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Current Drug Metabolism

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ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

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Research Article

Integrated 16S rRNA Sequencing and Untargeted Metabolomics Analysis to Reveal the Protective Mechanisms of Polygonatum sibiricum Polysaccharide on Type 2 Diabetes Mellitus Model Rats

Author(s): Hui Zhang, Hanzhou Li, Baochao Pan, Shufang Zhang, Xiuhai Su, Wenjuan Sun, Tianyu Zhang, Zhaiyi Zhang, Shuquan Lv* and Huantian Cui*

Volume 24, Issue 4, 2023

Published on: 12 May, 2023

Page: [270 - 282] Pages: 13

DOI: 10.2174/1389200224666230406114012

Price: $65

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Abstract

Background: Polygonatum sibiricum polysaccharide (PSP) can improve insulin resistance and inhibit oxidative stress. However, the detailed anti-diabetic mechanism of PSP is still poorly defined.

Methods: In this study, the anti-diabetic, anti-inflammatory and anti-oxidative effects of PSP were evaluated on a type 2 diabetes mellitus (T2DM) rat model. Furthermore, we investigated the changes in gut microbiota and serum metabolites in T2DM rats after PSP treatment through 16S rRNA sequencing and untargeted metabolomics analyses.

Results: Our results showed that PSP exhibited significant anti-diabetic, anti-inflammatory and anti-oxidative effects on T2DM model rats. In addition, 16S rRNA sequencing showed that PSP treatment decreased the Firmicutes/ Bacteroidetes ratio in the gut. At the genus level, PSP treatment increased the relative abundances of Blautia, Adlercreutzia, Akkermansia and Parabacteroides while decreasing Prevotella, Megamonas funiformis and Escherichia. Untargeted metabolomics analysis revealed that PSP treatment could affect 20 metabolites, including hexanoylglycine, (±)5(6)-DiHET, ecgonine, L-cysteine-S-sulfate, epitestosterone, (±)12(13)-DiHOME, glutathione, L-ornithine, Dmannose 6-phosphate, L-fucose, L-tryptophan, L-kynurenine, serotonin, melatonin, 3-hydroxyanthranilic acid, xylitol, UDP-D-glucuronate, hydroxyproline, 4-guanidinobutyric acid, D-proline in T2DM model rats, these metabolites are associated with arginine and proline metabolism, tryptophan metabolism, amino sugar and nucleotide sugar metabolism, pentose and glucuronate interconversions, glutathione metabolism, arginine biosynthesis, ascorbate and aldarate metabolism pathways. Spearman correlation analysis results showed that the modulatory effects of PSP on the arginine and proline metabolism, tryptophan metabolism, and glutathione metabolism pathways were related to the regulation of Prevotella, Megamonas funiformis, Escherichia, Blautia and Adlercreutzia.

Conclusion: Our research revealed the therapeutic, anti-inflammatory and anti-oxidative effects of PSP on T2DM. The mechanisms of PSP on T2DM are associated with improving the dysbiosis of gut microbiota and regulating arginine and proline metabolism, tryptophan metabolism, and glutathione metabolism in serum.

