Abstract
Our microbiome is shaped by multiple factors such as genetics and the immune system, diet, exposure to antimicrobials and other drugs, environmental factors or exchange/interaction with other microbiomes. Multiple studies have suggested that deregulation of the human microbiome contribute to the development of cancer. In this review, we try to elucidate which alterations in the microbiota are related with carcinogenesis; specially emphasizing in its role in lung cancer. We have analyzed a substantial body of studies, which conclude that the microbiota is a critical biomarker for tumorigenesis and cancer therapy response. It also significantly influences clinical characterization, prediction of response to specific treatments—particularly immunotherapy —and plays a key role in cancer prognosis. We ultimately concluded that the gut-lung microbiome axis is crucial for carcinogenesis. Dysbiosis is associated with prognosis. More prospective studies are needed to assess the true role of the microbiome in prognosis and response of lung cancer.
References
Vilchez-Vargas R, Skieceviciene J, Lehr K, Varkalaite G, Thon C, Urba M, Morkunas E, Kucinskas L, Bauraite K, Schanze D, Zenker M, Malfertheiner P, Kupcinskas J, Link A. Gut microbial similarity in twins is driven by shared environment and aging. EBioMedicine. 2022;79:104011. doi: 10.1016/j.ebiom.2022.104011.
Cani PD. Human gut microbiome: hopes, threats and promises. Gut. 2018;67(9):1716–25. doi:10.1136/gutjnl-2018-316723.
Li W, Deng Y, Chu Q, Zhang P. Gut microbiome and cancer immunotherapy. Cancer Lett. 2019 Apr 10;447:41-7. doi: 10.1016/j.canlet.2019.01.015.
Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, Liang S, Zhang W, Guan Y, Shen D, Peng Y, Zhang D, Jie Z, Wu W, Qin Y, Xue W, Li J, Han L, Lu D, Wu P, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490(7418):55-60. doi: 10.1038/nature11450.
Rodrigues VF, Elias-Oliveira J, Pereira IS, Pereira JA, Barbosa SC, Machado MSG, Carlos D. Akkermansia muciniphila and Gut Immune System: A Good Friendship That Attenuates Inflammatory Bowel Disease, Obesity, and Diabetes. Front Immunol. 2022;13:934695. doi: 10.3389/fimmu.2022.934695.
Roviello G, Iannone LF, Bersanelli M, Mini E, Catalano M. The gut microbiome and efficacy of cancer immunotherapy. Pharmacology & therapeutics. 2022;231:107973. doi: 10.1016/j.pharmthera.2021.107973.
Tsay JJ, Wu BG, Sulaiman I, Gershner K, Schluger R, Li Y, Yie TA, Meyn P, Olsen E, Perez L, Franca B, Carpenito J, Iizumi T, El-Ashmawy M, Badri M, Morton JT, Shen N, He L, Michaud G, Rafeq S, Bessich JL, Smith RL, Sauthoff H, Felner K, Pillai R, Zavitsanou AM, Koralov SB, Mezzano V, Loomis CA, Moreira AL, Moore W, Tsirigos A, Heguy A, Rom WN, Sterman DH, Pass HI, Clemente JC, Li H, Bonneau R, Wong KK, Papagiannakopoulos T, Segal LN. Lower Airway Dysbiosis Affects Lung Cancer Progression. Cancer Discov. 2021 Feb;11(2):293-307. doi: 10.1158/2159-8290.CD-20-0263.
Xin Y, Liu CG, Zang D, Chen J. Gut microbiota and dietary intervention: affecting immunotherapy efficacy in non-small cell lung cancer. Front Immunol. 2024 Feb 1;15:1343450. doi: 10.3389/fimmu.2024.1343450.
Lu H, Gao NL, Tong F, Wang J, Li H, Zhang R, Ma H, Yang N, Zhang Y, Wang Y, Liang Z, Zeng H, Chen WH, Dong X. Alterations of the Human Lung and Gut Microbiomes in Non-Small Cell Lung Carcinomas and Distant Metastasis. Microbiol Spectr. 2021 Dec 22;9(3):e0080221. doi: 10.1128/Spectrum.00802-21.
Matson V, Chervin CS, Gajewski TF. Cancer and the Microbiome-Influence of the Commensal Microbiota on Cancer, Immune Responses, and Immunotherapy. Gastroenterology. 2021 Jan;160(2):600-613. doi: 10.1053/j.gastro.2020.11.041.
