Disentangling the molecular mystery of tumour-microbiota interactions: Microbial metabolites

Abstract

	•Metabolites derived from both gut and intratumoural microbiota play important roles in cancer initiation and progression.
	•The dual roles of microbial metabolites pose an obstacle for clinical translations.
	•Absolute quantification and tracing techniques of microbial metabolites are essential for addressing the gaps in studies on microbial metabolites.
	•Integrating microbial metabolomics with multi-omics transcends current research paradigms.

Keywords

cancer / functional mechanisms / microbial metabolites / microbial metabolomics

References

[1] Park EM, Chelvanambi M, Bhutiani N, Kroemer G, Zitvogel L, Wargo JA. Targeting the gut and tumor microbiota in cancer. Nat Med. 2022;28(4):690-703.

[2] Danzi F, Pacchiana R, Mafficini A, et al. To metabolomics and beyond: a technological portfolio to investigate cancer metabolism. Signal Transduct Target Ther. 2023;8(1):137.

[3] Dizman N, Meza L, Bergerot P, et al. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat Med. 2022;28(4):704-712.

[4] Jiang SS, Xie YL, Xiao XY, et al. Fusobacterium nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer. Cell Host Microbe. 2023;31(5):781-797.e9.

[5] Cao Y, Oh J, Xue M, et al. Commensal microbiota from patients with inflammatory bowel disease produce genotoxic metabolites. Science. 2022;378(6618):eabm3233.

[6] Ma H, Yu Y, Wang M, et al. Correlation between microbes and colorectal cancer: tumor apoptosis is induced by sitosterols through promoting gut microbiota to produce short-chain fatty acids. Apoptosis: Int J Program Cell Death. 2019;24(1-2):168-183.

[7] Lavoie S, Chun E, Bae S, et al. Expression of free fatty acid receptor 2 by dendritic cells prevents their expression of interleukin 27 and is required for maintenance of mucosal barrier and immune response against colorectal tumors in mice. Gastroenterology. 2020;158(5):1359-1372.e9.

[8] Luu M, Riester Z, Baldrich A, et al. Microbial short-chain fatty acids modulate CD8(+) T cell responses and improve adoptive immunotherapy for cancer. Nat Commun. 2021;12(1):4077.

[9] Zagato E, Pozzi C, Bertocchi A, et al. Endogenous murine microbiota member Faecalibaculum rodentium and its human homologue protect from intestinal tumour growth. Nat Microbiol. 2020;5(3):511-524.

[10] Sawa H, Murakami H, Ohshima Y, et al. Histone deacetylase inhibitors such as sodium butyrate and trichostatin A inhibit vascular endothelial growth factor (VEGF) secretion from human glioblastoma cells. Brain Tumor Pathol. 2002;19(2):77-81.

[11] Xiao T, Wu S, Yan C, et al. Butyrate upregulates the TLR4 expression and the phosphorylation of MAPKs and NK-κB in colon cancer cell in vitro. Oncol Lett. 2018;16(4):4439-4447.

[12] Encarnação JC, Pires AS, Amaral RA, et al. Butyrate, a dietary fiber derivative that improves irinotecan effect in colon cancer cells. J Nutr Biochem. 2018;56:183-192.

[13] Garavaglia B, Vallino L, Ferraresi A, et al. Butyrate inhibits colorectal cancer cell proliferation through autophagy degradation of β-catenin regardless of APC and β-catenin mutational status. Biomedicines. 2022;10(5):1131.

[14] He Y, Ling Y, Zhang Z, et al. Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression. Redox Biol. 2023;65:102822.

[15] Zhu X, Li K, Liu G, et al. Microbial metabolite butyrate promotes anti-PD-1 antitumor efficacy by modulating T cell receptor signaling of cytotoxic CD8 T cell. Gut Microbes. 2023;15(2):2249143.

[16] Kang X, Liu C, Ding Y, et al. Roseburia intestinalis generated butyrate boosts anti-PD-1 efficacy in colorectal cancer by activating cytotoxic CD8(+) T cells. Gut. 2023;72(11):2112-2122.

[17] Lee SY, Jhun J, Woo JS, et al. Gut microbiome-derived butyrate inhibits the immunosuppressive factors PD-L1 and IL-10 in tumor-associated macrophages in gastric cancer. Gut Microbes. 2024;16(1):2300846.

