Deciphering the Potential Causal and Prognostic Relationships Between Gut Microbiota and Brain Tumors: Insights from Genetics Analysis and Machine Learning

Changwu Wu , Fushu Luo , Yongye Zhu , Chunbo Liu , Zheng Chen , Xiangyu Wang , Jun Tan , Qing Liu

Exploration ›› 2025, Vol. 5 ›› Issue (4) : e20240087

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Exploration ›› 2025, Vol. 5 ›› Issue (4) : e20240087 DOI: 10.1002/EXP.20240087
RESEARCH ARTICLE

Deciphering the Potential Causal and Prognostic Relationships Between Gut Microbiota and Brain Tumors: Insights from Genetics Analysis and Machine Learning

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Abstract

The concept of the microbiota-gut-brain axis has witnessed significant advancements, and observational studies revealed dysbiosis in the gut microbiota of patients with brain tumors. The causal relationship between gut microbiota and brain tumors and the potential prognostic value of microbiota are still unclear. Based on multiple Mendelian randomization analyses, this study confirms the causal effects of four gut microbes on meningioma, seven gut microbes on pituitary tumor, and eight gut microbes on glioma. Based on the Sherlock framework, this study identifies 103 meningioma-related microbe-related genes (MRGs), 40 pituitary tumor-related MRGs, and 63 glioma-related MRGs expressed in brain tissues. Almost all glioma-related MRGs are associated with tumor grade and prognosis. Lastly, the prognostic model based on machine learning and microbiota established in this study, namely microbe-related signature (MRS), could robustly predict the prognosis of glioma and provide insights for immunotherapy benefits. This study presents evidence of the causal effects of gut microbes on brain tumors, which contributes to our understanding of the microbiota-gut-brain axis. The relationship between glioma-related MRGs and glioma prognosis, along with the prognostic prediction capacity of MRS and its association with immunotherapy, provides support for the use of gut microbiota as biomarkers to evaluate the prognosis and treatment response of glioma.

Keywords

glioma / gut microbiota / machine learning / mendelian randomization / meningioma / prognosis

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Changwu Wu, Fushu Luo, Yongye Zhu, Chunbo Liu, Zheng Chen, Xiangyu Wang, Jun Tan, Qing Liu. Deciphering the Potential Causal and Prognostic Relationships Between Gut Microbiota and Brain Tumors: Insights from Genetics Analysis and Machine Learning. Exploration, 2025, 5(4): e20240087 DOI:10.1002/EXP.20240087

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References

[1]

E. Thursby and N. Juge, “Introduction to the Human Gut Microbiota,” Biochemical Journal 474 (2017): 1823-1836.

[2]

J. K. Nicholson, E. Holmes, J. Kinross, et al., “Host-Gut Microbiota Metabolic Interactions,” Science (80-) 336 (2012): 1262-1267.

[3]

A. M. O'Hara and F. Shanahan, “The Gut Flora as a Forgotten Organ,” Embo Reports 7 (2006): 688-693.

[4]

E. A. Mayer, R. Knight, S. K. Mazmanian, J. F. Cryan, and K. Tillisch, “Gut Microbes and the Brain: Paradigm Shift in Neuroscience,” Journal of Neuroscience 34 (2014): 15490-15496.

[5]

M. Stiernborg, S. Prast-Nielsen, P. A. Melas, et al., “Differences in the Gut Microbiome of Young Adults with Schizophrenia Spectrum Disorder: Using Machine Learning to Distinguish Cases from Controls,” Brain, Behavior, and Immunity 117 (2024): 298-309.

[6]

J. F. Cryan, K. J. O'riordan, C. S. M. Cowan, et al., “The Microbiota-Gut-Brain Axis,” Physiological Reviews 99 (2019): 1877-2013.

[7]

R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer Statistics, 2016,” CA: A Cancer Journal for Clinicians 66 (2016): 7-30.

[8]

Q. T. Ostrom, G. Cioffi, K. Waite, C. Kruchko, and J. S. Barnholtz-Sloan, “CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014-2018,” Neuro-oncol 23 (2021): iii1-iii105.

