# Exploring the gut microbiome and metabolomic interactions of antimetabolite drugs to optimize therapy **Authors:** Jingyang Chen, Yanan Wang, Lei Xu, Xiaona Li, Libo Zhao PMC · DOI: 10.1080/19490976.2026.2638009 · Gut Microbes · 2026-02-27 ## TL;DR This paper reviews how gut microbes interact with cancer drugs called antimetabolites, aiming to improve treatment outcomes by understanding these interactions. ## Contribution The paper provides a comprehensive framework for assessing chemotherapy-microbiota interactions and identifies potential microbial biomarkers. ## Key findings - Common antimetabolites affect gut microbial communities in complex ways. - Microbial biomarkers may predict treatment responses to antimetabolite drugs. - Advances in metagenomics and real-time monitoring are needed to optimize therapy. ## Abstract Antimetabolite drugs are cornerstones in treating various cancers and autoimmune diseases; however, their clinical utility is often hampered by systemic toxicity caused by drug-induced gut microbiota dysbiosis. Predicting patient responses remains a significant challenge. Several studies have highlighted the influence of gut microbiota on antimetabolite treatment outcomes, revealing complex bidirectional interactions between the drugs and microbial communities. This review synthesizes the effects of common antimetabolites (including 5-fluorouracil, methotrexate, gemcitabine, capecitabine, 6-mercaptopurine, and thioguanine) on gut microbial communities and outlines a framework (pharmacokinetics, endogenous metabolite production, immune modulation, and apoptotic pathway modulation) for assessing chemotherapy-microbiota interactions. Additionally, potential microbial biomarkers for predicting treatment responses and strategies for manipulating the gut microbiota to enhance therapeutic efficacy are discussed. Therefore, advances in methodologies such as metagenomics and real-time microbial monitoring will be essential for unraveling these interactions and promoting the precise application of antimetabolite drugs. ## Linked entities - **Chemicals:** 5-fluorouracil (PubChem CID 3385), methotrexate (PubChem CID 4112), gemcitabine (PubChem CID 60750), capecitabine (PubChem CID 60953), 6-mercaptopurine (PubChem CID 667490), thioguanine (PubChem CID 2723601) - **Diseases:** cancer (MONDO:0004992) ## Full-text entities - **Genes:** DCK (deoxycytidine kinase) [NCBI Gene 1633], IL17A (interleukin 17A) [NCBI Gene 3605] {aka CTLA-8, CTLA8, IL-17, IL-17A, IL17, ILA17}, IL22 (interleukin 22) [NCBI Gene 50616] {aka IL-21, IL-22, IL-D110, IL-TIF, ILTIF, TIFIL-23}, TRNG (tRNA-Gly) [NCBI Gene 4563] {aka MTTG}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, TLR4 (toll like receptor 4) [NCBI Gene 7099] {aka ARMD10, CD284, TLR-4, TOLL}, MYC (MYC proto-oncogene, bHLH transcription factor) [NCBI Gene 4609] {aka MRTL, MYCC, bHLHe39, c-Myc}, LPAR2 (lysophosphatidic acid receptor 2) [NCBI Gene 9170] {aka EDG-4, EDG4, LPA-2, LPA2}, TK1 (thymidine kinase 1) [NCBI Gene 7083], FPGS (folylpolyglutamate synthase) [NCBI Gene 2356], MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, CASP8 (caspase 8) [NCBI Gene 841] {aka ALPS2B, CAP4, Casp-8, FLICE, MACH, MCH5}, TLR2 (toll like receptor 2) [NCBI Gene 7097] {aka CD282, TIL4}, TIMP1 (TIMP metallopeptidase inhibitor 1) [NCBI Gene 7076] {aka