Microbiome as a predictive biomarker in locally advanced rectal cancer

Abstract

The incidence of locally advanced rectal cancer (LARC) among young people is rising alarmingly. In recent years, new protocols have been introduced for the management of LARC, some of which are associated with the risk of significant toxicity. Despite these advancements, robust predictive biomarkers for LARC have yet to be established. The microbiome has emerged as a potential biomarker due to its interaction with tumor multiomics. This article provides a critical overview of the current evidence on the microbiome and LARC, including its relationship with the immune system and epigenomics, and also highlights both the current limitations and future perspectives in the field.

Keywords

Microbiome / locally advanced rectal cancer / epigenomics / exposome / Fusobacterium nucleatum

References

[1] Morgan E,Gini A.Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN.Gut2023;72:338-44

[2] Fearon ER.A genetic model for colorectal tumorigenesis.Cell1990;61:759-67

[3] Botteri E,Berstad P.Lifestyle changes in middle age and risk of cancer: evidence from the European Prospective Investigation into Cancer and Nutrition.Eur J Epidemiol2024;39:147-59

[4] Seethaler B,Basrai M.Short-chain fatty acids are key mediators of the favorable effects of the Mediterranean diet on intestinal barrier integrity: data from the randomized controlled LIBRE trial.Am J Clin Nutr2022;116:928-42

[5] Cheng E,Ma C.Diet- and lifestyle-based prediction models to estimate cancer recurrence and death in patients with stage III colon cancer (CALGB 89803/Alliance).J Clin Oncol2022;40:740-51 PMCID:PMC8887946

[6] Mehta RS,Cao Y.Association of dietary patterns with risk of colorectal cancer subtypes classified by Fusobacterium nucleatum in tumor tissue.JAMA Oncol2017;3:921-7 PMCID:PMC5502000

[7] Wang K,Mehta RS.An empirical dietary pattern associated with the gut microbial features in relation to colorectal cancer risk.Gastroenterology2024;167:1371-83.e4

[8] Papier K,Balkwill A.Diet-wide analyses for risk of colorectal cancer: prospective study of 12,251 incident cases among 542,778 women in the UK.Nat Commun2025;16:375 PMCID:PMC11711514

[9] Papadimitriou N,Tsilidis KK.Identifying metabolomic mediators of the physical activity and colorectal cancer relationship. Cancer Epidemiol Biomarkers Prev. 2025.

[10] Jiang F,Sun J.Impact of ambient air pollution on colorectal cancer risk and survival: insights from a prospective cohort and epigenetic Mendelian randomization study.EBioMedicine2024;103:105126 PMCID:PMC11035091

[11] Bruno A,Milillo C.Orally ingested micro- and nano-plastics: a hidden driver of inflammatory bowel disease and colorectal cancer.Cancers2024;16:3079 PMCID:PMC11393928

[12] Stein MJ,Bohmann P.Diurnal timing of physical activity and risk of colorectal cancer in the UK Biobank.BMC Med2024;22:399 PMCID:PMC11409794

[13] Ogino S.Abstract IA019: molecular pathological epidemiology of tumor microbiota and immunity can give etiologic insights.Cancer Res2022;82:IA019

[14] Akimoto N,Zhong R.Rising incidence of early-onset colorectal cancer - a call to action.Nat Rev Clin Oncol2021;18:230-43 PMCID:PMC7994182

[15] Spaander MCW,Syngal S.Young-onset colorectal cancer.Nat Rev Dis Primers2023;9:21 PMCID:PMC10589420

[16] Capdevila J,Guillot M.SEOM-GEMCAD-TTD clinical guidelines for localized rectal cancer (2021).Clin Transl Oncol2022;24:646-57 PMCID:PMC8986677

[17] Cheng F,Sun C.Oxaliplatin-induced peripheral neurotoxicity in colorectal cancer patients: mechanisms, pharmacokinetics and strategies.Front Pharmacol2023;14:1231401 PMCID:PMC10427877

