Chemical Structure-based Graph Convolutional Model for Drug-Gut Microbiota Association Prediction

Abstract

The gut microbiota plays a crucial role in modulating drug metabolism, efficacy, and toxicity. However, experimental strategies heavily suffered from the technic challenges of the isolation and in vitro culture of individual microbiota species. Predicting gut microbiota-drug associations (GutMDA) is therefore essential for advancing microbiome-informed pharmacology. In this study, we proposed a graph convolutional network-based model GutMDA that utilizes chemical structure similarity for drug representation, and integrates gut microbiota and disease information to enable efficient and accurate prediction of drugmicrobiota associations. Benchmarking results on curated datasets show superior predictive performance compared to existing approaches. Additionally, the case studies showed that more than 90 percent of top 20 predicted associations have been validated experimentally in recent publications, which further demonstrates the accuracy of GutMDA. In a word, GutMDA provided an effective and interpretable tool for gut microbiotadrug associations prediction.

Keywords

Graph convolutional network / Gut microbiota / Drugmicrobiota association / Precision medicine

References

[1] ValdesA M, WalterJ, SegalE, SpectorT DBMJ, 2018, 361k2179

[2] ZhengS, ChangW, LiuW, LiangG, XuY, LinFJournal of Chemical Information and Modeling, 2019, 591215

[3] ZhangY, LiuX, LiF, YinJ, YangH, LiX, LiuX, ChaiX, NiuT, ZengS, JiaQ, ZhuFNucleic Acids Res., 2024, 52D1355

[4] FanH X, ShengS, ZhangFCNS Neurosci. Ther., 2022, 281675

[5] KimJ, LeeH KFront. Immunol., 2021, 12807648

[6] LibertucciJ, YoungV BNat. Microbiol., 2019, 435

[7] WeersmaR K, ZhernakovaA, FuJGut, 2020, 691510

[8] KlünemannM, AndrejevS, BlascheS, MateusA, PhapaleP, DevendranS, VappianiJ, SimonB, ScottT A, KafkiaENature, 2021, 597533

[9] ForslundK, HildebrandF, NielsenT, FalonyG, Le ChatelierE, SunagawaS, PriftiE, Vieira-SilvaS, GudmundsdottirV, Krogh PedersenHNature, 2015, 528262

[10] FreedbergD E, ToussaintN C, ChenS P, RatnerA J, WhittierS, WangT C, WangH H, AbramsJ AGastroenterology, 2015, 149883

[11] WangS, JuD, ZengXBiomedicines, 2024, 12194

[12] YinJ, ChenX, LiX, KangG, WangP, SongY, IjazU Z, YinH, HuangHFrontiers in Cellular and Infection Microbiology, 2022, 12920986

[13] KipfT N, WellingMarXiv e-prints, 2016

[14] ChenM, WeiZ, HuangZ, DingB, LiYSimple and Deep Graph Convolutional Networks, International Conference on Machine Learning, PMLR, 20201725

[15] ZhangS, TongH, XuJ, MaciejewskiRComputational Social Networks, 2019, 61

[16] YangH, DingY, TangJ, GuoFKnowledge-based Systems, 2022, 238107888

[17] LongY, WuM, KwohC K, LuoJ, LiXBioinformatics, 2020, 364918

[18] HitchingsR, KellyLTrends in Pharmacological Sciences, 2019, 40495

[19] ZimmermannM, Zimmermann-KogadeevaM, WegmannR, GoodmanA LScience, 2019, 363eaat9931

[20] TangJ, WuX, MouM, WangC, WangL, LiF, GuoM, YinJ, XieW, WangX, WangY, DingY, XueW, ZhuFNucleic Acids Research, 2021, 49D715

[21] HuaM, YuS, LiuT, YangX, WangHInterdiscip. Sci., 2022, 14669

[22] ZengX, YangX, FanJ, TanY, JuL, ShenW, WangY, WangX, ChenW, JuDNucleic Acids Research, 2021, 49D776

[23] SunY, ZhangD, CaiSFrontiers in Cellular and Infection Microbiology, 2018, 8424

[24] RajputA, ThakurA, SharmaS, KumarMNucleic Acids Res., 2018, 46D894

[25] AndersenP I, IanevskiA, LysvandH, VitkauskieneA, OksenychV, BjorasM, TellingK, LutsarI, DumpisU, IrieY, TensonT, KanteleA, KainovD EInt. J. Infect. Dis., 2020, 93268

