1932

Abstract

Studies in preclinical models support that the gut microbiota play a critical role in the development and progression of colorectal cancer (CRC). Specific microbial species and their corresponding virulence factors or associated small molecules can contribute to CRC development and progression either via direct effects on the neoplastic transformation of epithelial cells or through interactions with the host immune system. Induction of DNA damage, activation of Wnt/β-catenin and NF-κB proinflammatory pathways, and alteration of the nutrient's availability and the metabolic activity of cancer cells are the main mechanisms by which the microbiota contribute to CRC. Within the tumor microenvironment, the gut microbiota alter the recruitment, activation, and function of various immune cells, such as T cells, macrophages, and dendritic cells. Additionally, the microbiota shape the function and composition of cancer-associated fibroblasts and extracellular matrix components, fashioning an immunosuppressive and pro-tumorigenic niche for CRC. Understanding the complex interplay between gut microbiota and tumorigenesis can provide therapeutic opportunities for the prevention and treatment of CRC.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-042022-025619
2024-02-12
2024-04-27
Loading full text...

Full text loading...

/deliver/fulltext/physiol/86/1/annurev-physiol-042022-025619.html?itemId=/content/journals/10.1146/annurev-physiol-042022-025619&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I et al. 2021. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71:3209–49
    [Google Scholar]
  2. 2.
    Brenner H, Kloor M, Pox CP. 2014. Colorectal cancer. Lancet 383:99271490–502
    [Google Scholar]
  3. 3.
    Cancer Genome Atlas Network 2012. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:7407330–37
    [Google Scholar]
  4. 4.
    Kandoth C, McLellan MD, Vandin F, Ye K, Niu B et al. 2013. Mutational landscape and significance across 12 major cancer types. Nature 502:7471333–39
    [Google Scholar]
  5. 5.
    Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA et al. 2014. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505:7484495–501
    [Google Scholar]
  6. 6.
    Yaeger R, Chatila WK, Lipsyc MD, Hechtman JF, Cercek A et al. 2018. Clinical sequencing defines the genomic landscape of metastatic colorectal cancer. Cancer Cell 33:1125–36.e3
    [Google Scholar]
  7. 7.
    Clevers H. 2006. Wnt/β-catenin signaling in development and disease. Cell 127:3469–80
    [Google Scholar]
  8. 8.
    Simanshu DK, Nissley DV, McCormick F. 2017. RAS proteins and their regulators in human disease. Cell 170:117–33
    [Google Scholar]
  9. 9.
    Sanz-Garcia E, Argiles G, Elez E, Tabernero J. 2017. BRAF mutant colorectal cancer: prognosis, treatment, and new perspectives. Ann. Oncol. 28:112648–57
    [Google Scholar]
  10. 10.
    Li X-L, Zhou J, Chen Z-R, Chng W-J. 2015. p53 mutations in colorectal cancer—molecular pathogenesis and pharmacological reactivation. World J. Gastroenterol. 21:184–93
    [Google Scholar]
  11. 11.
    Guinney J, Dienstmann R, Wang X, de Reyniès A, Schlicker A et al. 2015. The consensus molecular subtypes of colorectal cancer. Nat. Med. 21:111350–56
    [Google Scholar]
  12. 12.
    Xiao Y, Freeman GJ. 2015. The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy. Cancer Discov. 5:116–18
    [Google Scholar]
  13. 13.
    Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. 2017. Global patterns and trends in colorectal cancer incidence and mortality. Gut 66:4683–91
    [Google Scholar]
  14. 14.
    Garrett WS. 2015. Cancer and the microbiota. Science 348:623080–86
    [Google Scholar]
  15. 15.
    Gopalakrishnan V, Helmink BA, Spencer CN, Reuben A, Wargo JA. 2018. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell 33:4570–80
    [Google Scholar]
  16. 16.
    Benedict C, Vogel H, Jonas W, Woting A, Blaut M et al. 2016. Gut microbiota and glucometabolic alterations in response to recurrent partial sleep deprivation in normal-weight young individuals. Mol. Metab. 5:121175–86
    [Google Scholar]
  17. 17.
    MetaHIT Consort. Forslund K, Hildebrand F, Nielsen T, Falony G et al. 2015. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528:7581262–66
    [Google Scholar]
  18. 18.
    Sonnenburg ED, Sonnenburg JL. 2014. Starving our microbial self: the deleterious consequences of a diet deficient in microbiota-accessible carbohydrates. Cell Metab. 20:5779–86
    [Google Scholar]
  19. 19.
    Foster JA, McVey Neufeld K-A. 2013. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 36:5305–12
    [Google Scholar]
  20. 20.