[18] He Y, Fu L, Li Y, et al. Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8(+) T cell immunity. Cell Metab. 2021;33(5):988-1000.e7.

[19] Wang X, Fang Y, Liang W, et al. Fusobacterium nucleatum facilitates anti-PD-1 therapy in microsatellite stable colorectal cancer. Cancer Cell. 2024;42(10):1729-1746.e8.

[20] Hu C, Xu B, Wang X, et al. Gut microbiota-derived short-chain fatty acids regulate group 3 innate lymphoid cells in HCC. Hepatology (Baltimore, MD). 2023;77(1):48-64.

[21] Ye L, Hou Y, Hu W, et al. Repressed Blautia-acetate immunological axis underlies breast cancer progression promoted by chronic stress. Nat Commun. 2023;14(1):6160.

[22] Miller KD, O’Connor S, Pniewski KA, et al. Acetate acts as a metabolic immunomodulator by bolstering T-cell effector function and potentiating antitumor immunity in breast cancer. Nat Cancer. 2023;4(10):1491-1507.

[23] Ryu TY, Kim K, Han TS, et al. Human gut-microbiome-derived propionate coordinates proteasomal degradation via HECTD2 upregulation to target EHMT2 in colorectal cancer. ISME J. 2022;16(5):1205-1221.

[24] Thirunavukkarasan M, Wang C, Rao A, et al. Short-chain fatty acid receptors inhibit invasive phenotypes in breast cancer cells. PLoS One. 2017;12(10):e0186334.

[25] Chen W, Wen L, Bao Y, et al. Gut flora disequilibrium promotes the initiation of liver cancer by modulating tryptophan metabolism and up-regulating SREBP2. Proc Natl Acad Sci USA. 2022;119(52):e2203894119.

[26] Tintelnot J, Xu Y, Lesker TR, et al. Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. Nature. 2023;615(7950):168-174.

[27] Bender MJ, McPherson AC, Phelps CM, et al. Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment. Cell. 2023;186(9):1846-1862.e26.

[28] Fong W, Li Q, Ji F, et al. Lactobacillus gallinarum-derived metabolites boost anti-PD1 efficacy in colorectal cancer by inhibiting regulatory T cells through modulating IDO1/Kyn/AHR axis. Gut. 2023;72(12):2272-2285.

[29] Han J, Zhang S, Xu Y, et al. Beneficial effect of antibiotics and microbial metabolites on expanded Vδ2Vγ9 T cells in hepatocellular carcinoma immunotherapy. Front Immunol. 2020;11:1380.

[30] Jia D, Wang Q, Qi Y, et al. Microbial metabolite enhances immunotherapy efficacy by modulating T cell stemness in pan-cancer. Cell. 2024;187(7):1651-1665.e21.

[31] Han JX, Tao ZH, Wang JL, et al. Microbiota-derived tryptophan catabolites mediate the chemopreventive effects of statins on colorectal cancer. Nat Microbiol. 2023;8(5):919-933.

[32] Zhang Q, Zhao Q, Li T, et al. Lactobacillus plantarum-derived indole-3-lactic acid ameliorates colorectal tumorigenesis via epigenetic regulation of CD8(+) T cell immunity. Cell Metab. 2023;35(6):943-960.e9.

[33] Luu TH, Bard JM, Carbonnelle D, et al. Lithocholic bile acid inhibits lipogenesis and induces apoptosis in breast cancer cells. Cell Oncol (Dordrecht). 2018;41(1):13-24.

[34] Pyo JS, Ko YS, Kang G, et al. Bile acid induces MUC2 expression and inhibits tumor invasion in gastric carcinomas. J Cancer Res Clin Oncol. 2015;141(7):1181-1188.

[35] Lin R, Zhan M, Yang L, et al. Deoxycholic acid modulates the progression of gallbladder cancer through N(6)-methyladenosine-dependent microRNA maturation. Oncogene. 2020;39(26):4983-5000.

[36] Shah SA, Volkov Y, Arfin Q, Abdel-Latif MM, Kelleher D. Ursodeoxycholic acid inhibits interleukin 1 beta [corrected] and deoxycholic acid-induced activation of NF-kappaB and AP-1 in human colon cancer cells. Int J Cancer. 2006;118(3):532-539.