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[1]
Artasensi, A.; Pedretti, A.; Vistoli, G.; Fumagalli, L. Type 2 diabetes mellitus: A review of multi-target drugs. Molecules, 2020, 25(8), 1987.
[http://dx.doi.org/10.3390/molecules25081987] [PMID: 32340373]
[2]
Daryabor, G.; Atashzar, M.R.; Kabelitz, D.; Meri, S.; Kalantar, K. The effects of type 2 diabetes mellitus on organ metabolism and the immune system. Front. Immunol., 2020, 11, 1582.
[http://dx.doi.org/10.3389/fimmu.2020.01582] [PMID: 32793223]
[3]
Vrancken, G.; Gregory, A.C.; Huys, G.R.B.; Faust, K.; Raes, J. Synthetic ecology of the human gut microbiota. Nat. Rev. Microbiol., 2019, 17(12), 754-763.
[http://dx.doi.org/10.1038/s41579-019-0264-8] [PMID: 31578461]
[4]
Charbonneau, M.R.; Blanton, L.V.; DiGiulio, D.B.; Relman, D.A.; Lebrilla, C.B.; Mills, D.A.; Gordon, J.I. A microbial perspective of human developmental biology. Nature, 2016, 535(7610), 48-55.
[http://dx.doi.org/10.1038/nature18845] [PMID: 27383979]
[5]
Vallianou, N.G.; Stratigou, T.; Tsagarakis, S. Microbiome and diabetes: Where are we now? Diabetes Res. Clin. Pract., 2018, 146, 111-118.
[http://dx.doi.org/10.1016/j.diabres.2018.10.008] [PMID: 30342053]
[6]
Gurung, M.; Li, Z.; You, H.; Rodrigues, R.; Jump, D.B.; Morgun, A.; Shulzhenko, N. Role of gut microbiota in type 2 diabetes pathophysiology. EBioMedicine, 2020, 51, 102590.
[http://dx.doi.org/10.1016/j.ebiom.2019.11.051] [PMID: 31901868]
[7]
Que, Y.; Cao, M.; He, J.; Zhang, Q.; Chen, Q.; Yan, C.; Lin, A.; Yang, L.; Wu, Z.; Zhu, D.; Chen, F.; Chen, Z.; Xiao, C.; Hou, K.; Zhang, B. Gut bacterial characteristics of patients with type 2 diabetes mellitus and the application potential. Front. Immunol., 2021, 12, 722206.
[http://dx.doi.org/10.3389/fimmu.2021.722206] [PMID: 34484230]
[8]
Yao, Y.; Yan, L.; Chen, H.; Wu, N.; Wang, W.; Wang, D. Cyclocarya paliurus polysaccharides alleviate type 2 diabetic symptoms by modulating gut microbiota and short-chain fatty acids. Phytomedicine, 2020, 77, 153268.
[http://dx.doi.org/10.1016/j.phymed.2020.153268] [PMID: 32663709]
[9]
Chen, M.; Xiao, D.; Liu, W.; Song, Y.; Zou, B.; Li, L.; Li, P.; Cai, Y.; Liu, D.; Liao, Q.; Xie, Z. Intake of Ganoderma lucidum polysaccharides reverses the disturbed gut microbiota and metabolism in type 2 diabetic rats. Int. J. Biol. Macromol., 2020, 155, 890-902.
[http://dx.doi.org/10.1016/j.ijbiomac.2019.11.047] [PMID: 31712153]
[10]
Xia, T.; Liu, C.S.; Hu, Y.N.; Luo, Z.Y.; Chen, F.L.; Yuan, L.X.; Tan, X.M. Coix seed polysaccharides alleviate type 2 diabetes mellitus via gut microbiota-derived short-chain fatty acids activation of IGF1/PI3K/AKT signaling. Food Res. Int., 2021, 150(Pt A), 110717.
[http://dx.doi.org/10.1016/j.foodres.2021.110717] [PMID: 34865748]
[11]
Cai, J.L.; Li, X.P.; Zhu, Y.L.; Yi, G.Q.; Wang, W.; Chen, X.Y.; Deng, G.M.; Yang, L.; Cai, H.Z.; Tong, Q.Z.; Zhou, L.; Tian, M.; Xia, X.H.; Liu, P. Polygonatum sibiricum polysaccharides (PSP) improve the palmitic acid (PA)-induced inhibition of survival, inflammation, and glucose uptake in skeletal muscle cells. Bioengineered, 2021, 12(2), 10147-10159.