    Carding S, Verbeke K, Vipond DT, Corfe BM, Owen LJ. 2015. Dysbiosis of the gut microbiota in disease. Microb. Ecol. Health Dis. 26:26191
    [Google Scholar]
  21. 21.
    Garrett WS. 2015. Cancer and the microbiota. Science 348:623080–86
    [Google Scholar]
  22. 22.
    Clay SL, Fonseca-Pereira D, Garrett WS. 2022. Colorectal cancer: the facts in the case of the microbiota. J. Clin. Investig. 132:4e155101
    [Google Scholar]
  23. 23.
    Glover TJ. 1930. The bacteriology of cancer. Canada Lancet Pract. 75:92–111
    [Google Scholar]
  24. 24.
    Wang Q, Liu Z, Ma A, Li Z, Liu B, Ma Q. 2023. Computational methods and challenges in analyzing intratumoral microbiome data. Trends Microbiol 31:7707–22
    [Google Scholar]
  25. 25.
    Nejman D, Livyatan I, Fuks G, Gavert N, Zwang Y et al. 2020. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 368:6494973–80
    [Google Scholar]
  26. 26.
    Poore GD, Kopylova E, Zhu Q, Carpenter C, Fraraccio S et al. 2020. Microbiome analyses of blood and tissues suggest cancer diagnostic approach. Nature 579:7800567–74
    [Google Scholar]
  27. 27.
    Bertocchi A, Carloni S, Ravenda PS, Bertalot G, Spadoni I et al. 2021. Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver. Cancer Cell 39:5708–24.e11
    [Google Scholar]
  28. 28.
    Galeano Niño JL, Wu H, LaCourse KD, Kempchinsky AG, Baryiames A et al. 2022. Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer. Nature 611:7937810–17
    [Google Scholar]
  29. 29.
    Sepich-Poore GD, Zitvogel L, Straussman R, Hasty J, Wargo JA, Knight R. 2021. The microbiome and human cancer. Science 371:6536eabc4552
    [Google Scholar]
  30. 30.
    Pleguezuelos-Manzano C, Puschhof J, Clevers H. 2022. Gut microbiota in colorectal cancer: associations, mechanisms, and clinical approaches. Annu. Rev. Cancer Biol. 6:65–84
    [Google Scholar]
  31. 31.
    Cullin N, Azevedo Antunes C, Straussman R, Stein-Thoeringer CK, Elinav E 2021. Microbiome and cancer. Cancer Cell 39:101317–41
    [Google Scholar]
  32. 32.
    Brennan CA, Garrett WS. 2016. Gut microbiota, inflammation, and colorectal cancer. Annu. Rev. Microbiol. 70:395–411
    [Google Scholar]
  33. 33.
    Pleguezuelos-Manzano C, Puschhof J, Huber AR, van Hoeck A, Wood HM et al. 2020. Mutational signature in colorectal cancer caused by genotoxic pks+E. coli. Nature 580:7802269–73
    [Google Scholar]
  34. 34.
    Arthur JC, Perez-Chanona E, Mühlbauer M, Tomkovich S, Uronis JM et al. 2012. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338:6103120–23
    [Google Scholar]
  35. 35.
    Wu S, Rhee K-J, Albesiano E, Rabizadeh S, Wu X et al. 2009. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat. Med. 15:91016–22
    [Google Scholar]
  36. 36.
    Kostic AD, Chun E, Robertson L, Glickman JN, Gallini CA et al. 2013. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 14:2207–15
    [Google Scholar]
  37. 37.
    Gur C, Ibrahim Y, Isaacson B, Yamin R, Abed J et al. 2015. Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity 42:2344–55
    [Google Scholar]
  38. 38.
    Rubinstein MR, Wang X, Liu W, Hao Y, Cai G, Han YW. 2013. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe 14:2195–206
    [Google Scholar]
  39. 39.
    Abed J, Emgård JEM, Zamir G, Faroja M, Almogy G et al. 2016. Fap2 mediates Fusobacterium nucleatum colorectal adenocarcinoma enrichment by binding to tumor-expressed Gal-GalNAc. Cell Host Microbe 20:2215–25
    [Google Scholar]
  40. 40.
    Cuevas-Ramos G, Petit CR, Marcq I, Boury M, Oswald E, Nougayrède J-P. 2010. Escherichia coli induces DNA damage in vivo and triggers genomic instability in mammalian cells. PNAS 107:2511537–42
    [Google Scholar]
  41. 41.
    Drewes JL, Chen J, Markham NO, Knippel RJ, Domingue JC et al. 2022. Human colon cancer-derived Clostridioides difficile strains drive colonic tumorigenesis in mice. Cancer Discov. 12:81873–85
    [Google Scholar]
  42. 42.
