Network pharmacology‐based exploration of gut microbiota‐derived metabolites for type‐2 diabetes

Nadia Widjaja; Stefeny Theresia Simatupang; Santi Tan; Raymond Rubianto Tjandrawinata

doi:10.22146/ijbiotech.107382

Network pharmacology‐based exploration of gut microbiota‐derived metabolites for type‐2 diabetes

https://doi.org/10.22146/ijbiotech.107382

Nadia Widjaja⁽¹⁾, Stefeny Theresia Simatupang⁽²⁾, Santi Tan⁽³⁾, Raymond Rubianto Tjandrawinata^(4*)

(1) Department of Dexa Omic Sciences (Dexomics), Dexa Medica, Titan Center, Jl. Boulevard Bintaro, Block B7/B1 No. 5 Bintaro Jaya Sector 7, South Tangerang, 15424, Indonesia
(2) Department of Dexa Omic Sciences (Dexomics), Dexa Medica, Titan Center, Jl. Boulevard Bintaro, Block B7/B1 No. 5 Bintaro Jaya Sector 7, South Tangerang, 15424, Indonesia
(3) Department of Dexa Omic Sciences (Dexomics), Dexa Medica, Titan Center, Jl. Boulevard Bintaro, Block B7/B1 No. 5 Bintaro Jaya Sector 7, South Tangerang, 15424, Indonesia
(4) Center for Pharmaceutical and Nutraceutical Research and Policy (CPNRP), Atma Jaya Catholic University of Indonesia, Jl. Jendral Sudirman No. 51, South Jakarta, 12930, Indonesia
(*) Corresponding Author

Abstract

Probiotics confer health benefits and have been investigated for their potential therapeutic properties in type‐2 diabetes (T2D) treatment. This study employs a network pharmacology approach to explore gut microbiota‐derived metabolites that potentially alleviate T2D. Several strains and species of gut microbiota were identified that may produce metabolites with therapeutic potential for T2D. Interestingly, quercetin produced by Bacteroides uniformis and daidzein produced by Bifidobacterium adolescentis and Bifidobacterium breve have been studied for their antidiabetic effects. Using a network pharmacology approach, it was found that quercetin may target AKT1 and EGFR, critical proteins involved in insulin signaling pathways related to T2D. Additionally, 10‐oxo‐11‐octadecenoic acid produced by Lactobacillus plantarum and 10‐keto‐12Z‐octadecenoic acid produced by Lactobacillus paracasei were found to target PPARG, a gene regulating insulin signaling. These findings were further validated by the molecular docking analysis, which showed suitable to satisfactory binding strengths.

Keywords

Diabetes; Gut microbiota; Insulin signaling; Network pharmacology

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References

Agus A, Planchais J, Sokol H. 2021. Gut microbiotaderived metabolites as central regulators in metabolic disorders. Gut 70(6):1174–1182. doi:10.1136/gutjnl 2020323071.

Alwhaibi A, Verma A, Adil M, Somanath P. 2019. The unconventional role of Akt1 in the advanced cancers and in diabetespromoted carcinogenesis. Pharmacol. Res. 145:104270. doi:10.1016/j.phrs.2019.104270.

Astuti N, Novitasari P, Tjandrawinata R, Nugroho A, Pramono S. 2022. Antidiabetic effect of andrographolide from Sambiloto herbs (Andrographis paniculata (Burm.f.) Nees) through the expression of PPARγ and GLUT4 in adipocytes. Indones. J. Biotechnol. 27(4):203– 211. doi:10.22146/ijbiotech.68800.

Bejar W, Hamden K, Salah R, Chouayekh H. 2013. Lactobacillus plantarum TN627 significantly reduces complications of alloxaninduced diabetes in rats. Anaerobe 24:4–11. doi:10.1016/j.anaerobe.2013.08.006.