[http://dx.doi.org/10.1080/21655979.2021.2001184] [PMID: 34872451]
[12]
Su, X.; Yu, W.; Liu, A.; Wang, C.; Li, X.; Gao, J.; Liu, X.; Jiang, W.; Yang, Y.; Lv, S. San-Huang-Yi-Shen capsule ameliorates diabetic nephropathy in rats through modulating the gut microbiota and overall metabolism. Front. Pharmacol., 2022, 12, 808867.
[http://dx.doi.org/10.3389/fphar.2021.808867] [PMID: 35058786]
[13]
Jiao, Y.; Wang, X.; Jiang, X.; Kong, F.; Wang, S.; Yan, C. Antidiabetic effects of Morus alba fruit polysaccharides on high-fat diet- and streptozotocin-induced type 2 diabetes in rats. J. Ethnopharmacol., 2017, 199, 119-127.
[http://dx.doi.org/10.1016/j.jep.2017.02.003] [PMID: 28163112]
[14]
Huang, S.; Peng, W.; Jiang, X.; Shao, K.; Xia, L.; Tang, Y.; Qiu, J. The effect of chromium picolinate supplementation on the pancreas and macroangiopathy in type II diabetes mellitus rats. J. Diabetes Res., 2014, 2014, 1-8.
[http://dx.doi.org/10.1155/2014/717219] [PMID: 25054160]
[15]
He, Q.; Li, J.K.; Li, F.; Li, R.G.; Zhan, G.Q.; Li, G.; Du, W.X.; Tan, H.B. Mechanism of action of gypenosides on type 2 diabetes and non-alcoholic fatty liver disease in rats. World J. Gastroenterol., 2015, 21(7), 2058-2066.
[http://dx.doi.org/10.3748/wjg.v21.i7.2058] [PMID: 25717238]
[16]
Lin, C.F.; Kuo, Y.T.; Chen, T.Y.; Chien, C.T. Quercetin-Rich Guava (Psidium guajava) juice in combination with trehalose reduces autophagy, apoptosis and pyroptosis formation in the kidney and pancreas of Type II Diabetic rats. Molecules, 2016, 21(3), 334.
[http://dx.doi.org/10.3390/molecules21030334] [PMID: 26978332]
[17]
Piccolo, B.D.; Graham, J.L.; Kang, P.; Randolph, C.E.; Shankar, K.; Yeruva, L.; Fox, R.; Robeson, M.S.; Moody, B.; LeRoith, T.; Stanhope, K.L.; Adams, S.H.; Havel, P.J. Progression of diabetes is associated with changes in the ileal transcriptome and ileal‐colon morphology in the UC Davis Type 2 Diabetes Mellitus rat. Physiol. Rep., 2021, 9(22), e15102.
[http://dx.doi.org/10.14814/phy2.15102] [PMID: 34806320]
[18]
Zhang, Q.; Hu, N. Effects of metformin on the gut microbiota in obesity and type 2 diabetes mellitus. Diabetes Metab. Syndr. Obes., 2020, 13, 5003-5014.
[http://dx.doi.org/10.2147/DMSO.S286430] [PMID: 33364804]
[19]
Matsumoto, T.; Noguchi, E.; Ishida, K.; Kobayashi, T.; Yamada, N.; Kamata, K. Metformin normalizes endothelial function by suppressing vasoconstrictor prostanoids in mesenteric arteries from OLETF rats, a model of type 2 diabetes. Am. J. Physiol. Heart Circ. Physiol., 2008, 295(3), H1165-H1176.
[http://dx.doi.org/10.1152/ajpheart.00486.2008] [PMID: 18641273]
[20]
Esser, N.; Legrand-Poels, S.; Piette, J.; Scheen, A.J.; Paquot, N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res. Clin. Pract., 2014, 105(2), 141-150.
[http://dx.doi.org/10.1016/j.diabres.2014.04.006] [PMID: 24798950]
[21]
Gerber, P.A.; Rutter, G.A. The role of oxidative stress and hypoxia in pancreatic beta-cell dysfunction in diabetes mellitus. Antioxid. Redox Signal., 2017, 26(10), 501-518.
[http://dx.doi.org/10.1089/ars.2016.6755] [PMID: 27225690]
[22]