    Pavlova NN, Zhu J, Thompson CB. 2022. The hallmarks of cancer metabolism: still emerging. Cell Metab. 34:3355–77
    [Google Scholar]
  43. 43.
    Salvucci M, Crawford N, Stott K, Bullman S, Longley DB, Prehn JHM. 2022. Patients with mesenchymal tumours and high Fusobacteriales prevalence have worse prognosis in colorectal cancer (CRC). Gut 71:1600–12
    [Google Scholar]
  44. 44.
    Nougayrède J-P, Homburg S, Taieb F, Boury M, Brzuszkiewicz E et al. 2006. Escherichia coli induces DNA double-strand breaks in eukaryotic cells. Science 313:5788848–51
    [Google Scholar]
  45. 45.
    Vizcaino MI, Crawford JM. 2015. The colibactin warhead crosslinks DNA. Nat. Chem. 7:5411–17
    [Google Scholar]
  46. 46.
    Bossuet-Greif N, Vignard J, Taieb F, Mirey G, Dubois D et al. 2018. The colibactin genotoxin generates DNA interstrand cross-links in infected cells. mBio 9:2e02393–17
    [Google Scholar]
  47. 47.
    Wilson MR, Jiang Y, Villalta PW, Stornetta A, Boudreau PD et al. 2019. The human gut bacterial genotoxin colibactin alkylates DNA. Science 363:6428eaar7785
    [Google Scholar]
  48. 48.
    Putze J, Hennequin C, Nougayrède J-P, Zhang W, Homburg S et al. 2009. Genetic structure and distribution of the colibactin genomic island among members of the family Enterobacteriaceae. Infect. Immun. 77:114696–4703
    [Google Scholar]
  49. 49.
    Dougherty MW, Jobin C. 2021. Shining a light on colibactin biology. Toxins 13:5346
    [Google Scholar]
  50. 50.
    Tripathi P, Shine EE, Healy AR, Kim CS, Herzon SB et al. 2017. ClbS is a cyclopropane hydrolase that confers colibactin resistance. J. Am. Chem. Soc. 139:4917719–22
    [Google Scholar]
  51. 51.
    Sadecki PW, Balboa SJ, Lopez LR, Kedziora KM, Arthur JC, Hicks LM. 2021. Evolution of polymyxin resistance regulates colibactin production in Escherichia coli. ACS Chem. Biol. 16:71243–54
    [Google Scholar]
  52. 52.
    Rehm N, Wallenstein A, Keizers M, Homburg S, Magistro G et al. 2022. Two polyketides intertwined in complex regulation: posttranscriptional CsrA-mediated control of colibactin and yersiniabactin synthesis in Escherichia coli. mBio 13:1e0381421
    [Google Scholar]
  53. 53.
    He Z, Gharaibeh RZ, Newsome RC, Pope JL, Dougherty MW et al. 2019. Campylobacter jejuni promotes colorectal tumorigenesis through the action of cytolethal distending toxin. Gut 68:2289–300
    [Google Scholar]
  54. 54.
    Man SM. 2011. The clinical importance of emerging Campylobacter species. Nat. Rev. Gastroenterol. Hepatol. 8:12669–85
    [Google Scholar]
  55. 55.
    Warren RL, Freeman DJ, Pleasance S, Watson P, Moore RA et al. 2013. Co-occurrence of anaerobic bacteria in colorectal carcinomas. Microbiome 1:16
    [Google Scholar]
  56. 56.
    Cao Y, Oh J, Xue M, Huh WJ, Wang J et al. 2022. Commensal microbiota from patients with inflammatory bowel disease produce genotoxic metabolites. Science 378:6618eabm3233
    [Google Scholar]
  57. 57.
    Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R et al. 2014. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40:1128–39
    [Google Scholar]
  58. 58.
    Greten FR, Grivennikov SI. 2019. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity 51:127–41
    [Google Scholar]
  59. 59.
    Schwitalla S, Ziegler PK, Horst D, Becker V, Kerle I et al. 2013. Loss of p53 in enterocytes generates an inflammatory microenvironment enabling invasion and lymph node metastasis of carcinogen-induced colorectal tumors. Cancer Cell 23:193–106
    [Google Scholar]
  60. 60.
    Greten FR, Eckmann L, Greten TF, Park JM, Li Z-W et al. 2004. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118:3285–96
    [Google Scholar]
  61. 61.
    Grivennikov SI, Greten FR, Karin M. 2010. Immunity, inflammation, and cancer. Cell 140:6883–99
    [Google Scholar]
  62. 62.
    Mauro C, Leow SC, Anso E, Rocha S, Thotakura AK et al. 2011. NF-κB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration. Nat. Cell Biol. 13:101272–79
    [Google Scholar]
  63. 63.