[37] Khare S, Mustafi R, Cerda S, et al. Ursodeoxycholic acid suppresses Cox-2 expression in colon cancer: roles of Ras, p38, and CCAAT/enhancer-binding protein. Nutr Cancer. 2008;60(3):389-400.

[38] Shen Y, Lu C, Song Z, et al. Ursodeoxycholic acid reduces antitumor immunosuppression by inducing CHIP-mediated TGF-β degradation. Nat Commun. 2022;13(1):3419.

[39] Mirji G, Worth A, Bhat SA, et al. The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer. Sci Immunol. 2022;7(75):eabn0704.

[40] Wang H, Rong X, Zhao G, et al. The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer. Cell Metab. 2022;34(4):581-594.e8.

[41] Mager LF, Burkhard R, Pett N, et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science. 2020;369(6510):1481-1489.

[42] Han S, Bao X, Zou Y, et al. D-lactate modulates M2 tumor-associated macrophages and remodels immunosuppressive tumor microenvironment for hepatocellular carcinoma. Sci Adv. 2023;9(29):eadg2697.

[43] Fan Q, Wu Y, Li M, et al. Lactobacillus spp. create a protective micro-ecological environment through regulating the core fucosylation of vaginal epithelial cells against cervical cancer. Cell Death Dis. 2021;12(12):1094.

[44] Totiger TM, Srinivasan S, Jala VR, et al. Urolithin A, a novel natural compound to target PI3K/AKT/mTOR pathway in pancreatic cancer. Mol Cancer Ther. 2019;18(2):301-311.

[45] Giménez-Bastida JA, Ávila-Gálvez M, Espín JC, González-Sarrías A. The gut microbiota metabolite urolithin A, but not other relevant urolithins, induces p53-dependent cellular senescence in human colon cancer cells. Food Chem Toxicol. 2020;139:111260.

[46] Denk D, Petrocelli V, Conche C, et al. Expansion of T memory stem cells with superior anti-tumor immunity by urolithin A-induced mitophagy. Immunity. 2022;55(11):2059-2073.e8.

[47] Matsushita M, Fujita K, Hayashi T, et al. Gut microbiota-derived short-chain fatty acids promote prostate cancer growth via IGF1 signaling. Cancer Res. 2021;81(15):4014-4026.

[48] Belcheva A, Irrazabal T, Robertson SJ, et al. Gut microbial metabolism drives transformation of MSH2-deficient colon epithelial cells. Cell. 2014;158(2):288-299.

[49] Okumura S, Konishi Y, Narukawa M, et al. Gut bacteria identified in colorectal cancer patients promote tumourigenesis via butyrate secretion. Nat Commun. 2021;12(1):5674.

[50] Ma Y, Chen H, Li H, et al. Intratumor microbiome-derived butyrate promotes lung cancer metastasis. Cell Rep Med. 2024;5(4):101488.

[51] Uribe-Herranz M, Rafail S, Beghi S, et al. Gut microbiota modulate dendritic cell antigen presentation and radiotherapy-induced antitumor immune response. J Clin Invest. 2020;130(1):466-479.

[52] Coutzac C, Jouniaux JM, Paci A, et al. Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer. Nat Commun. 2020;11(1):2168.

[53] Behary J, Amorim N, Jiang XT, et al. Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma. Nat Commun. 2021;12(1):187.

[54] Zhou P, Chang WY, Gong DA, et al. High dietary fructose promotes hepatocellular carcinoma progression by enhancing O-GlcNAcylation via microbiota-derived acetate. Cell Metab. 2023;35(11):1961-1975.e6.

[55] Gao X, Lin SH, Ren F, et al. Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia. Nat Commun. 2016;7:11960.

[56] Wang J, Yang Y, Shao F, et al. Acetate reprogrammes tumour metabolism and promotes PD-L1 expression and immune evasion by upregulating c-Myc. Nat Metab. 2024;6(5):914-932.

[57] Gomes AP, Ilter D, Low V, et al. Altered propionate metabolism contributes to tumour progression and aggressiveness. Nat Metab. 2022;4(4):435-443.

[58] Hezaveh K, Shinde RS, Klötgen A, et al. Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity. Immunity. 2022;55(2):324-340.e8.

[59] Cui W, Guo M, Liu D, et al. Gut microbial metabolite facilitates colorectal cancer development via ferroptosis inhibition. Nat Cell Biol. 2024;26:124-137.

[60] Ma C, Han M, Heinrich B, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018;360(6391):eaan5931.