[9]

C. G. Boer, K. Hatzikotoulas, L. Southam, et al., “Deciphering Osteoarthritis Genetics across 826,690 Individuals from 9 Populations,” Cell 184 (2021): 4784-4818.e17.

[10]

C. W. How, Y. S. Ong, S. S. Low, A. Pandey, P. L. Show, and J. B. Foo, “How Far Have We Explored Fungi to Fight Cancer?,” Seminars in Cancer Biology 86 (2022): 976-989.

[11]

X. Zhang, O. O. Coker, E. S. H. Chu, et al., “Dietary Cholesterol Drives Fatty Liver-Associated Liver Cancer by Modulating Gut Microbiota and Metabolites,” Gut 70 (2021): 761-774.

[12]

H. M. Ishaq, R. Yasin, I. S. Mohammad, et al., “The Gut-Brain-Axis: A Positive Relationship Between Gut Microbial Dysbiosis and Glioblastoma Brain Tumour,” Heliyon 10 (2024): e30494, https://doi.org/10.1016/J.HELIYON.2024.E30494.

[13]

D. Aljarrah, N. Chalour, A. Zorgani, T. Nissan, and M. Z. I. Pranjol, “Exploring the Gut Microbiota and Its Potential as a Biomarker in Gliomas,” Biomedicine and Pharmacotherapy 173 (2024): 116420, https://doi.org/10.1016/J.BIOPHA.2024.116420.

[14]

H. Jiang, W. Zeng, X. Zhang, Y. Pei, H. Zhang, and Y. Li, “The Role of Gut Microbiota in Patients with Benign and Malignant Brain Tumors: A Pilot Study,” Bioengineered 13 (2022): 7847-7859.

[15]

Y. Wen, L. Feng, H. Wang, et al., “Association Between Oral Microbiota and Human Brain Glioma Grade: A Case-Control Study,” Frontiers in Microbiology 12 (2021): 746568, https://doi.org/10.3389/FMICB.2021.746568/FULL.

[16]

W. Hou, J. Li, Z. Cao, et al., “Decorating Bacteria with a Therapeutic Nanocoating for Synergistically Enhanced Biotherapy,” Small 17 (2021): 2101810, https://doi.org/10.1002/SMLL.202101810.

[17]

G. D. Smith and G. Hemani, “Mendelian Randomization: Genetic Anchors for Causal Inference in Epidemiological Studies,” Human Molecular Genetics 23 (2014): R89-R98, https://doi.org/10.1093/hmg/ddu328.

[18]

X. Ye, Y. Bai, M. Li, et al., “Genetic Associations Between Circulating Immune Cells and Periodontitis Highlight the Prospect of Systemic Immunoregulation in Periodontal Care,” Elife 12 (2024): RP92895.

[19]

C. A. Emdin, A. V. Khera, and S. Kathiresan, “Mendelian Randomization,” JAMA—Journal of the American Medical Association 318 (2017): 1925.

[20]

S. Sanna, N. R. van Zuydam, A. Mahajan, et al., “Causal Relationships Among the Gut Microbiome, Short-Chain Fatty Acids and Metabolic Diseases,” Nature Genetics 51 (2019): 600-605.

[21]

Q. Wang, H. Dai, T. Hou, et al., “Dissecting Causal Relationships Between Gut Microbiota, Blood Metabolites, and Stroke: A Mendelian Randomization Study,” Journal of Stroke 25 (2023): 350-360.

[22]

A. Salvalaggio, L. Pini, M. Gaiola, et al., “White Matter Tract Density Index Prediction Model of Overall Survival in Glioblastoma,” JAMA Neurology 80 (2023): 1222, https://doi.org/10.1001/JAMANEUROL.2023.3284.

[23]

B. Zhang, J. Zhao, Y. Wang, et al., “CHRM3 is a Novel Prognostic Factor of Poor Prognosis and Promotes Glioblastoma Progression via Activation of Oncogenic Invasive Growth Factors,” Oncology Research 31 (2023): 917-927.

[24]

A. Kurilshikov, C. Medina-Gomez, R. Bacigalupe, et al., “Large-Scale Association Analyses Identify Host Factors Influencing Human Gut Microbiome Composition,” Nature Genetics 53 (2021): 156-165.