Calle M, Fernandez M. 2012. Inflammation and type 2 diabetes. Diabetes Metab. 38(3):183–191. doi:10.1016/j.diabet.2011.11.006.

Carding S, Verbeke K, Vipond D, Corfe B, Owen L. 2015. Dysbiosis of the gut microbiota in disease. Microb. Ecol. Health Dis. 26:26191. doi:10.3402/mehd.v26.26191.

Chaiyasut C, Sivamaruthi B, Lailerd N, Sirilun S, Thangaleela S, Khongtan S, Bharathi M, Kesika P, Saelee M, Choeisoongnern T, et al. 2023. Influence of Bifidobacterium breve on the glycaemic control, lipid profile and microbiome of type 2 diabetic subjects: A preliminary randomized clinical trial. Pharmaceuticals 16(5):695. doi:10.3390/ph16050695.

Cheng L, Qi C, Yang H, Lu M, Cai Y, Fu T, Ren J, Jin Q, Zhang X. 2022. gutMGene: A comprehensive database for target genes of gut microbes and microbial metabolites. Nucleic Acids Res. 50(D1):D795– D800. doi:10.1093/nar/gkab786.

Cheong S, Furuhashi K, Ito K, Nagaoka M, Yonezawa T, Miura Y, Yagasaki K. 2014. Daidzein promotes glucose uptake through glucose transporter 4 translocation to plasma membrane in L6 myocytes and improves glucose homeostasis in type 2 diabetic model mice. J. Nutr. Biochem. 25(2):136–143. doi:10.1016/j.jnutbio.2013.09.012.

Crovesy L, Masterson D, Rosado E. 2020. Profile of the gut microbiota of adults with obesity: A systematic review. Eur. J. Clin. Nutr. 74:1251–1262. doi:10.1038/s4143002006076.

Daina A, Michielin O, Zoete V. 2019. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res. 47(W1):W357–W364. doi:10.1093/nar/gkz382.

Das D, Sarkar S, Bordoloi J, Wann S, Kalita J, Manna P. 2018. Daidzein, its effects on impaired glucose and lipid metabolism and vascular inflammation associated with type 2 diabetes. BioFactors 44(5):407–417. doi:10.1002/biof.1439.

Doncheva N, Morris J, Gorodkin J, Jensen L. 2019. Cytoscape StringApp: Network analysis and visualization of proteomics data. J. Proteome Res. 18(2):623– 632. doi:10.1021/acs.jproteome.8b00702.

GaliciaGarcía U, BenitoVicente A, Jebari S, LarreaSebal A, Siddiqi H, Uribe K, Ostolaza H, Martín C. 2020. Pathophysiology of type 2 diabetes mellitus. Int. J. Mol. Sci. 21(17):6275. doi:10.3390/ijms21176275.

Hellmann J, Tang Y, Zhang M, Hai T, Bhatnagar A, Srivastava S, Spite M. 2015. Atf3 negatively regulates Ptgs2/Cox2 expression during acute inflammation. Prostaglandins Other Lipid Mediat. 116–117:49–56. doi:10.1016/j.prostaglandins.2015.01.001.

Hsieh P, Jin J, Chiang C, Chan P, Chen C, Shih K. 2009. COX2mediated inflammation in fat is crucial for obesitylinked insulin resistance and fatty liver. Obesity 17(6):1150–1157. doi:10.1038/oby.2008.674.

Huang X, Liu G, Guo J, Su Z. 2018. The PI3K/AKT pathway in obesity and type 2 diabetes. Int. J. Biol. Sci. 14(11):1483–1496. doi:10.7150/ijbs.27173.

Jandhyala S, Talukdar R, Subramanyam C, Vuyyuru H, Sasikala M, Reddy D. 2015. Role of the normal gut microbiota. World J. Gastroenterol. 21(29):8836– 8847. doi:10.3748/wjg.v21.i29.8787.