[26] DavisA P, GrondinC J, JohnsonR J, SciakyD, WiegersJ, WiegersT C, MattinglyC JNucleic Acids Research, 2021, 49D1138

[27] LipscombC EBulletin of The Medical Library Association, 2000, 88265

[28] YaoG, ZhangW, YangM, YangH, WangJ, ZhangH, WeiL, XieZ, LiWGenomics, Proteomics & Bioinformatics, 2020, 18760

[29] NorouziM, FleetD J, SalakhutdinovR. Hamming Distance Metric Learning[C]. Proceedings of the 26th International Conference on Neural Information Processing Systems, 20121061

[30] ValdeolivasA, TichitL, NavarroC, PerrinS, OdelinG, LevyN, CauP, RemyE, BaudotABioinformatics, 2019, 35497

[31] GhulamA, LeiX, GuoM, BianCIEEE Access, 2020, 872021

[32] LiuT H, ZhangC Y, ZhangH, JinJ, LiX, LiangS Q, XueY Z, YuanF L, ZhouY H, BianX W, WeiHImeta, 2024, 3e199

[33] ZhouZ, ZhuoL, FuX, ZouQBriefings in Bioinformatics, 2024, 25bbad483

[34] TianZ, YuY, FangH, XieW, GuoMBrief. Bioinform., 2023, 24bbac634

[35] DengL, HuangY, LiuX, LiuHBioinformatics, 2022, 381118

[36] LiJ, MiaoB, WangS, DongW, XuH, SiC, WangW, DuanS, LouJ, BaoZBriefings in Bioinformatics, 2022, 23bbac261

[37] DiviccaroS, CioffiL, PiazzaR, CarusoD, MelcangiR C, GiattiSBiomolecules, 2023, 131325

[38] PryorR, NorvaisasP, MarinosG, BestL, ThingholmL B, QuintaneiroL M, De HaesW, EsserD, WaschinaS, LujanCCell, 2019, 1781299

[39] CuiJ, RameshG, WuM, JensenE T, CragoO, BertoniA G, GaoC, HoffmanK L, SheridanP A, WongK EDiabetes, 2022, 712438

[40] HuangY-H, WuY-H, TangH-Y, ChenS-T, WangC-C, HoW -J, LinY-H, LiuG-H, LinP-Y, LoC-JPharmaceutics, 2022, 141857

[41] MuellerN T, DifferdingM K, ZhangM, MaruthurN M, JuraschekS P, MillerE RIII, AppelL J, YehH-CDiabetes Care, 2021, 441462

[42] DikeochaI J, Al-KabsiA M, MiftahussururM, AlshawshM AThe FASEB Journal, 2022, 36e22350

[43] WangX, ZhangY, LiZ, DuanZ, GuoM, WangZ, ZhuF, XueWNucleic Acids Res., 2024, 52W272

[44] LiY, LiF, DuanZ, LiuR, JiaoW, WuH, ZhuF, XueWNucleic Acids Res., 2025, 53D595

[45] ZhengL, ShiS, LuM, FangP, PanZ, ZhangH, ZhouZ, ZhangH, MouM, HuangS, TaoL, XiaW, LiH, ZengZ, ZhangS, ChenY, LiZ, ZhuFGenome Biol., 2024, 2541

[46] SzklarczykD, KirschR, KoutrouliM, NastouK, MehryaryF, HachilifR, GableA L, FangT, DonchevaN T, PyysaloS, BorkP, JensenL J, von MeringCNucleic Acids Research, 2023, 51D638

[47] UniProtCNucleic Acids Research, 2023, 51D523

[48] KanehisaM, FurumichiM, SatoY, KawashimaM, Ishiguro-WatanabeMNucleic Acids Research, 2023, 51D587

[49] CaspiR, BillingtonR, KeselerI M, KothariA, KrummenackerM, MidfordP E, OngW K, PaleyS, SubhravetiP, KarpP DNucleic Acids Research, 2020, 48D445

[50] WuytsS, AlvesR, Zimmermann-KogadeevaM, NishijimaS, BlascheS, DriessenM, GeyerP E, HercogR, KartalE, MaierL, MullerJ B, Garcia SantamarinaS, SchmidtT S B, SevinD C, TelzerowA, TreitP V, WenzelT, TypasA, PatilK R, MannM, KuhnM, BorkPMolecular Systems Biology, 2023, 19e11525

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Jilin University, The Editorial Department of Chemical Research in Chinese Universities and Springer-Verlag GmbH