[25]

S. Y. Shin, E. B. Fauman, A. K. Petersen, et al., “An Atlas of Genetic Influences on Human Blood Metabolites,” Nature Genetics 46 (2014): 543-550.

[26]

M. I. Kurki, J. Karjalainen, P. Palta, et al., “FinnGen Provides Genetic Insights From a Well-Phenotyped Isolated Population,” Nature 613 (2023): 508-518.

[27]

J. V. C. Bayley, C. C. Hadley, A. O. Harmanci, A. S. Harmanci, T. J. Klisch, and A. J. Patel, “Multiple Approaches Converge on Three Biological Subtypes of Meningioma and Extract New Insights from Published Studies,” Science Advances 8 (2022): eabm6247, https://doi.org/10.1126/SCIADV.ABM6247.

[28]

J. Guo, Q. Fang, Y. Liu, W. Xie, C. Li, and Y. Zhang, “Screening and Identification of Key Microenvironment-Related Genes in Non-Functioning Pituitary Adenoma,” Frontiers in Genetics 12 (2021): 627117, https://doi.org/10.3389/FGENE.2021.627117/FULL.

[29]

R. L. Bowman, Q. Wang, A. Carro, R. G. W. Verhaak, and M. Squatrito, “GlioVis Data Portal for Visualization and Analysis of Brain Tumor Expression Datasets,” Neuro-oncol 19 (2017): 139-141.

[30]

J. Zhao, A. X. Chen, R. D. Gartrell, et al., “Immune and Genomic Correlates of Response to Anti-PD-1 Immunotherapy in Glioblastoma,” Nature Medicine 25 (2019): 462-469.

[31]

Y. Li, C. Wu, X. Long, et al., “Single-Cell Transcriptomic Analysis of Glioblastoma Reveals Pericytes Contributing to the Blood-Brain-Tumor Barrier and Tumor Progression,” MedComm 5 (2024): e70014, https://doi.org/10.1002/MCO2.70014.

[32]

X. Liu, X. Tong, Y. Zou, et al., “Mendelian Randomization Analyses Support Causal Relationships Between Blood Metabolites and the Gut Microbiome,” Nature Genetics 54 (2022): 52-61.

[33]

S. Burgess and S. G. Thompson, “Avoiding Bias From Weak Instruments in Mendelian Randomization Studies,” International Journal of Epidemiology 40 (2011): 755-764.

[34]

G. Hemani, K. Tilling, and G. D. Smith, “Orienting the Causal Relationship Between Imprecisely Measured Traits Using GWAS Summary Data,” PLos Genetics 13 (2017): e1007081, https://doi.org/10.1371/journal.pgen.1007081.

[35]

M. Verbanck, C. Y. Chen, B. Neale, and R. Do, “Detection of Widespread Horizontal Pleiotropy in Causal Relationships Inferred from Mendelian Randomization Between Complex Traits and Diseases,” Nature Genetics 50 (2018): 693-698.

[36]

S. Burgess, A. Butterworth, and S. G. Thompson, “Mendelian Randomization Analysis With Multiple Genetic Variants Using Summarized Data,” Genetic Epidemiology 37 (2013): 658-665.

[37]

J. Bowden, G. D. Smith, and S. Burgess, “Mendelian Randomization With Invalid Instruments: Effect Estimation and Bias Detection Through Egger Regression,” International Journal of Epidemiology 44 (2015): 512-525.

[38]

J. Bowden, G. D. Smith, P. C. Haycock, and S. Burgess, “Consistent Estimation in Mendelian Randomization With Some Invalid Instruments Using a Weighted Median Estimator,” Genetic Epidemiology 40 (2016): 304-314.

[39]

F. P. Hartwig, G. D. Smith, and J. Bowden, “Robust Inference in Summary Data Mendelian Randomization via the Zero Modal Pleiotropy Assumption,” International Journal of Epidemiology 46 (2017): 1985-1998.