[18] van der Valk MJM, Hilling DE, Bastiaannet E, et al; IWWD Consortium. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study.Lancet2018;391:2537-45

[19] Zwart WH,Hospers GAP,Garcia-Aguilar J.The multimodal management of locally advanced rectal cancer: making sense of the new data.Am Soc Clin Oncol Educ Book2022;42:1-14

[20] Fokas E, Ströbel P, Fietkau R, et al; German Rectal Cancer Study Group. Tumor regression grading after preoperative chemoradiotherapy as a prognostic factor and individual-level surrogate for disease-free survival in rectal cancer. J Natl Cancer Inst. 2017;109:djx095.

[21] Cercek A,Strombom P.Adoption of total neoadjuvant therapy for locally advanced rectal cancer.JAMA Oncol2018;4:e180071 PMCID:PMC5885165

[22] Thomas AM,Asnicar F.Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation.Nat Med2019;25:667-78 PMCID:PMC9533319

[23] Wirbel J,Kartal E.Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer.Nat Med2019;25:679-89 PMCID:PMC7984229

[24] Serna G,Hernando J.Fusobacterium nucleatum persistence and risk of recurrence after preoperative treatment in locally advanced rectal cancer.Ann Oncol2020;31:1366-75 PMCID:PMC7542577

[25] Gur C,Isaacson B.Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack.Immunity2015;42:344-55 PMCID:PMC4361732

[26] Gur C,Shhadeh A.Fusobacterium nucleatum supresses anti-tumor immunity by activating CEACAM1.Oncoimmunology2019;8:e1581531 PMCID:PMC6492956

[27] Chen T,Zhang X.TOX expression decreases with progression of colorectal cancers and is associated with CD4 T-cell density and Fusobacterium nucleatum infection.Hum Pathol2018;79:93-101

[28] Wang X,Liang W.Fusobacterium nucleatum facilitates anti-PD-1 therapy in microsatellite stable colorectal cancer.Cancer Cell2024;42:1729-46.e8

[29] Mima K,Qian ZR.Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis.Gut2016;65:1973-80 PMCID:PMC4769120

[30] Vicente-Valor J,Paz-Cabezas M.Fecal microbiota strongly correlates with tissue microbiota composition in colorectal cancer but not in non-small cell lung cancer.Int J Mol Sci2025;26:717 PMCID:PMC11766298

[31] Valciukiene J,Poskus T.Tissue vs. fecal-derived bacterial dysbiosis in precancerous colorectal lesions: a systematic review.Cancers2023;15:1602 PMCID:PMC10000868

[32] Tesolato S,Gómez-Garre D.Gut microbiota profiles in feces and paired tumor and non-tumor tissues from colorectal cancer patients. Relationship to the body mass index.PLoS One2023;18:e0292551 PMCID:PMC10553240

[33] Yang Y,Peng J.Fusobacterium nucleatum increases proliferation of colorectal cancer cells and tumor development in mice by activating Toll-like receptor 4 signaling to nuclear factor-κB, and up-regulating expression of microRNA-21.Gastroenterology2017;152:851-66.e24 PMCID:PMC5555435

[34] Rubinstein MR,Liu W,Cai G.Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin.Cell Host Microbe2013;14:195-206 PMCID:PMC3770529

[35] Rubinstein MR,Lagana SM.Fusobacterium nucleatum promotes colorectal cancer by inducing Wnt/β-catenin modulator Annexin A1.EMBO Rep2019;20:e47638 PMCID:PMC6446206

[36] Derosa L,Silva CAC.Custom scoring based on ecological topology of gut microbiota associated with cancer immunotherapy outcome.Cell2024;187:3373-89.e16

[37] Sivan A,Hubert N.Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy.Science2015;350:1084-9 PMCID:PMC4873287