Kanehisa M, Furumichi M, Sato Y, Kawashima M, IshiguroWatanabe M. 2023. KEGG for taxonomybased analysis of pathways and genomes. Nucleic Acids Res. 51(D1):D587–D592. doi:10.1093/nar/gkac963.

Karunakaran U, Lee J, Elumalai S, Moon J, Won K. 2019. Myricetin prevents thapsigargininduced CDK5P66Shc signalosome mediated pancreatic β cell dysfunction. Free Radic. Biol. Med. 141:59–66. doi:10.1016/j.freeradbiomed.2019.05.038.

Kasai C, Sugimoto K, Moritani I, Tanaka J, Oya Y, Inoue H, Tameda M, Shiraki K, Ito M, Takei Y, et al. 2015. Comparison of the gut microbiota composition between obese and nonobese individuals in a Japanese population, as analyzed by terminal restriction fragment length polymorphism and nextgeneration sequencing. BMC Gastroenterol. 15(1):1– 10. doi:10.1186/s1287601503302.

Keiser M, Roth B, Armbruster B, Ernsberger P, Irwin J, Shoichet B. 2007. Relating protein pharmacology by ligand chemistry. Nat. Biotechnol. 25(2):197–206. doi:10.1038/nbt1284.

Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, Li Q, Shoemaker B, Thiessen P, Yu B, et al. 2023. PubChem 2023 update. Nucleic Acids Res. 51(D1):D1373– D1380. doi:10.1093/nar/gkac956.

Knekt P, Kumpulainen J, Järvinen R, Rissanen H, Heliövaara M, Reunanen A, Hakulinen T, Aromaa A. 2002. Flavonoid intake and risk of chronic diseases. Am. J. Clin. Nutr. 76(3):560–568. doi:10.1093/ajcn/76.3.560.

Kuleshov M, Jones M, Rouillard A, Fernandez N, Duan Q, Wang Z, Koplev S, Jenkins S, Jagodnik K, Lachmann A, et al. 2016. Enrichr: A comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 44(W1):W90–W97. doi:10.1093/nar/gkw377.

Kurniawan R, Taslim N, Hardinsyah H, Syauki A, Idris I, Aman A, Permatasari H, Wiyarta E, Surya R, Mayulu N, et al. 2024. Pharmacoinformatics and cellular studies of algal peptides as functional molecules to modulate type2 diabetes markers. Future Foods 9:100354. doi:10.1016/j.fufo.2024.100354.

Larsen N, Vogensen F, van den Berg F, Nielsen D, Andreasen A, Pedersen B, AlSoud W, Sørensen S, Hansen L, Jakobsen M. 2010. Gut microbiota in human adults with type 2 diabetes differs from nondiabetic adults. PLoS ONE 5(2):e9085. doi:10.1371/journal.pone.0009085.

Li L, Li C, Lv M, Hu Q, Guo L, Xiong D. 2020a. Correlation between alterations of gut microbiota and miR1225p expression in patients with type 2 diabetes mellitus. Ann. Transl. Med. 8(22):1481. doi:10.21037/atm206717.

Li Q, Chang Y, Zhang K, Chen H, Tao S, Zhang Z. 2020b. Implication of the gut microbiome composition of type 2 diabetic patients from Northern China. Sci. Rep. 10(1):1–8. doi:10.1038/s41598020622243.

Li X, Wang N, Yin B, Fang D, Jiang T, Fang S, Zhao J, Zhang H, Wang G, Chen W. 2016a. Effects of Lactobacillus plantarum CCFM0236 on hyperglycaemia and insulin resistance in highfat and streptozotocininduced type 2 diabetic mice. J. Appl. Microbiol. 121(6):1727–1736. doi:10.1111/jam.13276.

Li Y, Yao J, Han C, Yang J, Chaudhry M, Wang S, Liu H, Yin Y. 2016b. Quercetin, inflammation and immunity. Nutrients 8(3):167. doi:10.3390/nu8030167.