Yaribeygi, H.; Sathyapalan, T.; Atkin, S.L.; Sahebkar, A. Molecular mechanisms linking oxidative stress and diabetes mellitus. Oxid. Med. Cell. Longev., 2020, 2020, 1-13.
[http://dx.doi.org/10.1155/2020/8609213] [PMID: 32215179]
[23]
Jakubiak, G.K.; Osadnik, K.; Lejawa, M.; Kasperczyk, S.; Osadnik, T.; Pawlas, N. Oxidative stress in association with metabolic health and obesity in young adults. Oxid. Med. Cell. Longev., 2021, 2021, 1-19.
[http://dx.doi.org/10.1155/2021/9987352] [PMID: 34257828]
[24]
Thackray, V.G. Sex, microbes, and polycystic ovary syndrome. Trends Endocrinol. Metab., 2019, 30(1), 54-65.
[http://dx.doi.org/10.1016/j.tem.2018.11.001] [PMID: 30503354]
[25]
Gruneck, L.; Kullawong, N.; Kespechara, K.; Popluechai, S. Gut microbiota of obese and diabetic Thai subjects and interplay with dietary habits and blood profiles. Peer. J., 2020, 8, e9622.
[http://dx.doi.org/10.7717/peerj.9622] [PMID: 32832269]
[26]
Stojanov, S.; Berlec, A.; Štrukelj, B. The influence of probiotics on the firmicutes/bacteroidetes ratio in the treatment of obesity and inflammatory bowel disease. Microorganisms, 2020, 8(11), 1715.
[http://dx.doi.org/10.3390/microorganisms8111715] [PMID: 33139627]
[27]
Wang, Y.; Wu, Y.; Wang, B.; Xu, H.; Mei, X.; Xu, X.; Zhang, X.; Ni, J.; Li, W. Bacillus amyloliquefaciens SC06 protects mice against high-fat diet-induced obesity and liver injury via regulating host metabolism and gut microbiota. Front. Microbiol., 2019, 10, 1161.
[http://dx.doi.org/10.3389/fmicb.2019.01161] [PMID: 31191487]
[28]
Ellekilde, M.; Krych, L.; Hansen, C.H.F.; Hufeldt, M.R.; Dahl, K.; Hansen, L.H.; Sørensen, S.J.; Vogensen, F.K.; Nielsen, D.S.; Hansen, A.K. Characterization of the gut microbiota in leptin deficient obese mice – Correlation to inflammatory and diabetic parameters. Res. Vet. Sci., 2014, 96(2), 241-250.
[http://dx.doi.org/10.1016/j.rvsc.2014.01.007] [PMID: 24556473]
[29]
Lv, M.; Li, L.; Li, W.; Yang, F.; Hu, Q.; Xiong, D. Mechanism research on the interaction regulation of Escherichia and IFN-γ for the occurrence of T2DM. Ann. Palliat. Med., 2021, 10(10), 10391-10400.
[http://dx.doi.org/10.21037/apm-21-2318] [PMID: 34763485]
[30]
Jenq, R.R.; Taur, Y.; Devlin, S.M.; Ponce, D.M.; Goldberg, J.D.; Ahr, K.F.; Littmann, E.R.; Ling, L.; Gobourne, A.C.; Miller, L.C.; Docampo, M.D.; Peled, J.U.; Arpaia, N.; Cross, J.R.; Peets, T.K.; Lumish, M.A.; Shono, Y.; Dudakov, J.A.; Poeck, H.; Hanash, A.M.; Barker, J.N.; Perales, M.A.; Giralt, S.A.; Pamer, E.G.; van den Brink, M.R.M. Intestinal blautia is associated with reduced death from graft-versus-host disease. Biol. Blood Marrow Transplant., 2015, 21(8), 1373-1383.
[http://dx.doi.org/10.1016/j.bbmt.2015.04.016] [PMID: 25977230]
[31]
Shaw, K.A.; Bertha, M.; Hofmekler, T.; Chopra, P.; Vatanen, T.; Srivatsa, A.; Prince, J.; Kumar, A.; Sauer, C.; Zwick, M.E.; Satten, G.A.; Kostic, A.D.; Mulle, J.G.; Xavier, R.J.; Kugathasan, S. Dysbiosis, inflammation, and response to treatment: A longitudinal study of pediatric subjects with newly diagnosed inflammatory bowel disease. Genome Med., 2016, 8(1), 75.