CLGI, EPA, EPO, HCI, TIMP, TIMP-1}, STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] {aka ADMIO, ADMIO1, APRF, HIES}, SLC46A1 (solute carrier family 46 member 1) [NCBI Gene 113235] {aka G21, HCP1, HsPCFT, PCFT, hPCFT}, PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 5295] {aka AGM7, GRB1, IMD36, p85, p85-ALPHA, p85alpha}, FOS (Fos proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 2353] {aka AP-1, C-FOS, p55}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, NLRP3 (NLR family pyrin domain containing 3) [NCBI Gene 114548] {aka AGTAVPRL, AII, AVP, C1orf7, CIAS1, CLR1.1}, IL10 (interleukin 10) [NCBI Gene 3586] {aka CSIF, GVHDS, IL-10, IL10A, TGIF}, PRKN (parkin RBR E3 ubiquitin protein ligase) [NCBI Gene 5071] {aka AR-JP, LPRS2, PARK2, PDJ}, TYMS (thymidylate synthetase) [NCBI Gene 7298] {aka DKCD, HST422, TMS, TS}, NOD1 (nucleotide binding oligomerization domain containing 1) [NCBI Gene 10392] {aka CARD4, CLR7.1, NLRC1, hNod1}, BCRP1 (BCR pseudogene 1) [NCBI Gene 644079] {aka BCR-1}, ABCA4 (ATP binding cassette subfamily A member 4) [NCBI Gene 24] {aka ABC10, ABCR, ARMD2, CORD3, FFM, RMP}, thymidylate synthase [NCBI Gene 29414528], hypoxanthine phosphoribosyltransferase [NCBI Gene 29416373], DPYD (dihydropyrimidine dehydrogenase) [NCBI Gene 1806] {aka DHP, DHPDHASE, DPD, DYPD}, TTR (transthyretin) [NCBI Gene 7276] {aka AMYLD1, ATTR, CTS, CTS1, HEL111, HsT2651}, CYP26B1 (cytochrome P450 family 26 subfamily B member 1) [NCBI Gene 56603] {aka CYP26A2, P450RAI-2, P450RAI2, RHFCA}, HPRT1 (hypoxanthine phosphoribosyltransferase 1) [NCBI Gene 3251] {aka HGPRT, HPRT}, AHR (aryl hydrocarbon receptor) [NCBI Gene 196] {aka FVH3, RP85, bHLHe76}, ABCC2 (ATP binding cassette subfamily C member 2) [NCBI Gene 1244] {aka ABC30, CMOAT, DJS, MRP2, cMRP}, PINK1 (PTEN induced kinase 1) [NCBI Gene 65018] {aka BRPK, PARK6}, MYLK3 (myosin light chain kinase 3) [NCBI Gene 91807] {aka MLCK, MLCK2, caMLCK}, NOD2 (nucleotide binding oligomerization domain containing 2) [NCBI Gene 64127] {aka ACUG, BLAU, BLAUS, CARD15, CD, CLR16.3}, AOX3P (aldehyde oxidase 3, pseudogene) [NCBI Gene 107126360] {aka AOH1, AOX3}, ABCC10 (ATP binding cassette subfamily C member 10) [NCBI Gene 89845] {aka EST182763, MRP7, SIMRP7}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, UPP1 (uridine phosphorylase 1) [NCBI Gene 7378] {aka UDRPASE, UP, UPASE, UPP}, FOXM1 (forkhead box M1) [NCBI Gene 2305] {aka FKHL16, FOXM1A, FOXM1B, FOXM1C, HFH-11, HFH11}, DPYS (dihydropyrimidinase) [NCBI Gene 1807] {aka DHP, DHPase}, PGR (progesterone receptor) [NCBI Gene 5241] {aka NR3C3, PR}, FOXP3 (forkhead box P3) [NCBI Gene 50943] {aka AIID, DIETER, IPEX, JM2, PIDX, XPID}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, CASP3 (caspase 3) [NCBI Gene 836] {aka CPP32, CPP32B, SCA-1}, NPPA (natriuretic peptide A) [NCBI Gene 4878] {aka ANF, ANP, ATFB6, ATRST2, CDD, CDD-ANF}, ATN1 (atrophin 1) [NCBI Gene 1822] {aka B37, CHEDDA, D12S755E, DRPLA, HRS, NOD}, NLRP7 (NLR family pyrin domain containing 7) [NCBI Gene 199713] {aka CLR19.4, HYDM, NALP7, NOD12, OZEMA25, PAN7}, FOXO3 (forkhead box O3) [NCBI Gene 2309] {aka AF6q21, FKHRL1, FKHRL1P2, FOXO2, FOXO3A}, XDH (xanthine dehydrogenase) [NCBI Gene 7498] {aka XAN1, XDH/XO, XO, XOR}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, CD274 (CD274 molecule) [NCBI Gene 29126] {aka