Li Z, Li Y, Overstreet J, Chung S, Niu A, Fan X, Wang S, Wang Y, Zhang MZ, Harris R. 2018. Inhibition of epidermal growth factor receptor activation is associated with improved diabetic nephropathy and insulin resistance in type 2 diabetes. Diabetes 67(9):1847–1857. doi:10.2337/db171513.

Liu T, Liu J, Hao L. 2021. Network pharmacological study and molecular docking analysis of Qiweitangping in treating diabetic coronary heart disease. Evid.Based Complement. Alternat. Med. p. 9925556. doi:10.1155/2021/9925556.

Liu Y, Grimm M, Dai W, Hou M, Xiao ZX, Cao Y. 2020. CBDock: a web server for cavity detectionguided protein–ligand blind docking. Acta Pharmacol. Sin. 41(1):138–144. doi:10.1038/s4140101902286.

Manaf A, Tjandrawinata R, Malinda D. 2016. Insulin sensitizer in prediabetes: A clinical study with DLBS3233, a combined bioactive fraction of Cinnamomum burmanii and Lagerstroemia speciosa. Drug Des. Devel. Ther. 10:1279–1289. doi:10.2147/DDDT.S97568.

MarínPeñalver J, MartínTimón I, SevillanoCollantes C, del CañizoGómez F. 2016. Update on the treatment of type 2 diabetes mellitus. World J. Diabetes 7(17):354–395. doi:10.4239/wjd.v7.i17.354.

Markosyan N, Li J, Sun Y, Richman L, Lin J, Yan F, Quinones L, Sela Y, Yamazoe T, Gordon N, et al. 2019. Tumor cell–intrinsic EPHA2 suppresses antitumor immunity by regulating PTGS2 (COX2). J. Clin. Invest. 129(9):3594–3609. doi:10.1172/JCI127755.

Miao R, Fang X, Wei J, Wu H, Wang X, Tian J. 2022. Akt: A potential drug target for metabolic syndrome. Front. Physiol. 13:822333. doi:10.3389/fphys.2022.822333.

Nailufar F, Tandrasasmita O, Tjandrawinata R. 2011. DLBS3233 increases glucose uptake by mediating upregulation of PPARγ and PPARδ expression. Bionut. 1(2):71–78. doi:10.1016/j.bionut.2010.12.002.

Oh KK, Choi I, Gupta H, Raja G, Sharma S, Won SM, Jeong JJ, Lee SB, Cha MG, Kwon GH, et al. 2022a. New insight into gut microbiotaderived metabolites to enhance liver regeneration via network pharmacology study. Artif. Cells Nanomed. Biotechnol. 51(1):1–12. doi:10.1080/21691401.2022.2155661.

Oh KK, Gupta H, Min BH, Ganesan R, Sharma S, Won SM, Jeong JJ, Lee SB, Cha MG, Kwon GH, et al. 2022b. Elucidation of prebiotics, probiotics, postbiotics, and target from gut microbiota to alleviate obesity via network pharmacology study. Cells 11(18):2903. doi:10.3390/cells11182903.

Oyedemi SO, Nwaogu G, Chukwuma CI, Adeyemi OT, Matsabisa MG, Swain SS, Aiyegoro OA. 2020. Quercetin modulates hyperglycemia by improving the pancreatic antioxidant status and enzymes activities linked with glucose metabolism in type 2 diabetes model of rats: In silico studies of molecular interaction of quercetin with hexokinase and catalase. J. Food Biochem. 44(2):e13127. doi:10.1111/jfbc.13127.

Panda S, Kar A. 2007. Apigenin (4‘,5,7 trihydroxyflavone) regulates hyperglycaemia, thyroid dysfunction and lipid peroxidation in alloxaninduced diabetic mice. J. Pharm. Pharmacol. 59(11):1543–1548. doi:10.1211/jpp.59.11.0012.