Peters BA, Pass HI, Burk RD, Xue X, Goparaju C, Sollecito CC, Grassi E, Segal LN, Tsay JJ, Hayes RB, Ahn J. The lung microbiome, peripheral gene expression, and recurrence-free survival after resection of stage II non-small cell lung cancer. Genome Med. 2022 Oct 27;14(1):121. doi: 10.1186/s13073-022-01126-7.
Laroumagne S, Lepage B, Hermant C, Plat G, Phelippeau M, Bigay-Game L, Lozano S, Guibert N, Segonds C, Mallard V, Augustin N, Didier A, Mazieres J. Bronchial colonisation in patients with lung cancer: a prospective study. Eur Respir J. 2013;42(1):220-9. doi: 10.1183/09031936.00062212.
Ankudavicius V, Nikitina D, Lukosevicius R, Tilinde D, Salteniene V, Poskiene L, et al. Detailed characterization of the lung-gut microbiome axis reveals the link between PD-L1 and the microbiome in non-small-cell lung cancer patients. Int J Mol Sci. 2024;25(4):2323. doi:10.3390/ijms25042323.
Chen J, Yu X, Wu X, Chai K, Wang S. Causal relationships between gut microbiota, immune cell, and non-small cell lung cancer: A two-step, two-sample Mendelian randomization study. J Cancer. 2024;15(7):1890–7. doi:10.7150/jca.92699.
Jiang H, Zeng W, Zhang X, Li Y, Wang Y, Peng A, Cao D. Gut microbiota and its metabolites in non-small cell lung cancer and brain metastasis: from alteration to potential microbial markers and drug targets. Front Cell Infect Microbiol. 2024;13:1211855. doi: 10.3389/fcimb.2023.1211855.
Qiu B, Xi Y, Liu F, Li Y, Xie X, Guo J, Guo S, Wu Y, Wu L, Liang T, Ding Y, Zhang J, Wu Q, Liu H. Gut Microbiome Is Associated With the Response to Chemoradiotherapy in Patients With Non-small Cell Lung Cancer. Int J Radiat Oncol Biol Phys. 2023;115(2):407-418. doi: 10.1016/j.ijrobp.2022.07.032.
Saifon W, Sensorn I, Trachu N, Oranratnachai S, Charoenyingwattana A, Runcharoen C, Monnamo N, Sukkasem W, Inchareon P, Suwatanapongched T, Chansriwong P, Ativitavas T, Panvichian R, Chantratita W, Reungwetwattana T. Gastrointestinal microbiota profile and clinical correlations in advanced EGFR-WT and EGFR-mutant non-small cell lung cancer. BMC cancer. 2022;22(1):963. doi: 10.1186/s12885-022-10050-3.
Kim Y, Kang J, Lim H, Lee S, Lee W, Ko Y, et al. A critical review on the role of gut microbiota in cancer immunotherapy. Oncol Lett. 2020;19(6):4427–35. doi:10.3892/ol.2020.11343.
Takenaka IKTM, Bartelli TF, Defelicibus A, Sendoya JM, Golubicki M, Robbio J, Serpa MS, Branco GP, Santos LBC, Claro LCLC, dos Santos GO, Kupper BEC, da Silva IT, Llera AS, de Mello CAL, Riechelmann RP, Dias-Neto E, Iseas S, Aguiar S, Nunes DN. Exome and tissue-associated microbiota as predictive markers of response to neoadjuvant treatment in locally advanced rectal cancer. Front Oncol. 2022;12:809441. doi: 10.3389/fonc.2022.809441.
Daillere R, Vétizou M, Waldschmitt N, Yamazaki T, Isnard C, Poirier-Colame V, et al. Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects. Immunity. 2016;45(4):931–43. doi:10.1016/j.immuni.2016.09.009.
Nie X, Li L, Yi M, Qin W, Zhao W, Li F, Wu B, Yuan X. The Intestinal Microbiota Plays as a Protective Regulator Against Radiation Pneumonitis. Radiat Res. 2020;194(1):52-60. doi: 10.1667/RR15579.1.
Vétizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, Poirier-Colame V, Roux A, Becharef S, Formenti S, Golden E, Cording S, Eberl G, Schlitzer A, Ginhoux F, Mani S, Zitvogel L. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science (New York, N.Y.). 2015;350(6264):1079–1084. doi: 10.1126/science.aad1329.