[61] Nguyen TT, Lian S, Ung TT, Xia Y, Han JY, Jung YD. Lithocholic acid stimulates IL-8 expression in human colorectal cancer cells via activation of Erk1/2 MAPK and suppression of STAT3 activity. J Cell Biochem. 2017;118(9):2958-2967.

[62] Nguyen TT, Ung TT, Li S, et al. Lithocholic acid induces miR21, promoting PTEN inhibition via STAT3 and ERK-1/2 signaling in colorectal cancer cells. Int J Mol Sci. 2021;22(19):10209.

[63] Jenkins GJ, Cronin J, Alhamdani A, et al. The bile acid deoxycholic acid has a non-linear dose response for DNA damage and possibly NF-kappaB activation in oesophageal cells, with a mechanism of action involving ROS. Mutagenesis. 2008;23(5):399-405.

[64] Cong J, Liu P, Han Z, et al. Bile acids modified by the intestinal microbiota promote colorectal cancer growth by suppressing CD8(+) T cell effector functions. Immunity. 2024;57(4):876-889.e11.

[65] Song X, An Y, Chen D, et al. Microbial metabolite deoxycholic acid promotes vasculogenic mimicry formation in intestinal carcinogenesis. Cancer Sci. 2022;113(2):459-477.

[66] Eaton JE, Silveira MG, Pardi DS, et al. High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Am J Gastroenterol. 2011;106(9):1638-1645.

[67] Yang S, Dai H, Lu Y, Li R, Gao C, Pan S. Trimethylamine N-oxide promotes cell proliferation and angiogenesis in colorectal cancer. J Immunol Res. 2022;2022:7043856.

[68] Ternes D, Tsenkova M, Pozdeev VI, et al. The gut microbial metabolite formate exacerbates colorectal cancer progression. Nat Metab. 2022;4(4):458-475.

[69] Colbert LE, El Alam MB, Wang R, et al. Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring. Cancer Cell. 2023;41(11):1945-1962.e11.

[70] Eskra JN, Schlicht MJ, Bosland MC. Effects of black raspberries and their ellagic acid and anthocyanin constituents on taxane chemotherapy of castration-resistant prostate cancer cells. Sci Rep. 2019;9(1):4367.

[71] Ottman N, Davids M, Suarez-Diez M, et al. Genome-scale model and omics analysis of metabolic capacities of Akkermansia muciniphila reveal a preferential mucin-degrading lifestyle. Appl Environ Microbiol. 2017;83(18):e01014-e01017.

[72] Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell. 2016;165(6):1332-1345.

[73] Mann ER, Lam YK, Uhlig HH. Short-chain fatty acids: linking diet, the microbiome and immunity. Nat Rev Immunol. 2024;24(8):577-595.

[74] Wang T, Cai G, Qiu Y, et al. Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers. ISME J. 2012;6(2):320-9.

[75] Zhu W, Si Y, Xu J, et al. Methyltransferase like 3 promotes colorectal cancer proliferation by stabilizing CCNE1 mRNA in an m6A-dependent manner. J Cell Mol Med. 2020;24(6):3521-3533.

[76] Yu DC, Waby JS, Chirakkal H, Staton CA, Corfe BM. Butyrate suppresses expression of neuropilin I in colorectal cell lines through inhibition of Sp1 transactivation. Mol Cancer. 2010;9:276.

[77] Chen Y, Liu Y, Wang Y, et al. Prevotellaceae produces butyrate to alleviate PD-1/PD-L1 inhibitor-related cardiotoxicity via PPARα-CYP4×1 axis in colonic macrophages. J Exp Clin Cancer Res. 2022;41(1):1.

[78] Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883-899.

[79] Singh N, Gurav A, Sivaprakasam S, et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity. 2014;40(1):128-139.

[80] Furusawa Y, Obata Y, Fukuda S, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504(7480):446-450.

[81] Maslowski KM, Vieira AT, Ng A, et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009;461(7268):1282-1286.

[82] Guertin DA, Wellen KE. Acetyl-CoA metabolism in cancer. Nat Rev Cancer. 2023;23(3):156-172.

[83] Wang X, Cai Z, Wang Q, et al. Bacteroides methylmalonyl-CoA mutase produces propionate that promotes intestinal goblet cell differentiation and homeostasis. Cell Host Microbe. 2024;32(1):63-78.e7.