Parhofer KG. 2015. Interaction between glucose and lipid metabolism: More than diabetic dyslipidemia. Diabetes Metab. J. 39(5):353–362. doi:10.4093/dmj.2015.39.5.353.

Park S, Zhang T, Kang S. 2023. Fecal microbiota composition, their interactions, and metagenome function in US adults with type 2 diabetes according to enterotypes. Int. J. Mol. Sci. 24(11):9533. doi:10.3390/ijms24119533.

Park SA, Choi MS, Cho SY, Seo JS, Jung UJ, Kim MJ, Sung MK, Park YB, Lee MK. 2006. Genistein and daidzein modulate hepatic glucose and lipid regulating enzyme activities in C57BL/KsJdb/db mice. Life Sci. 79(12):1207– 1213. doi:10.1016/j.lfs.2006.03.022.

Permadi W, Hestiantoro A, Ritonga MA, Ferrina AI, Iswari WA, Sumapraia K, Muharram R, Djuwantono T, Wiweko B, Tjandrawinata R. 2021. Administration of cinnamon and Lagersroemia speciosa extract on lipid profile of polycystic ovarian syndrome women with high body mass index. J. Hum. Reprod. Sci. 14(1):16. doi:10.4103/jhrs.JHRS_141_20.

Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. 2004. UCSF Chimera—A visualization system for exploratory research and analysis. J. Comput. Chem. 25(13):1605– 1612. doi:10.1002/jcc.20084.

Piñero J, Bravo À, QueraltRosinach N, GutiérrezSacristán A, DeuPons J, Centeno E, GarcíaGarcía J, Sanz F, Furlong LI. 2017. DisGeNET: A comprehensive platform integrating information on human diseaseassociated genes and variants. Nucleic Acids Res. 45(D1):D833–D839. doi:10.1093/nar/gkw943.

Piñero J, QueraltRosinach N, Bravo A, DeuPons J, BauerMehren A, Baron M, Sanz F, Furlong LI. 2015. DisGeNET: A discovery platform for the dynamical exploration of human diseases and their genes. Database p. bav028. doi:10.1093/database/bav028.

Piñero J, Saüch J, Sanz F, Furlong LI. 2021. The DisGeNET cytoscape app: Exploring and visualizing disease genomics data. Comput. Struct. Biotechnol. J. 19:2960–2967. doi:10.1016/j.csbj.2021.05.015.

Raimondi S, Roncaglia L, De Lucia M, Amaretti A, Leonardi A, Pagnoni UM, Rossi M. 2009. Bioconversion of soy isoflavones daidzin and daidzein by Bifidobacterium strains. Appl. Microbiol. Biotechnol. 81(5):943–950. doi:10.1007/s0025300817194.

Ramírez-Espinosa JJ, Saldaña-Ríos J, García-Jiménez S, Villalobos-Molina R, Ávila-Villarreal G, Rodríguez-Ocampo AN, Bernal-Fernández G, Estrada-Soto S. 2017. Chrysin induces antidiabetic, antidyslipidemic and antiinflammatory effects in athymic nude diabetic mice. Molecules 23(1):67. doi:10.3390/molecules23010067.

Ren B, Qin W, Wu F, Wang S, Pan C, Wang L, Zeng B, Ma S, Liang J. 2016. Apigenin and naringenin regulate glucose and lipid metabolism, and ameliorate vascular dysfunction in type 2 diabetic rats. Eur. J. Pharmacol. 773:13–23. doi:10.1016/j.ejphar.2016.01.002.

Rinninella E, Raoul P, Cintoni M, Franceschi F, Miggiano GAD, Gasbarrini A, Mele MC. 2019. What is the healthy gut microbiota composition? A changing ecosystem across age, environment, diet, and diseases. Microorganisms 7(1):14. doi:10.3390/microorganisms7010014.

Rooks MG, Garrett WS. 2016. Gut microbiota, metabolites and host immunity. Nat. Rev. Immunol. 16(6):341–352. doi:10.1038/nri.2016.42.