[40]

J. Fan, Y. Zhou, R. Meng, et al., “Cross-Talks Between Gut Microbiota and Tobacco Smoking: A Two-Sample Mendelian Randomization Study,” BMC Medicine 21 (2023): 163.

[41]

A. Peh, J. A. O'Donnell, B. R. S. Broughton, and F. Z. Marques, “Gut Microbiota and Their Metabolites in Stroke: A Double-Edged Sword,” Stroke; A Journal of Cerebral Circulation 53 (2022): 1788-1801.

[42]

V. Ridaura and Y. Belkaid, “Gut Microbiota: The Link to Your Second Brain,” Cell 161 (2015): 193-194.

[43]

X. He, C. K. Fuller, Y. Song, et al., “Sherlock: Detecting Gene-Disease Associations by Matching Patterns of Expression QTL and GWAS,” American Journal of Human Genetics 92 (2013): 667-680.

[44]

Z. Liu, L. Liu, S. Weng, et al., “Machine Learning-Based Integration Develops an Immune-Derived lncRNA Signature for Improving Outcomes in Colorectal Cancer,” Nature Communications 13 (2022) 816, https://doi.org/10.1038/S41467-022-28421-6.

[45]

C. Wu, W. Long, C. Qin, et al., “Liquid Biopsy-based Identification of Prognostic and Immunotherapeutically Relevant Gene Signatures in Lower Grade Glioma,” J Big Data 10 (2023): 19.

[46]

C. Wu, S. Gong, Y. Duan, et al., “A Tumor Microenvironment-Based Prognostic Index for Osteosarcoma,” Journal of Biomedical Science 30 (2023): 23.

[47]

P. Charoentong, F. Finotello, M. Angelova, et al., “Pan-Cancer Immunogenomic Analyses Reveal Genotype-Immunophenotype Relationships and Predictors of Response to Checkpoint Blockade,” Cell Reports 18 (2017): 248-262.

[48]

C. Wu, C. Qin, W. Long, X. Wang, K. Xiao, and Q. Liu, “Tumor Antigens and Immune Subtypes of Glioblastoma: The Fundamentals of mRNA Vaccine and Individualized Immunotherapy Development,” Journal of Big Data 9 (2022): 92, https://doi.org/10.1186/s40537-022-00643-x.

[49]

B. S. Melin, J. S. Barnholtz-Sloan, M. R. Wrensch, et al., “Genome-Wide Association Study of Glioma Subtypes Identifies Specific Differences in Genetic Susceptibility to Glioblastoma and Non-Glioblastoma Tumors,” Nature Genetics 49 (2017): 789-794.

[50]

D. Erny, A. L. H. De Angelis, D. Jaitin, et al., “Host Microbiota Constantly Control Maturation and Function of Microglia in the CNS,” Nature Neuroscience 18 (2015): 965-977.

[51]

T. Clavel, J. C. Gomes-Neto, I. Lagkouvardos, and A. E. Ramer-Tait, “Deciphering Interactions Between the Gut Microbiota and the Immune System Via Microbial Cultivation and Minimal Microbiomes,” Immunological Reviews 279 (2017): 8-22.

[52]

Z. Li, W. Xiong, Z. Liang, et al., “Critical Role of the Gut Microbiota in Immune Responses and Cancer Immunotherapy,” Journal of Hematology and Oncology 17 (2024): 33.

[53]

M. S. Rooney, S. A. Shukla, C. J. Wu, G. Getz, and N. Hacohen, “Molecular and Genetic Properties of Tumors Associated With Local Immune Cytolytic Activity,” Cell 160 (2015): 48-61.

[54]

Y. Ge, X. Wang, Y. Guo, et al., “Gut Microbiota Influence Tumor Development and Alter Interactions with the Human Immune System,” Journal of Experimental and Clinical Cancer Research 40 (2021): 42, https://doi.org/10.1186/S13046-021-01845-6.

[55]

L. H. Morais, H. L. Schreiber, and S. K. Mazmanian, “The Gut Microbiota-Brain Axis in Behaviour and Brain Disorders,” Nature Reviews Microbiology 19 (2021): 241-255.