[84] Dupraz L, Magniez A, Rolhion N, et al. Gut microbiota-derived short-chain fatty acids regulate IL-17 production by mouse and human intestinal γδ T cells. Cell Rep. 2021;36(1):109332.

[85] He KY, Lei XY, Wu DH, et al. Akkermansia muciniphila protects the intestine from irradiation-induced injury by secretion of propionic acid. Gut Microbes. 2023;15(2):2293312.

[86] Agus A, Planchais J, Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe. 2018;23(6):716-724.

[87] Sári Z, Mikó E, Kovács T, et al. Indoxylsulfate, a metabolite of the microbiome, has cytostatic effects in breast cancer via activation of AHR and PXR receptors and induction of oxidative stress. Cancers. 2020;12(10):2915.

[88] Sári Z, Mikó E, Kovács T, et al. Indolepropionic acid, a metabolite of the microbiome, has cytostatic properties in breast cancer by activating AHR and PXR receptors and inducing oxidative stress. Cancers. 2020;12(9):2411.

[89] Collins SL, Stine JG, Bisanz JE, Okafor CD, Patterson AD. Bile acids and the gut microbiota: metabolic interactions and impacts on disease. Nat Rev Microbiol. 2023;21(4):236-247.

[90] Kim M, Vogtmann E, Ahlquist DA, et al. Fecal metabolomic signatures in colorectal adenoma patients are associated with gut microbiota and early events of colorectal cancer pathogenesis. mBio. 2020;11(1):e03186-e03219.

[91] Gao R, Wu C, Zhu Y, et al. Integrated analysis of colorectal cancer reveals cross-cohort gut microbial signatures and associated serum metabolites. Gastroenterology. 2022;163(4):1024-1037.e9.

[92] Jenkins GJ, D’Souza FR, Suzen SH, et al. Deoxycholic acid at neutral and acid pH, is genotoxic to oesophageal cells through the induction of ROS: the potential role of anti-oxidants in Barrett’s oesophagus. Carcinogenesis. 2007;28(1):136-142.

[93] Jin D, Huang K, Xu M, et al. Deoxycholic acid induces gastric intestinal metaplasia by activating STAT3 signaling and disturbing gastric bile acids metabolism and microbiota. Gut Microbes. 2022;14(1):2120744.

[94] Mao J, Chen X, Wang C, Li W, Li J. Effects and mechanism of the bile acid (farnesoid X) receptor on the Wnt/β-catenin signaling pathway in colon cancer. Oncol Lett. 2020;20(1):337-345.

[95] Wu J, Gong J, Geng J, Song Y. Deoxycholic acid induces the overexpression of intestinal mucin, MUC2, via NF-kB signaling pathway in human esophageal adenocarcinoma cells. BMC Cancer. 2008;8:333.

[96] Song S, Byrd JC, Koo JS, Bresalier RS. Bile acids induce MUC2 overexpression in human colon carcinoma cells. Cancer. 2005;103(8):1606-1614.

[97] Hang S, Paik D, Yao L, et al. Bile acid metabolites control T(H)17 and T(reg) cell differentiation. Nature. 2019;576(7785):143-148.

[98] Campbell C, McKenney PT, Konstantinovsky D, et al. Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells. Nature. 2020;581(7809):475-479.

[99] Mitsuyoshi H, Nakashima T, Sumida Y, et al. Ursodeoxycholic acid protects hepatocytes against oxidative injury via induction of antioxidants. Biochem Biophys Res Commun. 1999;263(2):537-542.

[100] Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472(7341):57-63.

[101] Bae S, Ulrich CM, Neuhouser ML, et al. Plasma choline metabolites and colorectal cancer risk in the Women’s Health Initiative Observational Study. Cancer Res. 2014;74(24):7442-752.

[102] Xu R, Wang Q, Li L. A genome-wide systems analysis reveals strong link between colorectal cancer and trimethylamine N-oxide (TMAO), a gut microbial metabolite of dietary meat and fat. BMC Genomics [Electron Resour]. 2015;16(suppl 7):S4.

[103] Yue C, Yang X, Li J, et al. Trimethylamine N-oxide prime NLRP3 inflammasome via inhibiting ATG16L1-induced autophagy in colonic epithelial cells. Biochem Biophys Res Commun. 2017;490(2):541-551.