    Hashemi Goradel N, Najafi M, Salehi E, Farhood B, Mortezaee K. 2019. Cyclooxygenase-2 in cancer: a review. J. Cell. Physiol. 234:55683–99
    [Google Scholar]
  64. 64.
    Taniguchi K, Karin M. 2018. NF-κB, inflammation, immunity and cancer: coming of age. Nat. Rev. Immunol. 18:5309–24
    [Google Scholar]
  65. 65.
    Endo A, Pärtty A, Kalliomäki M, Isolauri E, Salminen S. 2014. Long-term monitoring of the human intestinal microbiota from the 2nd week to 13 years of age. Anaerobe 28:149–56
    [Google Scholar]
  66. 66.
    Carrow HC, Batachari LE, Chu H. 2020. Strain diversity in the microbiome: lessons from Bacteroides fragilis. PLOS Pathog. 16:12e1009056
    [Google Scholar]
  67. 67.
    Sears CL, Geis AL, Housseau F. 2014. Bacteroides fragilis subverts mucosal biology: from symbiont to colon carcinogenesis. J. Clin. Investig. 124:104166–72
    [Google Scholar]
  68. 68.
    Round JL, Mazmanian SK. 2010. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. PNAS 107:2712204–9
    [Google Scholar]
  69. 69.
    Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. 2005. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122:1107–18
    [Google Scholar]
  70. 70.
    Boleij A, Hechenbleikner EM, Goodwin AC, Badani R, Stein EM et al. 2015. The Bacteroides fragilis toxin gene is prevalent in the colon mucosa of colorectal cancer patients. Clin. Infect. Dis. 60:2208–15
    [Google Scholar]
  71. 71.
    Toprak NU, Yagci A, Gulluoglu BM, Akin ML, Demirkalem P et al. 2006. A possible role of Bacteroides fragilis enterotoxin in the aetiology of colorectal cancer. Clin. Microbiol. Infect. 12:8782–86
    [Google Scholar]
  72. 72.
    Cheng WT, Kantilal HK, Davamani F. 2020. The mechanism of Bacteroides fragilis toxin contributes to colon cancer formation. Malays. . J. Med. Sci. 27:49–21
    [Google Scholar]
  73. 73.
    Wu S, Powell J, Mathioudakis N, Kane S, Fernandez E, Sears CL. 2004. Bacteroides fragilis enterotoxin induces intestinal epithelial cell secretion of interleukin-8 through mitogen-activated protein kinases and a tyrosine kinase-regulated nuclear factor-κB pathway. Infect. Immun. 72:105832–39
    [Google Scholar]
  74. 74.
    Liu Q-Q, Li C-M, Fu L-N, Wang H-L, Tan J et al. 2020. Enterotoxigenic Bacteroides fragilis induces the stemness in colorectal cancer via upregulating histone demethylase JMJD2B. Gut Microbes 12:11788900
    [Google Scholar]
  75. 75.
    Allen J, Rosendahl Huber A, Pleguezuelos-Manzano C, Puschhof J, Wu S et al. 2022. Colon tumors in enterotoxigenic Bacteroides fragilis (ETBF)-colonized mice do not display a unique mutational signature but instead possess host-dependent alterations in the APC gene. Microbiol. Spectr. 10:3e0105522
    [Google Scholar]
  76. 76.
    Yang Y, Weng W, Peng J, Hong L, Yang L et al. 2017. 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. Gastroenterology 152:4851–66.e24
    [Google Scholar]
  77. 77.
    Han YW, Redline RW, Li M, Yin L, Hill GB, McCormick TS. 2004. Fusobacterium nucleatum induces premature and term stillbirths in pregnant mice: implication of oral bacteria in preterm birth. Infect. Immun. 72:42272–79
    [Google Scholar]
  78. 78.
    Hajishengallis G. 2015. Periodontitis: from microbial immune subversion to systemic inflammation. Nat. Rev. Immunol. 15:130–44
    [Google Scholar]
  79. 79.
    Coppenhagen-Glazer S, Sol A, Abed J, Naor R, Zhang X et al. 2015. Fap2 of Fusobacterium nucleatum is a galactose-inhibitable adhesin involved in coaggregation, cell adhesion, and preterm birth. Infect. Immun. 83:31104–13
    [Google Scholar]
  80. 80.
    Park J, Shokeen B, Haake SK, Lux R. 2016. Characterization of Fusobacterium nucleatum ATCC 23726 adhesins involved in strain-specific attachment to Porphyromonas gingivalis. Int. J. Oral. Sci. 8:3138–44
    [Google Scholar]
  81. 81.