[38] Bender MJ,Phelps CM.Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment.Cell2023;186:1846-62.e26 PMCID:PMC10148916

[39] Daillère R,Waldschmitt N.Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects.Immunity2016;45:931-43

[40] Szallasi Z,Sztupinszki Z.Are tumor-associated carbohydrates the missing link between the gut microbiome and response to immune checkpoint inhibitor treatment in cancer?.Oncoimmunology2024;13:2324493 PMCID:PMC10913702

[41] Park JS,Wu M.Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance.Nature2023;617:377-85 PMCID:PMC10219577

[42] Fidelle M,Alves Costa Silva C.A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers.Science2023;380:eabo2296

[43] Cremonesi E,Garzon JFG.Gut microbiota modulate T cell trafficking into human colorectal cancer.Gut2018;67:1984-94

[44] Ebert MP,Balluff B.TFAP2E-DKK4 and chemoresistance in colorectal cancer.N Engl J Med2012;366:44-53

[45] Jensen GL,Volz M.Improved pathologic response to chemoradiation in MGMT methylated locally advanced rectal cancer.Clin Transl Radiat Oncol2023;42:100667 PMCID:PMC10406619

[46] Mima K,Qian ZR.Tumor LINE-1 methylation level and colorectal cancer location in relation to patient survival.Oncotarget2016;7:55098-109 PMCID:PMC5342404

[47] Del Re B, Giorgi G. Long INterspersed element-1 mobility as a sensor of environmental stresses.Environ Mol Mutagen2020;61:465-93

[48] Tsang JS,Sharaf O.Global DNA methylation is altered by neoadjuvant chemoradiotherapy in rectal cancer and may predict response to treatment - a pilot study.Eur J Surg Oncol2014;40:1459-66

[49] Meng X,Wang R.The prognostic role of EZH2 expression in rectal cancer patients treated with neoadjuvant chemoradiotherapy.Radiat Oncol2014;9:188 PMCID:PMC4163172

[50] Zouggar A,Benoit YD.Intestinal microbiota influences DNA methylome and susceptibility to colorectal cancer.Genes2020;11:808 PMCID:PMC7397125

[51] Ansari I,Gutekunst J.The microbiota programs DNA methylation to control intestinal homeostasis and inflammation.Nat Microbiol2020;5:610-9

[52] Kopp M,Steigleder M,Rychlik M.Development of stable isotope dilution assays for the quantitation of intra- and extracellular folate patterns of Bifidobacterium adolescentis.J Chromatogr A2016;1469:48-59

[53] Huang X,Xie W.Metagenomic analysis of intratumoral microbiome linking to response to neoadjuvant chemoradiotherapy in rectal cancer.Int J Radiat Oncol Biol Phys2023;117:1255-69

[54] Teng H,Sui X.Gut microbiota-mediated nucleotide synthesis attenuates the response to neoadjuvant chemoradiotherapy in rectal cancer.Cancer Cell2023;41:124-38.e6

[55] Kim MJ,Park JW.Gut microbiome associated with low anterior resection syndrome after rectal cancer surgery.Sci Rep2023;13:8578 PMCID:PMC10220038

[56] González-Mercado VJ,Penedo FJ.Gut microbiota perturbation is associated with acute sleep disturbance among rectal cancer patients.J Sleep Res2020;29:e12915 PMCID:PMC7644135

[57] White MG,Alshenaifi J.Young-onset rectal cancer: unique tumoral microbiome and correlation with response to neoadjuvant therapy.Ann Surg2023;278:538-48 PMCID:PMC10528779

[58] Yi Y,Shi W.Gut microbiome components predict response to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: a prospective, longitudinal study.Clin Cancer Res2021;27:1329-40

[59] Takenaka IKTM,Defelicibus A.Exome and tissue-associated microbiota as predictive markers of response to neoadjuvant treatment in locally advanced rectal cancer.Front Oncol2022;12:809441 PMCID:PMC8982181