[http://dx.doi.org/10.1186/s13073-016-0331-y] [PMID: 27412252]
[32]
Henning, S.M.; Yang, J.; Hsu, M.; Lee, R.P.; Grojean, E.M.; Ly, A.; Tseng, C.H.; Heber, D.; Li, Z. Decaffeinated green and black tea polyphenols decrease weight gain and alter microbiome populations and function in diet-induced obese mice. Eur. J. Nutr., 2018, 57(8), 2759-2769.
[http://dx.doi.org/10.1007/s00394-017-1542-8] [PMID: 28965248]
[33]
Wei, X.; Tao, J.; Xiao, S.; Jiang, S.; Shang, E.; Zhu, Z.; Qian, D.; Duan, J. Xiexin Tang improves the symptom of type 2 diabetic rats by modulation of the gut microbiota. Sci. Rep., 2018, 8(1), 3685.
[http://dx.doi.org/10.1038/s41598-018-22094-2] [PMID: 29487347]
[34]
Shin, N.R.; Lee, J.C.; Lee, H.Y.; Kim, M.S.; Whon, T.W.; Lee, M.S.; Bae, J.W. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut, 2014, 63(5), 727-735.
[http://dx.doi.org/10.1136/gutjnl-2012-303839] [PMID: 23804561]
[35]
Cao, Y.; Yao, G.; Sheng, Y.; Yang, L.; Wang, Z.; Yang, Z.; Zhuang, P.; Zhang, Y. JinQi jiangtang tablet regulates gut microbiota and improve insulin sensitivity in type 2 diabetes mice. J. Diabetes Res., 2019, 2019, 1-12.
[http://dx.doi.org/10.1155/2019/1872134] [PMID: 30733971]
[36]
Chu, S.; Zhang, F.; Wang, H.; Xie, L.; Chen, Z.; Zeng, W.; Zhou, Z.; Hu, F. Aqueous extract of guava (Psidium guajava L.) leaf ameliorates hyperglycemia by promoting hepatic glycogen synthesis and modulating gut microbiota. Front. Pharmacol., 2022, 13, 907702.
[http://dx.doi.org/10.3389/fphar.2022.907702] [PMID: 35721172]
[37]
Kövamees, O.; Shemyakin, A.; Checa, A.; Wheelock, C.E.; Lundberg, J.O.; Östenson, C.G.; Pernow, J. Arginase inhibition improves microvascular endothelial function in patients with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab., 2016, 101(11), 3952-3958.
[http://dx.doi.org/10.1210/jc.2016-2007] [PMID: 27399350]
[38]
Hasslacher, C.; Kopischke, H.G.; Bürklin, E.; Gechter, F.; Reichenbacher, R. In vivo studies on basement membrane synthesis in diabetic and nondiabetic rats. Res. Exp. Med., 1982, 181(3), 245-251.
[http://dx.doi.org/10.1007/BF01851197] [PMID: 7163652]
[39]
Vidhya, S.; Ramya, R.; Coral, K.; Sulochana, K.N.; Bharathidevi, S.R. Free amino acids hydroxyproline, lysine, and glycine promote differentiation of retinal pericytes to adipocytes: A protective role against proliferative diabetic retinopathy. Exp. Eye Res., 2018, 173, 179-187.
[http://dx.doi.org/10.1016/j.exer.2018.05.004] [PMID: 29752946]
[40]
Chen, T.; Zheng, X.; Ma, X.; Bao, Y.; Ni, Y.; Hu, C.; Rajani, C.; Huang, F.; Zhao, A.; Jia, W.; Jia, W. Tryptophan predicts the risk for future type 2 diabetes. PLoS One, 2016, 11(9), e0162192.
[http://dx.doi.org/10.1371/journal.pone.0162192] [PMID: 27598004]
[41]
Yu, E.; Papandreou, C.; Ruiz-Canela, M.; Guasch-Ferre, M.; Clish, C.B.; Dennis, C.; Liang, L.; Corella, D.; Fitó, M.; Razquin, C.; Lapetra, J.; Estruch, R.; Ros, E.; Cofán, M.; Arós, F.; Toledo, E.; Serra-Majem, L.; Sorlí, J.V.; Hu, F.B.; Martinez-Gonzalez, M.A.; Salas-Salvado, J. Association of tryptophan metabolites with incident type 2 diabetes in the predimed trial: A case–cohort study. Clin. Chem., 2018, 64(8), 1211-1220.