[104] Lu Y, Yuan X, Wang M, et al. Gut microbiota influence immunotherapy responses: mechanisms and therapeutic strategies. J Hematol Oncol. 2022;15(1):47.

[105] Csóka B, Himer L, Selmeczy Z, et al. Adenosine A2A receptor activation inhibits T helper 1 and T helper 2 cell development and effector function. FASEB J. 2008;22(10):3491-3499.

[106] Pietzke M, Meiser J, Vazquez A. Formate metabolism in health and disease. Mol Metab. 2020;33:23-37.

[107] Delbrouck C, Kiweler N, Chen O, et al. Formate promotes invasion and metastasis in reliance on lipid metabolism. Cell Rep. 2023;42(9):113034.

[108] Xu J, Yang Y, Li X, et al. Pleiotropic activities of succinate: the interplay between gut microbiota and cardiovascular diseases. iMeta. 2023;2(3):e124.

[109] Abdelazeem KNM, Kalo MZ, Beer-Hammer S, Lang F. The gut microbiota metabolite urolithin A inhibits NF-κB activation in LPS stimulated BMDMs. Sci Rep. 2021;11(1):7117.

[110] Singh R, Chandrashekharappa S, Bodduluri SR, et al. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat Commun. 2019;10(1):89.

[111] Lv MY, Shi CJ, Pan FF, et al. Urolithin B suppresses tumor growth in hepatocellular carcinoma through inducing the inactivation of Wnt/β-catenin signaling. J Cell Biochem. 2019;120(10):17273-17282.

[112] Bell HN, Rebernick RJ, Goyert J, et al. Reuterin in the healthy gut microbiome suppresses colorectal cancer growth through altering redox balance. Cancer Cell. 2022;40(2):185-200.e6.

[113] Konishi H, Fujiya M, Tanaka H, et al. Probiotic-derived ferrichrome inhibits colon cancer progression via JNK-mediated apoptosis. Nat Commun. 2016;7:12365.

[114] Song W, Hu P, Guo S, et al. Oxidative stress and endoplasmic reticulum stress contribute to L. paracasei subsp. paracasei M5L exopolysaccharide-induced apoptosis in HT-29 cells. Food Sci Nutr. 2021;9(3):1676-1687.

[115] Liu JL, Xu X, Rixiati Y, et al. Dysfunctional circadian clock accelerates cancer metastasis by intestinal microbiota triggering accumulation of myeloid-derived suppressor cells. Cell Metab. 2024;36(6):1320-1334.e9.

[116] Ma Y, Chen H, Li H, et al. Intratumor microbiome-derived butyrate promotes lung cancer metastasis. Cell Rep Med. 2024;5(4):101488.

[117] Dai JH, Tan XR, Qiao H, Liu N. Emerging clinical relevance of microbiome in cancer: promising biomarkers and therapeutic targets. Protein Cell. 2024;15(4):239-260.

[118] Irajizad E, Kenney A, Tang T, et al. A blood-based metabolomic signature predictive of risk for pancreatic cancer. Cell Rep Med. 2023;4(9):101194.

[119] Chen F, Dai X, Zhou CC, et al. Integrated analysis of the faecal metagenome and serum metabolome reveals the role of gut microbiome-associated metabolites in the detection of colorectal cancer and adenoma. Gut. 2022;71(7):1315-1325.

[120] Sun Y, Zhang X, Hang D, et al. Integrative plasma and fecal metabolomics identify functional metabolites in adenoma-colorectal cancer progression and as early diagnostic biomarkers. Cancer Cell. 2024;42(8):1386-1400.e8.

[121] Coker OO, Liu C, Wu WKK, et al. Altered gut metabolites and microbiota interactions are implicated in colorectal carcinogenesis and can be non-invasive diagnostic biomarkers. Microbiome. 2022;10(1):35.

[122] Kong C, Liang L, Liu G, et al. Integrated metagenomic and metabolomic analysis reveals distinct gut-microbiome-derived phenotypes in early-onset colorectal cancer. Gut. 2023;72(6):1129-1142.

[123] Botticelli A, Vernocchi P, Marini F, et al. Gut metabolomics profiling of non-small cell lung cancer (NSCLC) patients under immunotherapy treatment. J Transl Med. 2020;18(1):49.

[124] Nomura M, Nagatomo R, Doi K, et al. Association of short-chain fatty acids in the gut microbiome with clinical response to treatment with nivolumab or pembrolizumab in patients with solid cancer tumors. JAMA Netw Open. 2020;3(4):e202895.