[56]

X. Hou, H. Du, Y. Deng, et al., “Gut Microbiota Mediated the Individualized Efficacy of Temozolomide via Immunomodulation in Glioma,” Journal of Translational Medicine 21 (2023): 198, https://doi.org/10.1186/S12967-023-04042-5.

[57]

S. Huang, J. Chen, Z. Cui, et al., “Lachnospiraceae-Derived Butyrate Mediates Protection of High Fermentable Fiber Against Placental Inflammation in Gestational Diabetes Mellitus,” Science Advances 9 (2023): eadi7337.

[58]

M. Marizzoni, P. Mirabelli, E. Mombelli, et al., “A Peripheral Signature of Alzheimer's Disease Featuring Microbiota-Gut-Brain Axis Markers,” Alzheimer's Research & Therapy 15 (2023): 101, https://doi.org/10.1186/S13195-023-01218-5.

[59]

W. Zhao, J. Lei, S. Ke, et al., “Fecal Microbiota Transplantation Plus Tislelizumab and Fruquintinib in Refractory Microsatellite Stable Metastatic Colorectal Cancer: An Open-Label, Single-Arm, Phase II Trial (RENMIN-215),” EClinicalMedicine 66 (2023): 102315, https://doi.org/10.1016/J.ECLINM.2023.102315.

[60]

C.-L. Lin, T.-H. Ying, S.-F. Yang, C.-L. Lin, H.-L. Chiou, and Y.-H. Hsieh, “Magnolin Targeting of the JNK/Sp1/MMP15 Signaling Axis Suppresses Cervical Cancer Microenvironment and Metastasis via Microbiota Modulation,” Cancer Letters 583 (2023): 216584.

[61]

X. Zhang, D. Yu, D. Wu, et al., “Tissue-Resident Lachnospiraceae Family Bacteria Protect Against Colorectal Carcinogenesis by Promoting Tumor Immune Surveillance,” Cell Host and Microbe 31 (2023): 418-432.e8.

[62]

M. Zhang, Y. Lv, S. Hou, Y. Liu, Y. Wang, and X. Wan, “Differential Mucosal Microbiome Profiles Across Stages of Human Colorectal Cancer,” Life (Basel, Switzerland) 11 (2021): 831, https://doi.org/10.3390/LIFE11080831.

[63]

Y. Lu, J. Chen, J. Zheng, et al., “Mucosal Adherent Bacterial Dysbiosis in Patients with Colorectal Adenomas,” Scientific Reports 6 (2016): 26337, https://doi.org/10.1038/SREP26337.

[64]

E. Niccolai, S. Baldi, G. Nannini, et al., “Breast Cancer: The First Comparative Evaluation of Oncobiome Composition Between Males and Females,” Biology of Sex Differences 14 (2023): 37, https://doi.org/10.1186/S13293-023-00523-W.

[65]

Q. Zhao, T. Yang, Y. Yan, et al., “Alterations of Oral Microbiota in Chinese Patients With Esophageal Cancer,” Frontiers in Cellular and Infection Microbiology 10 (2020): 541144, https://doi.org/10.3389/FCIMB.2020.541144.

[66]

Z. Qi, Z. Zhibo, Z. Jing, et al., “Prediction Model of Poorly Differentiated Colorectal Cancer (CRC) Based on Gut Bacteria,” BMC Microbiology 22 (2022): 312, https://doi.org/10.1186/S12866-022-02712-W.

[67]

Y. Li, G. Liu, R. Gong, and Y. Xi, “Gut Microbiome Dysbiosis in Patients With Endometrial Cancer vs. Healthy Controls Based on 16S rRNA Gene Sequencing,” Current Microbiology 80 (2023): 239, https://doi.org/10.1007/S00284-023-03361-6.

[68]

H. Kim, H. S. Roh, J. E. Kim, S. D. Park, W. H. Park, and J. Y. Moon, “Compound K Attenuates Stromal Cell-Derived Growth Factor 1 (SDF-1)-Induced Migration of C6 Glioma Cells,” Nutrition Research and Practice 10 (2016): 259.