    Liu P-F, Shi W, Zhu W, Smith JW, Hsieh S-L et al. 2010. Vaccination targeting surface FomA of Fusobacterium nucleatum against bacterial co-aggregation: implication for treatment of periodontal infection and halitosis. Vaccine 28:193496–505
    [Google Scholar]
  82. 82.
    Kostic AD, Gevers D, Pedamallu CS, Michaud M, Duke F et al. 2012. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res 22:2292–98
    [Google Scholar]
  83. 83.
    Castellarin M, Warren RL, Freeman JD, Dreolini L, Krzywinski M et al. 2012. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res. 22:2299–306
    [Google Scholar]
  84. 84.
    Thomas AM, Manghi P, Asnicar F, Pasolli E, Armanini F et al. 2019. Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation. Nat. Med. 25:4667–78
    [Google Scholar]
  85. 85.
    Abed J, Maalouf N, Manson AL, Earl AM, Parhi L et al. 2020. Colon cancer-associated Fusobacterium nucleatum may originate from the oral cavity and reach colon tumors via the circulatory system. Front. Cell Infect. Microbiol. 10:400
    [Google Scholar]
  86. 86.
    Kölbl AC, Jeschke U, Friese K, Andergassen U. 2016. The role of TF- and Tn-antigens in breast cancer metastasis. Histol. Histopathol. 31:6613–21
    [Google Scholar]
  87. 87.
    Patil SA, Bshara W, Morrison C, Chandrasekaran EV, Matta KL, Neelamegham S. 2014. Overexpression of α2,3sialyl T-antigen in breast cancer determined by miniaturized glycosyltransferase assays and confirmed using tissue microarray immunohistochemical analysis. Glycoconj. J. 31:6–7509–21
    [Google Scholar]
  88. 88.
    McCoy AN, Araújo-Pérez F, Azcárate-Peril A, Yeh JJ, Sandler RS, Keku TO. 2013. Fusobacterium is associated with colorectal adenomas. PLOS ONE 8:1e53653
    [Google Scholar]
  89. 89.
    Queen J, Domingue JC, White JR, Stevens C, Udayasuryan B et al. 2022. Comparative analysis of colon cancer-derived Fusobacterium nucleatum subspecies: inflammation and colon tumorigenesis in murine models. mBio 13:e0299121
    [Google Scholar]
  90. 90.
    McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC et al. 2018. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin. Infect. Dis. 66:7e1–48
    [Google Scholar]
  91. 91.
    Nakatsu G, Li X, Zhou H, Sheng J, Wong SH et al. 2015. Gut mucosal microbiome across stages of colorectal carcinogenesis. Nat. Commun. 6:8727
    [Google Scholar]
  92. 92.
    Yu J, Feng Q, Wong SH, Zhang D, Liang QY et al. 2017. Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer. Gut 66:170–78
    [Google Scholar]
  93. 93.
    Long X, Wong CC, Tong L, Chu ESH, Ho Szeto C et al. 2019. Peptostreptococcus anaerobius promotes colorectal carcinogenesis and modulates tumour immunity. Nat. Microbiol. 4:122319–30
    [Google Scholar]
  94. 94.
    Warburg O. 1956. On the origin of cancer cells. Science 123:3191309–14
    [Google Scholar]
  95. 95.
    Sedlak JC, Yilmaz ÖH, Roper J. 2023. Metabolism and colorectal cancer. Annu. Rev. Pathol. Mech. Dis. 18:467–92
    [Google Scholar]
  96. 96.
    Luengo A, Gui DY, Vander Heiden MG. 2017. Targeting metabolism for cancer therapy. Cell Chem. Biol. 24:91161–80
    [Google Scholar]
  97. 97.
    Zitvogel L, Daillère R, Roberti MP, Routy B, Kroemer G. 2017. Anticancer effects of the microbiome and its products. Nat. Rev. Microbiol. 15:8465–78
    [Google Scholar]
  98. 98.
    Wang T, Cai G, Qiu Y, Fei N, Zhang M et al. 2012. Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers. ISME J 6:2320–29
    [Google Scholar]
  99. 99.
    O'Keefe SJD. 2016. Diet, microorganisms and their metabolites, and colon cancer. Nat. Rev. Gastroenterol. Hepatol. 13:12691–706
    [Google Scholar]
  100. 100.
    Donohoe DR, Collins LB, Wali A, Bigler R, Sun W, Bultman SJ. 2012. The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol. Cell 48:4612–26
    [Google Scholar]
  101. 101.
    Belcheva A, Irrazabal T, Robertson SJ, Streutker C, Maughan H et al. 2014. Gut microbial metabolism drives transformation of Msh2-deficient colon epithelial cells. Cell 158:2288–99
    [Google Scholar]
  102. 102.