Katayama Y, Yamada T, Shimamoto T, Iwasaku M, Kaneko Y, Uchino J, Takayama K. The role of the gut microbiome on the efficacy of immune checkpoint inhibitors in Japanese responder patients with advanced non-small cell lung cancer. Transl Lung Cancer Res. 2019;8(6):847-53. doi: 10.21037/tlcr.2019.10.23
Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre ML, Chang EB, Gajewski TF. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science (New York, N.Y.). 2015;350(6264):1084–9. doi: 10.1126/science.aac4255.
Zhu Z, Huang J, Li X, Xing J, Chen Q, Liu R, Hua F, Qiu Z, Song Y, Bai C, Mo YY, Zhang Z. Gut microbiota regulate tumor metastasis via circRNA/miRNA networks. Gut Microbes. 2020 Nov 9;12(1):1788891. doi: 10.1080/19490976.2020.1788891.
Liu B, Chau J, Dai Q, Zhong C, Zhang J. Exploring Gut Microbiome in Predicting the Efficacy of Immunotherapy in Non-Small Cell Lung Cancer. Cancers (Basel). 2022 Nov 1;14(21):5401. doi: 10.3390/cancers14215401.
Jang HJ, Choi JY, Kim K, Yong SH, Kim YW, Kim SY, Kim EY, Jung JY, Kang YA, Park MS, Kim YS, Cho YJ, Lee SH. Relationship of the lung microbiome with PD-L1 expression and immunotherapy response in lung cancer. Respir Res. 2021;22(1):322. doi: 10.1186/s12931-021-01919-1.
Shoji F, Yamashita T, Kinoshita F, Takamori S, Fujishita T, Toyozawa R, Ito K, Yamazaki K, Nakashima N, Okamoto T. Artificial intelligence-derived gut microbiome as a predictive biomarker for therapeutic response to immunotherapy in lung cancer: protocol for a multicentre, prospective, observational study. BMJ open. 2022;12(6):e061674. doi: 10.1136/bmjopen-2022-061674.
Chau J, Yadav M, Liu B, Furqan M, Dai Q, Shahi S, et al. Prospective correlation between the patient microbiome with response to and development of immune-mediated adverse effects to immunotherapy in lung cancer. BMC Cancer. 2021;21(1):808. doi:10.1186/s12885-021-08530-z.
Tan B, Liu YX, Tang H, Chen D, Xu Y, Chen MJ, Li Y, Wang MZ, Qian JM. Gut microbiota shed new light on the management of immune-related adverse events. Thoracic cancer. 2022;13(19):2681–91. doi: 10.1111/1759-7714.14626.
Andrews MC, Duong CPM, Gopalakrishnan V, Iebba V, Chen WS, Derosa L, et al. Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade. Nat Med. 2021;27(8):1432–41. doi:10.1038/s41591-021-01406-6.
Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, Luke JJ, Gajewski TF. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science (New York, N.Y.). 2018;359(6371):104-108. doi: 10.1126/science.aao3290.
Matson V, Chervin CS, Gajewski TF. Cancer and the Microbiome-Influence of the Commensal Microbiota on Cancer, Immune Responses, and Immunotherapy. Gastroenterology. 2021 Jan;160(2):600-613. doi: 10.1053/j.gastro.2020.11.041
Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillere R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, Fidelle M, Flament C, Poirier-Colame V, Opolon P, Klein C, Iribarren K, Mondragón L, Jacquelot N, Qu B, Ferrere G, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science (New York, N.Y.). 2018;359(6371):91–7. doi: 10.1126/science.aan3706.
Littmann ER, Lee JJ, Denny JE, Alam Z, Maslanka JR, Zarin I, Matsuda R, Carter RA, Susac B, Saffern MS, Fett B, Mattei LM, Bittinger K, Abt MC. Host immunity modulates the efficacy of microbiota transplantation for treatment of Clostridioides difficile infection. Nat Commun. 2021;12(1):755. doi: 10.1038/s41467-020-20793-x.
Li R, Li J, Zhou X. Lung microbiome: new insights into the pathogenesis of respiratory diseases. Signal Transduct Target Ther. 2024 Jan 17;9(1):19. doi: 10.1038/s41392-023-01722-y.
Liu W, Xu J, Pi Z, Chen Y, Jiang G, Wan Y, Mao W. Untangling the web of intratumor microbiota in lung cancer. Biochim Biophys Acta Rev Cancer. 2023;1878(6):189025. doi: 10.1016/j.bbcan.2023.189025.

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Copyright (c) 2025 María Morales, Victoria Moreno, Beatriz Garrido, Laura Moll; Irene Hernández (Revisor IPAO); Andrea Fernández, Sandra falagán, Gustavo Rubio, Enrique Casado, María Sereno