Rose PW, Prlić A, Altunkaya A, Bi C, Bradley AR, Christie CH, Costanzo LD, Duarte JM, Dutta S, Feng Z, et al. 2016. The RCSB Protein Data Bank: Integrative view of protein, gene and 3D structural information. Nucleic Acids Res. 45(D1):D271–D281. doi:10.1093/nar/gkw1000.

Safran M, Rosen N, Twik M, BarShir R, Stein TI, Dahary D, Fishilevich S, Lancet D. 2021. The GeneCards Suite. Practical Guide to Life Science Databases. Singapore: Springer Nature. p. 27–56. doi:10.1007/978 9811658129_2.

Sedighi M, Razavi S, Navab-Moghadam F, Khamseh ME, Alaei-Shahmiri F, Mehrtash A, Amirmozafari N. 2017. Comparison of gut microbiota in adult patients with type 2 diabetes and healthy individuals. Microb. Pathog. 111:362–369. doi:10.1016/j.micpath.2017.08.038.

Semwal DK, Semwal RB, Combrinck S, Viljoen A. 2016. Myricetin: A dietary molecule with diverse biological activities. Nutrients 8(2):90. doi:10.3390/nu8020090.

Sigismund S, Avanzato D, Lanzetti L. 2018. Emerging functions of the EGFR in cancer. Mol. Oncol. 12(1):3–20. doi:10.1002/18780261.12155.

Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, Stein T, Nudel R, Lieder I, Mazor Y, et al. 2016. The GeneCards Suite: From gene data mining to disease genome sequence analyses. Curr. Protoc. Bioinformatics 54:1.30.1–1.30.33. doi:10.1002/cpbi.5.

Tan S, Tjandrawinata R, Prasasty V. 2023a. Molecular mechanism of DLBS3233 bioactive fraction in type2 diabetes mellitus: Network pharmacology and docking study. Sains Malays. 52(12):3497–3509. doi:10.17576/jsm2023521212.

Tan S, Yulandi A, Tjandrawinata R. 2023b. Network pharmacology study of Phyllanthus niruri: Potential target proteins and their hepatoprotective activities. J. Appl. Pharm. Sci. 13(12):232–242. doi:10.7324/JAPS.2023.146937.

Tang D, Chen M, Huang X, Zhang G, Zeng L, Zhang G, Wu S, Wang Y. 2023. SRplot: A free online platform for data visualization and graphing. PLoS One 18(11):e0294236. doi:10.1371/journal.pone.0294236.

Tang Y, Li M, Wang J, Pan Y, Wu FX. 2015. CytoNCA: A cytoscape plugin for centrality analysis and evaluation of protein interaction networks. Biosystems 127:67–72. doi:10.1016/j.biosystems.2014.11.005.

Tao YW, Gu YL, Mao XQ, Zhang L, Pei YF. 2020. Effects of probiotics on type II diabetes mellitus: A metaanalysis. J. Transl. Med. 18(1):30. doi:10.1186/s12967020022132.

The UniProt Consortium. 2023. UniProt: The universal protein knowledgebase in 2023. Nucleic Acids Res. 51(D1):D523–D531. doi:10.1093/nar/gkac1052.

Tjandrawinata R. 2016. Patogenesis diabetes tipe 2: Resistensi insulin dan defisiensi insulin. URL https://www.researchgate.net/publication/292615802 _Patogenesis_Diabetes_Tipe_2_Resistensi_Insulin_ dan_Defisiensi_Insulin.

Tjandrawinata R, Suastika K, Nofiarny D. 2012. DLBS3233 extract, a novel insulin sensitizer with negligible risk of hypoglycemia: A phaseI study. Int. J. Diabetes Metab. 20(1):13–12. doi:10.1159/000497721.