    Poulogiannis G, Frayling IM, Arends MJ. 2010. DNA mismatch repair deficiency in sporadic colorectal cancer and Lynch syndrome. Histopathology 56:2167–79
    [Google Scholar]
  103. 103.
    Nakanishi S, Cleveland JL. 2021. Polyamine homeostasis in development and disease. Med. Sci. 9:228
    [Google Scholar]
  104. 104.
    Puleston DJ, Baixauli F, Sanin DE, Edwards-Hicks J, Villa M et al. 2021. Polyamine metabolism is a central determinant of helper T cell lineage fidelity. Cell 184:164186–202.e20
    [Google Scholar]
  105. 105.
    Rossi T, Vergara D, Fanini F, Maffia M, Bravaccini S, Pirini F. 2020. Microbiota-derived metabolites in tumor progression and metastasis. Int. J. Mol. Sci. 21:165786
    [Google Scholar]
  106. 106.
    Goodwin AC, Shields CED, Wu S, Huso DL, Wu X et al. 2011. Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis. PNAS 108:3715354–59
    [Google Scholar]
  107. 107.
    Johnson CH, Dejea CM, Edler D, Hoang LT, Santidrian AF et al. 2015. Metabolism links bacterial biofilms and colon carcinogenesis. Cell Metab 21:6891–97
    [Google Scholar]
  108. 108.
    Tomkovich S, Dejea CM, Winglee K, Drewes JL, Chung L et al. 2019. Human colon mucosal biofilms from healthy or colon cancer hosts are carcinogenic. J. Clin. Investig. 129:41699–712
    [Google Scholar]
  109. 109.
    Gupta N, Martin PM, Prasad PD, Ganapathy V. 2006. SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter. Life Sci 78:212419–25
    [Google Scholar]
  110. 110.
    Li H, Myeroff L, Smiraglia D, Romero MF, Pretlow TP et al. 2003. SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. PNAS 100:148412–17
    [Google Scholar]
  111. 111.
    Sivaprakasam S, Bhutia YD, Yang S, Ganapathy V. 2017. Short-chain fatty acid transporters: role in colonic homeostasis. Comprehensive Physiology R Terjung 299–314 Bethesda, MD: Wiley & Sons, 1st ed..
    [Google Scholar]
  112. 112.
    Thibault R, De Coppet P, Daly K, Bourreille A, Cuff M et al. 2007. Down-regulation of the monocarboxylate transporter 1 is involved in butyrate deficiency during intestinal inflammation. Gastroenterology 133:61916–27
    [Google Scholar]
  113. 113.
    Doherty JR, Yang C, Scott KEN, Cameron MD, Fallahi M et al. 2014. Blocking lactate export by inhibiting the Myc target MCT1 disables glycolysis and glutathione synthesis. Cancer Res 74:3908–20
    [Google Scholar]
  114. 114.
    Marchiq I, Pouysségur J. 2016. Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H+ symporters. J. Mol. Med. 94:2155–71
    [Google Scholar]
  115. 115.
    Wei W, Sun W, Yu S, Yang Y, Ai L 2016. Butyrate production from high-fiber diet protects against lymphoma tumor. Leukemia Lymphoma 57:102401–8
    [Google Scholar]
  116. 116.
    McDowall JS, Murphy BJ, Haumann M, Palmer T, Armstrong FA, Sargent F. 2014. Bacterial formate hydrogenlyase complex. PNAS 111:38E3948–56
    [Google Scholar]
  117. 117.
    Ternes D, Tsenkova M, Pozdeev VI, Meyers M, Koncina E et al. 2022. The gut microbial metabolite formate exacerbates colorectal cancer progression. Nat. Metab. 4:4458–75
    [Google Scholar]
  118. 118.
    Brennan CA, Clay SL, Lavoie SL, Bae S, Lang JK et al. 2021. Fusobacterium nucleatum drives a pro-inflammatory intestinal microenvironment through metabolite receptor-dependent modulation of IL-17 expression. Gut Microbes 13:11987780
    [Google Scholar]
  119. 119.
    Hurtado CG, Wan F, Housseau F, Sears CL. 2018. Roles for interleukin 17 and adaptive immunity in pathogenesis of colorectal cancer. Gastroenterology 155:61706–15
    [Google Scholar]
  120. 120.
    Sanders ME, Merenstein DJ, Reid G, Gibson GR, Rastall RA. 2019. Probiotics and prebiotics in intestinal health and disease: from biology to the clinic. Nat. Rev. Gastroenterol. Hepatol. 16:10605–16
    [Google Scholar]
  121. 121.
    Bell HN, Rebernick RJ, Goyert J, Singhal R, Kuljanin M et al. 2022. Reuterin in the healthy gut microbiome suppresses colorectal cancer growth through altering redox balance. Cancer Cell 40:2185–200.e6
    [Google Scholar]
  122. 122.