[125] Zhu C, Wang Y, Zhu R, et al. Gut microbiota and metabolites signatures of clinical response in anti-PD-1/PD-L1 based immunotherapy of biliary tract cancer. Biomark Res. 2024;12(1):56.

[126] Xie J, Liu M, Deng X, et al. Gut microbiota reshapes cancer immunotherapy efficacy: mechanisms and therapeutic strategies. Imeta. 2024;3(1):e156.

[127] Alexander JL, Posma JM, Scott A, et al. Pathobionts in the tumour microbiota predict survival following resection for colorectal cancer. Microbiome. 2023;11(1):100.

[128] Yang Y, Misra BB, Liang L, et al. Integrated microbiome and metabolome analysis reveals a novel interplay between commensal bacteria and metabolites in colorectal cancer. Theranostics. 2019;9(14):4101-4114.

[129] Dai JH, Tan XR, Qiao H, Liu N. Emerging clinical relevance of microbiome in cancer: promising biomarkers and therapeutic targets. Protein Cell. 2024;15(4):239-260.

[130] Chen L, Zhao R, Kang Z, et al. Delivery of short chain fatty acid butyrate to overcome Fusobacterium nucleatum-induced chemoresistance. J Control Release. 2023;363:43-56.

[131] Han K, Nam J, Xu J, et al. Generation of systemic antitumour immunity via the in situ modulation of the gut microbiome by an orally administered inulin gel. Nat Biomed Eng. 2021;5(11):1377-1388.

[132] Huang J, Liu D, Wang Y, et al. Ginseng polysaccharides alter the gut microbiota and kynurenine/tryptophan ratio, potentiating the antitumour effect of antiprogrammed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) immunotherapy. Gut. 2022;71(4):734-745.

[133] Singh V, Yeoh BS, Chassaing B, et al. Dysregulated microbial fermentation of soluble fiber induces cholestatic liver cancer. Cell. 2018;175(3):679-694.e22.

[134] Arifuzzaman M, Won TH, Li TT, et al. Inulin fibre promotes microbiota-derived bile acids and type 2 inflammation. Nature. 2022;611(7936):578-584.

[135] Spencer CN, McQuade JL, Gopalakrishnan V, et al. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science. 2021;374(6575):1632-1640.

[136] Yang J, Wei H, Lin Y, et al. High soluble fiber promotes colorectal tumorigenesis through modulating gut microbiota and metabolites in mice. Gastroenterology. 2024;166(2):323-337.e7.

[137] Lu YQ, Qiao H, Tan XR, Liu N. Broadening oncological boundaries: the intratumoral microbiota. Trends Microbiol. 2024;32(8):807-822.

[138] Ojala T, Häkkinen AE, Kankuri E, Kankainen M. Current concepts, advances, and challenges in deciphering the human microbiota with metatranscriptomics. Trends Genet. 2023;39(9):686-702.

[139] Wishart DS, Oler E, Peters H, et al. MiMeDB: the human microbial metabolome database. Nucleic Acids Res. 2023;51(D1):D611-D620.

[140] Yu G, Xu C, Zhang D, Ju F, Ni Y. MetOrigin: discriminating the origins of microbial metabolites for integrative analysis of the gut microbiome and metabolome. Imeta. 2022;1(1):e10.

[141] Zuffa S, Schmid R, Bauermeister A, et al. microbeMASST: a taxonomically informed mass spectrometry search tool for microbial metabolomics data. Nat Microbiol. 2024;9(2):336-345.

[142] Cheng L, Qi C, Yang H, et al. gutMGene: a comprehensive database for target genes of gut microbes and microbial metabolites. Nucleic Acids Res. 2022;50(D1):D795-D800.

[143] Han S, Van Treuren W, Fischer CR, et al. A metabolomics pipeline for the mechanistic interrogation of the gut microbiome. Nature. 2021;595(7867):415-420.

[144] Aksenov AA, da Silva R, Knight R, Lopes NP, Dorrestein PC. Global chemical analysis of biology by mass spectrometry. Nat Rev Chem. 2017;1(7):0054.

[145] Gentry EC, Collins SL, Panitchpakdi M, et al. Reverse metabolomics for the discovery of chemical structures from humans. Nature. 2024;626(7998):419-426.