Tjokroprawiro A, Murtiwi S, Tjandrawinata R. 2016. DLBS3233, a combined bioactive fraction of Cinnamomum burmanii and Lagerstroemia speciosa, in type2 diabetes mellitus patients inadequately controlled by metformin and other oral antidiabetic agents. J. Complement. Integr. Med. 13(4):413–420. doi:10.1515/jcim20160031.

Tonucci L, dos Santos K, de Oliveira L, Ribeiro S, Martino H. 2017. Clinical application of probiotics in type 2 diabetes mellitus: A randomized, doubleblind, placebocontrolled study. Clin. Nutr. 36(1):85–92. doi:10.1016/j.clnu.2015.11.011.

Trott O, Olson A. 2010. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31(2):455–461. doi:10.1002/jcc.21334.

Truebestein L, Hornegger H, Anrather D, Hartl M, Fleming K, Stariha J, Pardon E, Steyaert J, Burke J, Leonard T. 2021. Structure of autoinhibited Akt1 reveals mechanism of PIP3mediated activation. Proc. Natl. Acad. Sci. U. S. A. 118(33):e2101496118. doi:10.1073/pnas.2101496118.

Vallianou N, Kounatidis D, Tsilingiris D, Panagopoulos F, Christodoulatos G, Evangelopoulos A, Karampela I, Dalamaga M. 2023. The role of nextgeneration probiotics in obesity and obesityassociated disorders: Current knowledge and future perspectives. Int. J. Mol. Sci. 24(7):6755. doi:10.3390/ijms24076755.

Świderska E, Strycharz J, Wróblewski A, Szemraj J, Drzewoski J, Śliwińska A. 2020. Role of PI3K/AKT pathway in insulinmediated glucose uptake. Blood Glucose Levels. IntechOpen. chapter 3. URL https://www.intechopen.com/books/bloodglucosel evels/roleofpi3kaktpathwayininsulinmediated glucoseuptake.

Widjaja N, Agustina C, Felicia, Wijaya F, Limanjaya J, Yulandi A, Waturangi D, Simatupang S, Tan S, Tjandrawinata R. 2025. Gut microbiome in adult Asians with obesity, type 2 diabetes mellitus, and a combination of obesity and type 2 diabetes mellitus. Biomedicines Factors Health (BMFH) doi:10.12938/bmfh.2025001.

Wu X, Park S. 2022. Fecal bacterial community and metagenome function in Asians with type 2 diabetes, according to enterotypes. Biomedicines 10(11):2998. doi:10.3390/biomedicines10112998.

Wulandari A, Tandrasasmita O, Tjandrawinata R. 2016. Immunomodulatory and macrophage activating activity of Lactobacillus fermentum DLBSA204 in response to respiratory infection in a cellular model. Biotechnol. Res. Asia 13(3):1291–1302. doi:10.13005/bbra/2269.

Xie Z, Bailey A, Kuleshov M, Clarke D, Evangelista J, Jenkins S, Lachmann A, Wojciechowicz M, Kropiwnicki E, Jagodnik K, et al. 2021. Gene set knowledge discovery with Enrichr. Curr. Protoc. 1(3):e90. doi:10.1002/cpz1.90.

Zeng Z, Yuan Q, Yu R, Zhang J, Ma H, Chen S. 2019. Ameliorative effects of probiotic Lactobacillus paracasei NL41 on insulin sensitivity, oxidative stress, and betacell function in a type 2 diabetes mellitus rat model. Mol. Nutr. Food Res. 63(22):1900457. doi:10.1002/mnfr.201900457.

Zhang J, Wang S, Zeng Z, Qin Y, Shen Q, Li P. 2020. Antidiabetic effects of Bifidobacterium animalis 01 through improving hepatic insulin sensitivity in type 2 diabetic rat model. J. Funct. Foods 67:103843. doi:10.1016/j.jff.2020.103843.

DOI: https://doi.org/10.22146/ijbiotech.107382