[69]

A. Patrizz, A. Dono, S. Zorofchian, et al., “Glioma and Temozolomide Induced Alterations in Gut Microbiome,” Scientific Reports 10 (2020): 21002, https://doi.org/10.1038/S41598-020-77919-W.

[70]

Y. Fan, Q. Su, J. Chen, Y. Wang, and S. He, “Gut Microbiome Alterations Affect Glioma Development and Foxp3 Expression in Tumor Microenvironment in Mice,” Frontiers in Oncology 12 (2022): 836953, https://doi.org/10.3389/FONC.2022.836953.

[71]

J. Tao, S. Li, R. Y. Gan, C. N. Zhao, X. Meng, and H. B. Li, “Targeting Gut Microbiota With Dietary Components on Cancer: Effects and Potential Mechanisms of Action,” Critical Reviews in Food Science and Nutrition 60 (2020): 1025-1037.

[72]

Y. Yang, Y. An, Y. Dong, et al., “Fecal Microbiota Transplantation: No Longer Cinderella in Tumour Immunotherapy,” Ebiomedicine 100 (2024): 104967.

[73]

D. Davar, A. K. Dzutsev, J. A. McCulloch, et al., “Fecal Microbiota Transplant Overcomes Resistance to Anti-PD-1 Therapy in Melanoma Patients,” Science (80-) 371 (2021): 595-602.

[74]

M. F. Sanmamed, O. Carranza-Rua, C. Alfaro, et al., “Serum Interleukin-8 Reflects Tumor Burden and Treatment Response Across Malignancies of Multiple Tissue Origins,” Clinical Cancer Research 20 (2014): 5697-5707.

[75]

S. H. Law, M. L. Chan, G. K. Marathe, F. Parveen, C. H. Chen, and L. Y. Ke, “An Updated Review of Lysophosphatidylcholine Metabolism in Human Diseases,” International Journal of Molecular Sciences 20 (2019): 1149, https://doi.org/10.3390/IJMS20051149.

[76]

H. Chen, J. Ma, J. Liu, et al., “Lysophosphatidylcholine Disrupts Cell Adhesion and Induces Anoikis in Hepatocytes,” FEBS Letters 596 (2022): 510-525.

[77]

D. Yu, Q. Xuan, C. Zhang, et al., “Metabolic Alterations Related to Glioma Grading Based On Metabolomics and Lipidomics Analyses,” Metabolites 10 (2020): 478.

[78]

B. Lin, Z. Ye, Z. Ye, et al., “Gut Microbiota in Brain Tumors: An Emerging Crucial Player,” CNS Neuroscience and Therapeutics 29 (2023): 84-97.

[79]

J. Liang, T. Li, J. Zhao, C. Wang, and H. Sun, “Current Understanding of the human Microbiome in Glioma,” Frontiers in Oncology 12 (2022): 781741, https://doi.org/10.3389/FONC.2022.781741.

[80]

R. Naghavian, W. Faigle, P. Oldrati, et al., “Microbial Peptides Activate Tumour-Infiltrating Lymphocytes in Glioblastoma,” Nature 617 (2023): 807-817.

[81]

D. Altshuler, M. J. Daly, and E. S. Lander, “Genetic Mapping in Human Disease,” Science 322 (2008): 881-888.

[82]

G. D'Alessandro, F. Antonangeli, F. Marrocco, et al., “Gut Microbiota Alterations Affect Glioma Growth and Innate Immune Cells Involved in Tumor Immunosurveillance in Mice,” European Journal of Immunology 50 (2020): 705-711.

[83]

H. Zheng, T. Yan, Y. Han, et al., “Nomograms for Prognostic Risk Assessment in Glioblastoma Multiforme: Applications and Limitations,” Clinical Genetics 102 (2022): 359-368.

[84]

M. Zhao, G. Jiang, H. Zhou, et al., “Gut Microbiota: A Potential Target for Improved Cancer Therapy,” Journal of Cancer Research and Clinical Oncology 149 (2023): 541-552.

[85]

Y. Lyu, H. Yang, and L. Chen, “Metabolic Regulation on the Immune Environment of Glioma Through Gut Microbiota,” Seminars in Cancer Biology 86 (2022): 990-997.

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