    Katsyuba E, Romani M, Hofer D, Auwerx J. 2020. NAD+ homeostasis in health and disease. Nat. Metab. 2:19–31
    [Google Scholar]
  123. 123.
    Chellappa K, McReynolds MR, Lu W, Zeng X, Makarov M et al. 2022. NAD precursors cycle between host tissues and the gut microbiome. Cell Metab 34:121947–59.e5
    [Google Scholar]
  124. 124.
    Chowdhry S, Zanca C, Rajkumar U, Koga T, Diao Y et al. 2019. NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling. Nature 569:7757570–75
    [Google Scholar]
  125. 125.
    Zitvogel L, Ayyoub M, Routy B, Kroemer G. 2016. Microbiome and anticancer immunosurveillance. Cell 165:2276–87
    [Google Scholar]
  126. 126.
    Takenaka MC, Quintana FJ. 2017. Tolerogenic dendritic cells. Semin. Immunopathol. 39:2113–20
    [Google Scholar]
  127. 127.
    Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT et al. 2018. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359:637191–97
    [Google Scholar]
  128. 128.
    Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N et al. 2015. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350:62641079–84
    [Google Scholar]
  129. 129.
    Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K et al. 2015. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350:62641084–89
    [Google Scholar]
  130. 130.
    Roberti MP, Yonekura S, Duong CPM, Picard M, Ferrere G et al. 2020. Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer. Nat. Med. 26:6919–31
    [Google Scholar]
  131. 131.
    Teng H, Wang Y, Sui X, Fan J, Li S et al. 2023. Gut microbiota-mediated nucleotide synthesis attenuates the response to neoadjuvant chemoradiotherapy in rectal cancer. Cancer Cell 41:1124–38.e6
    [Google Scholar]
  132. 132.
    Ziegler PK, Bollrath J, Pallangyo CK, Matsutani T, Canli Ö et al. 2018. Mitophagy in intestinal epithelial cells triggers adaptive immunity during tumorigenesis. Cell 174:188–101.e16
    [Google Scholar]
  133. 133.
    Overacre-Delgoffe AE, Bumgarner HJ, Cillo AR, Burr AHP, Tometich JT et al. 2021. Microbiota-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer. Immunity 54:122812–24.e4
    [Google Scholar]
  134. 134.
    Baumjohann D, Brossart P. 2021. T follicular helper cells: linking cancer immunotherapy and immune-related adverse events. J. Immunother. Cancer 9:6e002588
    [Google Scholar]
  135. 135.
    Łuksza M, Riaz N, Makarov V, Balachandran VP, Hellmann MD et al. 2017. A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. Nature 551:7681517–20
    [Google Scholar]
  136. 136.
    Bessell CA, Isser A, Havel JJ, Lee S, Bell DR et al. 2020. Commensal bacteria stimulate antitumor responses via T cell cross-reactivity. JCI Insight 5:8e135597
    [Google Scholar]
  137. 137.
    Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillère R et al. 2013. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342:6161971–76
    [Google Scholar]
  138. 138.
    Daillère R, Vétizou M, Waldschmitt N, Yamazaki T, Isnard C et al. 2016. Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects. Immunity 45:4931–43
    [Google Scholar]
  139. 139.
    Fluckiger A, Daillère R, Sassi M, Sixt BS, Liu P et al. 2020. Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage. Science 369:6506936–42
    [Google Scholar]
  140. 140.
    MetaHIT Consort. Li J, Jia H, Cai X, Zhong H et al. 2014. An integrated catalog of reference genes in the human gut microbiome. Nat. Biotechnol. 32:8834–41
    [Google Scholar]
  141. 141.
    Tanoue T, Morita S, Plichta DR, Skelly AN, Suda W et al. 2019. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature 565:7741600–5
    [Google Scholar]
  142. 142.
    Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA et al. 2013. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341:6145569–73
    [Google Scholar]
  143. 143.
    Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G et al. 2013. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504:7480446–50
    [Google Scholar]
  144. 144.
    Coutzac C, Jouniaux J-M, Paci A, Schmidt J, Mallardo D et al. 2020. Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer. Nat. Commun. 11:12168
    [Google Scholar]
  145. 145.
    Uribe-Herranz M, Rafail S, Beghi S, Gil-de-Gómez L, Verginadis I et al. 2019. Gut microbiota modulate dendritic cell antigen presentation and radiotherapy-induced antitumor immune response. J. Clin. Investig. 130:1466–79
    [Google Scholar]
  146. 146.
    Golden EB, Frances D, Pellicciotta I, Demaria S, Helen Barcellos-Hoff M, Formenti SC 2014. Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. OncoImmunology 3:4e28518
    [Google Scholar]
  147. 147.