[http://dx.doi.org/10.1373/clinchem.2018.288720] [PMID: 29884676]
[42]
Kumar, M.P.; Mamidala, E.; Al-Ghanim, K.A.; Al-Misned, F.; Mahboob, S. Evaluation of the andrographolides role and its indoleamine 2,3-dioxygenase inhibitory potential and attendant molecular mechanism against STZ-induced diabetic rats. Saudi J. Biol. Sci., 2020, 27(2), 713-719.
[http://dx.doi.org/10.1016/j.sjbs.2019.12.007] [PMID: 32210693]
[43]
Brandacher, G.; Winkler, C.; Aigner, F.; Schwelberger, H.; Schroecksnadel, K.; Margreiter, R.; Fuchs, D.; Weiss, H. Bariatric surgery cannot prevent tryptophan depletion due to chronic immune activation in morbidly obese patients. Obes. Surg., 2006, 16(5), 541-548.
[http://dx.doi.org/10.1381/096089206776945066] [PMID: 16687019]
[44]
Frese, T.; Bach, A.G.; Mühlbauer, E.; Pönicke, K.; Brömme, H.J.; Welp, A.; Peschke, E. Pineal melatonin synthesis is decreased in type 2 diabetic Goto–Kakizaki rats. Life Sci., 2009, 85(13-14), 526-533.
[http://dx.doi.org/10.1016/j.lfs.2009.08.004] [PMID: 19695268]
[45]
Matsuoka, K; Kato, K; Takao, T; Ogawa, M; Ishii, Y; Shimizu, F; Masuda, J; Takada, A Concentrations of various tryptophan metabolites are higher in patients with diabetes mellitus than in healthy aged male adults. Diabetol. Int., 2016, 8(1), 69-75.
[http://dx.doi.org/10.1007/s13340-016-0282-y] [PMID: 30603309]
[46]
Matsuoka, K.; Kato, K.; Takao, T.; Ogawa, M.; Ishii, Y.; Shimizu, F.; Masuda, J.; Takada, A. Concentrations of various tryptophan metabolites are higher in patients with diabetes mellitus than in healthy aged male adults. Diabetol. Int., 2017, 8(1), 69-75.
[http://dx.doi.org/10.1007/s13340-016-0282-y] [PMID: 30603309]
[47]
Pawlak, K.; Kowalewska, A.; Mysliwiec, M.; Pawlak, D. 3-hydroxyanthranilic acid is independently associated with monocyte chemoattractant protein-1 (CCL2) and macrophage inflammatory protein-1β (CCL4) in patients with chronic kidney disease. Clin. Biochem., 2010, 43(13-14), 1101-1106.
[http://dx.doi.org/10.1016/j.clinbiochem.2010.06.008] [PMID: 20599874]
[48]
Lu, S.C. Regulation of glutathione synthesis. Mol. Aspects Med., 2009, 30(1-2), 42-59.
[http://dx.doi.org/10.1016/j.mam.2008.05.005] [PMID: 18601945]
[49]
Sekhar, R.V.; McKay, S.V.; Patel, S.G.; Guthikonda, A.P.; Reddy, V.T.; Balasubramanyam, A.; Jahoor, F. Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine. Diabetes Care, 2011, 34(1), 162-167.
[http://dx.doi.org/10.2337/dc10-1006] [PMID: 20929994]
[50]
Livingstone, C.; Davis, J. Review: Targeting therapeutics against glutathione depletion in diabetes and its complications. Br. J. Diabetes Vasc. Dis., 2007, 7(6), 258-265.
[http://dx.doi.org/10.1177/14746514070070060201]
[51]
Krause, M.S.; McClenaghan, N.H.; Flatt, P.R.; Homem de Bittencourt, P.I.; Murphy, C.; Newsholme, P. l-Arginine is essential for pancreatic β-cell functional integrity, metabolism and defense from inflammatory challenge. J. Endocrinol., 2011, 211(1), 87-97.
[http://dx.doi.org/10.1530/JOE-11-0236] [PMID: 21784771]

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