et al., Low dietary fiber intake increases Collinsella abundance in the gut microbiota of overweight and obese pregnant women, Gut Microbes 9 (2018) 189-201.
[29]	Y. Feng, G. Cao, D. Chen, et al., Microbiome-metabolomics reveals gut microbiota associated with glycine-conjugated metabolites and polyamine metabolism in chronic kidney disease, Cell. Mol. Life Sci. 76 (2019) 4961-4978.
[30]	D. Chen, G. Cao, H. Chen, et al., Identification of serum metabolites associating with chronic kidney disease progression and anti-fibrotic effect of 5-methoxytryptophan, Nat. Commun. 10 (2019), 1476.
[31]	C.J. Chang, C. Lin, C.C. Lu, et al., Ganoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota, Nat. Commun. 6 (2015), 7489.
[32]	S. Dong, Q. Liu, X. Zhou, et al., Effects of losartan, atorvastatin, and aspirin on blood pressure and gut microbiota in spontaneously hypertensive rats, Molecules 28 (2023), 612.
[33]	S.J. Chadban, R.C. Atkins, Glomerulonephritis, Lancet 365 (2005) 1797-1806.
[34]	A.C. Webster, E.V. Nagler, R.L. Morton, et al., Chronic kidney disease, Lancet 389 (2017) 1238-1252.
[35]	B. Liu, Y. Cao, D. Wang, et al., Zhen-wu-Tang induced mitophagy to protect mitochondrial function in chronic glomerulonephritis via PI3K/AKT/mTOR and AMPK pathways, Front. Pharmacol. 12 (2021), 777670.
[36]	M. Chi, K. Ma, J. Wang, et al., The immunomodulatory effect of the gut microbiota in kidney disease, J. Immunol. Res. 2021 (2021), 5516035.
[37]	A. Rutsch, J.B. Kantsjo, F. Ronchi, The gut-brain axis: How microbiota and host inflammasome influence brain physiology and pathology, Front. Immunol. 11 (2020), 604179.
[38]	Y. Zhao, Y. Liu, S. Li, et al., Role of lung and gut microbiota on lung cancer pathogenesis, J. Cancer Res. Clin. Oncol. 147 (2021) 2177-2186.
[39]	P. Wang, T. Wang, X. Zheng, et al., Gut microbiota, key to unlocking the door of diabetic kidney disease, Nephrology (Carlton) 26 (2021) 641-649.
[40]	A. Zaky, S.J. Glastras, M.Y.W. Wong, et al., The role of the gut microbiome in diabetes and obesity-related kidney disease, Int. J. Mol. Sci. 22 (2021), 9641.
[41]	R. Suraya, T. Nagano, K. Kobayashi, et al., Microbiome as a target for cancer therapy, Integr. Cancer Ther. 19 (2020), 1534735420920721.
[42]	R.C. Newsome, R.Z. Gharaibeh, C.M. Pierce, et al., Interaction of bacterial Genera associated with therapeutic response to immune checkpoint PD-1 blockade in a United States cohort, Genome Med. 14 (2022), 35.
[43]	R. Chen, J. Wang, R. Zhan, et al., Fecal metabonomics combined with 16S rRNA gene sequencing to analyze the changes of gut microbiota in rats with kidney-Yang deficiency syndrome and the intervention effect of You-Gui pill, J. Ethnopharmacol. 244 (2019), 112139.
[44]	M. Vacca, G. Celano, F.M. Calabrese, et al., The controversial role of human gut Lachnospiraceae, Microorganisms 8 (2020), 573.
[45]	K. Sasaki, J. Inoue, D. Sasaki, et al., Construction of a model culture system of human colonic microbiota to detect decreased Lachnospiraceae abundance and butyrogenesis in the feces of ulcerative colitis patients, Biotechnol. J. 14 (2019), e1800555.
[46]	J. Yang, S.Y. Lim, Y.S. Ko, et al., Intestinal barrier disruption and dysregulated mucosal immunity contribute to kidney fibrosis in chronic kidney disease, Nephrol. Dial. Transplant 34 (2019) 419-428.
[47]	Y. Zeng, Z. Dai, F. Lu, et al., Emodin via colonic irrigation modulates gut microbiota and reduces uremic toxins in rats with chronic kidney disease, Oncotarget 7 (2016) 17468-17478.
[48]	C. Barrios, M. Beaumont, T. Pallister, et al., Gut-microbiota-metabolite axis in early renal function decline, PLoS One 10 (2015), e0134311.
[49]	L. Nazzal, J. Roberts, P. Singh, et al., Microbiome perturbation by oral vancomycin reduces plasma concentration of two gut-derived uremic solutes, indoxyl sulfate and p-cresyl sulfate, in end-stage renal disease, Nephrol. Dial. Transplant 32 (2017) 1809-1817.
[50]	M.T. Pallotta, S. Rossini, C. Suvieri, et al., Indoleamine 2, 3-dioxygenase 1 (IDO1): An up-to-date overview of an eclectic immunoregulatory enzyme, FEBS J. 289 (2022) 6099-6118.
[51]	H.M. Roager, T.R. Licht, Microbial tryptophan catabolites in health and disease, Nat. Commun. 9 (2018), 3294.
[52]	J. Liu, H. Miao, D. Deng, et al., Gut microbiota-derived tryptophan metabolism mediates renal fibrosis by aryl hydrocarbon receptor signaling activation, Cell. Mol. Life Sci. 78 (2021) 909-922.
[53]	S. Kalim, E.P. Rhee, An overview of renal metabolomics, Kidney Int. 91 (2017) 61-69.
[54]	C.Y. Yang, T. Chen, W. Lu, et al., Synbiotics alleviate the gut indole load and dysbiosis in chronic kidney disease, Cells 10 (2021), 114.
[55]	S. Cigarran Guldris, E. Gonzalez Parra, A. Cases Amenos, Gut microbiota in chronic kidney disease, Nefrologia 37 (2017) 9-19.
[56]	J. Wong, E. Vilar, K. Farrington, Endotoxemia in end-stage kidney disease, Semin. Dial. 28 (2015) 59-67.
[57]	S. Mohammad, C. Thiemermann, Role of metabolic endotoxemia in systemic inflammation and potential interventions, Front. Immunol. 11 (2020), 594150.