[146] Deng Y, Yao Y, Wang Y, et al. An end-to-end deep learning method for mass spectrometry data analysis to reveal disease-specific metabolic profiles. Nat Commun. 2024;15(1):7136.

[147] Feng Y, Soni A, Brightwell G, et al. The potential new microbial hazard monitoring tool in food safety: integration of metabolomics and artificial intelligence. Trends Food Sci Technol. 2024;149:104555.

[148] Hernández Medina R, Kutuzova S, Nielsen KN, et al. Machine learning and deep learning applications in microbiome research. ISME Commun. 2022;2(1):98.

[149] Chen L, Zhernakova DV, Kurilshikov A, et al. Influence of the microbiome, diet and genetics on inter-individual variation in the human plasma metabolome. Nat Med. 2022;28(11):2333-2343.

[150] Tang W, Zheng H, Xu S, et al. MMINP: a computational framework of microbe-metabolite interactions-based metabolic profiles predictor based on the O2-PLS algorithm. Gut Microbes. 2023;15(1):2223349.

[151] Farr Zuend C, Lamont A, Noel-Romas L, et al. Increased genital mucosal cytokines in Canadian women associate with higher antigen-presenting cells, inflammatory metabolites, epithelial barrier disruption, and the depletion of L. crispatus. Microbiome. 2023;11(1):159.

[152] Jin C, Wu S, Liang Z, et al. Multi-omics reveal mechanisms of high enteral starch diet mediated colonic dysbiosis via microbiome-host interactions in young ruminant. Microbiome. 2024;12(1):38.

[153] Qu P, Rom O, Li K, et al. DT-109 ameliorates nonalcoholic steatohepatitis in nonhuman primates. Cell Metab. 2023;35(5):742-757.e10.

[154] Zeng X, Xing X, Gupta M, et al. Gut bacterial nutrient preferences quantified in vivo. Cell. 2022;185(18):3441-3456.e19.

[155] Bultman SJ. Molecular pathways: gene-environment interactions regulating dietary fiber induction of proliferation and apoptosis via butyrate for cancer prevention. Clin Cancer Res. 2014;20(4):799-803.

[156] Rodrigues LM, Uribe-Lewis S, Madhu B, Honess DJ, Stubbs M, Griffiths JR. The action of β-hydroxybutyrate on the growth, metabolism and global histone H3 acetylation of spontaneous mouse mammary tumours: evidence of a β-hydroxybutyrate paradox. Cancer Metab. 2017;5:4.

[157] Ye D, Li X, Shen J, Xia X. Microbial metabolomics: from novel technologies to diversified applications. TrAC Trends Anal Chem. 2022;148:116540.

[158] Maghini DG, Dvorak M, Dahlen A, et al. Quantifying bias introduced by sample collection in relative and absolute microbiome measurements. Nat Biotechnol. 2024;42(2):328-338.

[159] Xie G, Wang L, Chen T, et al. A metabolite array technology for precision medicine. Anal Chem. 2021;93(14):5709-5717.

[160] Li J, Chen Z, Wang Q, et al. Microbial and metabolic profiles unveil mutualistic microbe-microbe interaction in obesity-related colorectal cancer. Cell Rep Med. 2024;5(3):101429.

[161] Fu A, Yao B, Dong T, et al. Tumor-resident intracellular microbiota promotes metastatic colonization in breast cancer. Cell. 2022;185(8):1356-1372.e26.

[162] Qiao H, Tan XR, Li H, et al. Association of intratumoral microbiota with prognosis in patients with nasopharyngeal carcinoma from 2 hospitals in China. JAMA Oncol. 2022;8(9):1301-1309.

[163] He Y, Wu W, Zheng HM, et al. Regional variation limits applications of healthy gut microbiome reference ranges and disease models. Nat Med. 2018;24(10):1532-1535.

[164] Silva CAC, Piccinno G, Suissa D, et al. Influence of microbiota-associated metabolic reprogramming on clinical outcome in patients with melanoma from the randomized adjuvant dendritic cell-based MIND-DC trial. Nat Commun. 2024;15(1):1633.

[165] Julkunen H, Cichońska A, Tiainen M, et al. Atlas of plasma NMR biomarkers for health and disease in 118, 461 individuals from the UK Biobank. Nat Commun. 2023;14(1):604.

RIGHTS & PERMISSIONS

2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.