ADMIO5, B7-H, B7H1, PD-L1, PDCD1L1, PDCD1LG1}, CCNE1 (cyclin E1) [NCBI Gene 898] {aka CCNE, pCCNE1}, MYD88 (MYD88 innate immune signal transduction adaptor) [NCBI Gene 4615] {aka IMD68, MYD88D, WM1}, CCNA2 (cyclin A2) [NCBI Gene 890] {aka CCN1, CCNA}, ABCB1 (ATP binding cassette subfamily B member 1) [NCBI Gene 5243] {aka ABC20, CD243, CLCS, ENPAT, GP170, MDR1}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53} - **Diseases:** RA (MESH:D001172), PDAC (MESH:D021441), C. difficile infections (MESH:D003015), osteosarcoma (MESH:D012516), hepatic and renal dysfunction (MESH:D008107), inflammation (MESH:D007249), arthritis (MESH:D001168), leukemia (MESH:D007938), CRC (MESH:D015179), pancreatic cancer (MESH:D010190), FUMP (MESH:C538234), deficient (MESH:D007153), hand-foot syndrome (MESH:D060831), acute lymphoblastic leukemia (MESH:D054198), diabetes (MESH:D003920), gastrointestinal and cardiovascular toxicities (MESH:D005767), bone marrow suppression (MESH:D001855), dysbiosis (MESH:D064806), bacteremia (MESH:D016470), colitis (MESH:D003092), cancer (MESH:D009369), infection (MESH:D007239), gastrointestinal, bone marrow, cardiac, neurologic, renal, and hepatic toxicities (MESH:D000081003), advanced (MESH:D020178), neuroinflammation (MESH:D000090862), rectal cancer (MESH:D012004), cytotoxic (MESH:D064420), abdominal pain (MESH:D015746), autoimmune diseases (MESH:D001327), gastric cancer (MESH:D013274), mucosal damage (MESH:D052016), obese (MESH:D009765), breast cancer (MESH:D001943), IBD (MESH:D015212), irritable bowel syndrome (MESH:D043183), enteritis (MESH:D004751), gallbladder cancer (MESH:D005706), central nervous system lymphoma (MESH:D008223), TGN (MESH:C566309), diarrhea (MESH:D003967), allergies (MESH:D004342), liver injury (MESH:D017093), ovarian, bladder, non-small cell lung, pancreatic, and breast cancer (MESH:D010051), DILI (MESH:D056486), DR (MESH:D002313), psoriasis (MESH:D011565), intestinal and liver damage (MESH:D007410), esophageal cancer (MESH:D004938), cardiotoxic (MESH:D066126), AOS (MESH:C535741), SAM dysregulation (MESH:D021081), psoriatic arthritis (MESH:D015535), choriocarcinoma (MESH:D002822), vomiting (MESH:D014839), febrile neutropenia (MESH:D064147), bladder cancer (MESH:D001749), overdose (MESH:D062787), ulcerative colitis (MESH:D003093) - **Chemicals:** 5-hydroxyindole-3-acetic acid (MESH:D006897), Curcumin (MESH:D003474), FOLFOX (MESH:C410216), bile acid (MESH:D001647), DCA (MESH:D003840), 6-thioinosine-monophosphate (-), cisplatin (MESH:D002945), 2, 4-diamino-N-10-methylpteroic acid (MESH:C000203), adenosine (MESH:D000241), heptose (MESH:D006539), 6-TX (MESH:C054700), indole-3-lactic acid (MESH:C024139), 6-methylmercaptopurine (MESH:C010240), TG (MESH:D013866), CHP (MESH:C048279), oligosaccharides (MESH:D009844), salt (MESH:D012492), paclitaxel (MESH:D017239), saikosaponin-A (MESH:C025759), amino acid (MESH:D000596), uracil (MESH:D014498), Cryptotanshinone (MESH:C037886), Butyrate (MESH:D002087), Polysaccharides (MESH:D011134), Capecitabine (MESH:D000069287), lactic acid (MESH:D019344), L-aspartic acid (MESH:D001224), Queuosine (MESH:D009704), guanine (MESH:D006147), 6-MP (MESH:D015122), deoxycytidine triphosphate (MESH:C024107), selenium (MESH:D012643), carbohydrate (MESH:D002241), 2',2'-difluorodeoxyuridine (MESH:C084565), fatty acid (MESH:D005227), arginine (MESH:D001120), UroA (MESH:C026423), dTMP (MESH:D013938), IPA (MESH:C015292), AZA (MESH:D001379), ribonucleotide (MESH:D012265), starch (MESH:D013213), propionate (MESH:D011422), fructo-oligosaccharide (MESH:C116580), 6-thioguanine nucleotide (MESH:C003964), prebiotics (MESH:D056692), gemcitabine triphosphate (MESH:C533693), MTX (MESH:D008727), 5-fluorouridine monophosphate (MESH:C016462), sodium butyrate (MESH:D020148), GLN (MESH:D005973), cytarabine (MESH:D003561), pyrimidines (MESH:D011743), L-valine (MESH:D014633), polyamine (MESH:D011073), alpha-fluoro-beta-ureidopropionic acid (MESH:C045635), RA (MESH:D011883), ampicillin (MESH:D000667), phospholipid (MESH:D010743), ATP (MESH:D000255) - **Species:** Streptococcus (genus) [taxon 1301], Anaerostipes hadrus (species) [taxon 649756], Bifidobacterium longum (species) [taxon 216816], Akkermansia muciniphila (species) [taxon 239935], Weissella paramesenteroides (species) [taxon 1249], Desulfovibrio desulfuricans (species) [taxon 876], Burkholderiales (order) [taxon 80840], Mesomycoplasma hyorhinis (species) [taxon 2100], Escherichia coli (E. coli, species) [taxon 562], Blautia wexlerae (species) [taxon 418240], Bacillus subtilis (species) [taxon 1423], Bacteria Latreille et al. 1825 (Bacteria stick insect, genus) [taxon 629395], Mus musculus (house mouse, species) [taxon 10090], Aerococcus (genus) [taxon 1375], Caenorhabditis elegans (species) [taxon 6239], Lactobacillales (order) [taxon 186826], Segatella copri (species) [taxon 165179], Bacteroides fragilis (species) [taxon 817], Alistipes (genus) [taxon 239759], Rattus norvegicus (brown rat, species) [taxon 10116], Saccharomyces cerevisiae (baker's yeast, species) [taxon 4932], Homo sapiens (human, species) [taxon 9606], Lacticaseibacillus rhamnosus (species) [taxon 47715], Saccharomyces boulardii [taxon 252598], Shigella (genus) [taxon 620], Enterococcus faecalis (species) [taxon 1351], Bacillota (clostridial firmicutes, phylum) [taxon 1239], Tobamovirus (genus) [taxon 12234], Cucumovirus (genus) [taxon 12304], Fusobacterium nucleatum (species) [taxon 851], Parabacteroides distasonis (species) [taxon 823], Pseudomonadota (proteobacteria, phylum) [taxon 1224], Collinsella aerofaciens (species) [taxon 74426], Paraprevotella (genus) [taxon 577309], Enterococcus faecium (species) [taxon 1352], Trichovirus (genus) [taxon 40276], Clostridium butyricum (species) [taxon 1492], Salvia miltiorrhiza (Chinese salvia, species) [taxon 226208], Phocaeicola vulgatus (species) [taxon 821], Bacteroidia (class) [taxon 200643], Clostridia (class) [taxon 186801], Bacteroides thetaiotaomicron (species) [taxon 818], Lactiplantibacillus plantarum (species) [taxon 1590], gut metagenome (species) [taxon 749906], Ruminococcus (genus) [taxon 1263], Bacilli (class) [taxon 91061], Lactobacillus acidophilus (species) [taxon 1579], Poria (genus) [taxon 87367], Limosilactobacillus reuteri (species) [taxon 1598] - **Mutations:** G12D - **Cell lines:** HCT-116/BR — Homo sapiens (Human), Colon carcinoma, Cancer cell line (CVCL_0291) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12959226/full.md ## Figures 6 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12959226/full.md ## References 228 references — full list in the complete paper: https://tomesphere.com/paper/PMC12959226/full.md --- Source: https://tomesphere.com/paper/PMC12959226