    Grivennikov SI, Wang K, Mucida D, Stewart CA, Schnabl B et al. 2012. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491:7423254–58
    [Google Scholar]
  148. 148.
    Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA et al. 2011. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145:5745–57
    [Google Scholar]
  149. 149.
    Dupaul-Chicoine J, Yeretssian G, Doiron K, Bergstrom KSB, McIntire CR et al. 2010. Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity 32:3367–78
    [Google Scholar]
  150. 150.
    Nowarski R, Jackson R, Gagliani N, de Zoete MR, Palm NW et al. 2015. Epithelial IL-18 equilibrium controls barrier function in colitis. Cell 163:61444–56
    [Google Scholar]
  151. 151.
    Lavoie S, Chun E, Bae S, Brennan CA, Gallini Comeau CA et al. 2020. 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 158:51359–72.e9
    [Google Scholar]
  152. 152.
    Canale FP, Ramello MC, Núñez N, Furlan CLA, Bossio SN et al. 2018. CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells. Cancer Res 78:1115–28
    [Google Scholar]
  153. 153.
    Bachem A, Makhlouf C, Binger KJ, de Souza DP, Tull D et al. 2019. Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8+ cells. Immunity 51:2285–97.e5
    [Google Scholar]
  154. 154.
    Caputa G, Castoldi A, Pearce EJ. 2019. Metabolic adaptations of tissue-resident immune cells. Nat. Immunol. 20:7793–801
    [Google Scholar]
  155. 155.
    Luoma AM, Suo S, Wang Y, Gunasti L, Porter CBM et al. 2022. Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy. Cell 185:162918–35.e29
    [Google Scholar]
  156. 156.
    Savas P, Virassamy B, Ye C, Salim A et al. 2018. Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat. Med. 24:7986–93
    [Google Scholar]
  157. 157.
    Mager LF, Burkhard R, Pett N, Cooke NCA, Brown K et al. 2020. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science 369:65101481–89
    [Google Scholar]
  158. 158.
    Wang T, Gnanaprakasam JNR, Chen X, Kang S, Xu X et al. 2020. Inosine is an alternative carbon source for CD8+-T-cell function under glucose restriction. Nat. Metab. 2:7635–47
    [Google Scholar]
  159. 159.
    Bell HN, Huber AK, Singhal R, Korimerla N, Rebernick RJ et al. 2023. Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer. Cell Metab 35:1134–49.e6
    [Google Scholar]
  160. 160.
    Chen H, Tong T, Lu S-Y, Ji L, Xuan B et al. 2023. Urea cycle activation triggered by host-microbiota maladaptation driving colorectal tumorigenesis. Cell Metab. 35:4651–66.e7
    [Google Scholar]
  161. 161.
    Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M et al. 2020. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20:3174–86
    [Google Scholar]
  162. 162.
    Owens BMJ, Simmons A. 2013. Intestinal stromal cells in mucosal immunity and homeostasis. Mucosal. Immunol. 6:2224–34
    [Google Scholar]
  163. 163.
    Otte J-M, Rosenberg IM, Podolsky DK. 2003. Intestinal myofibroblasts in innate immune responses of the intestine. Gastroenterology 124:71866–78
    [Google Scholar]
  164. 164.
    Pang G, Couch L, Batey R, Clancy R, Cripps A. 1994. GM-CSF, IL-1α, IL-1β, IL-6, IL-8, IL-10, ICAM-1 and VCAM-1 gene expression and cytokine production in human duodenal fibroblasts stimulated with lipopolysaccharide, IL-1α and TNF-α. Clin. Exp. Immunol. 96:3437–43
    [Google Scholar]
  165. 165.
    Torres S, Bartolomé RA, Mendes M, Barderas R, Fernandez-Aceñero MJ et al. 2013. Proteome profiling of cancer-associated fibroblasts identifies novel proinflammatory signatures and prognostic markers for colorectal cancer. Clin. Cancer Res. 19:216006–19
    [Google Scholar]
  166. 166.
    Chen K, Liu Q, Tsang LL, Ye Q, Chan HC et al. 2017. Human MSCs promotes colorectal cancer epithelial-mesenchymal transition and progression via CCL5/β-catenin/Slug pathway. Cell Death Dis 8:5e2819
    [Google Scholar]
  167. 167.
    Pinchuk IV, Saada JI, Beswick EJ, Boya G, Qiu SM et al. 2008. PD-1 ligand expression by human colonic myofibroblasts/fibroblasts regulates CD4+ T-cell activity. Gastroenterology 135:41228–37.e2
    [Google Scholar]
  168. 168.
    Saada JI, Pinchuk IV, Barrera CA, Adegboyega PA, Suarez G et al. 2006. Subepithelial myofibroblasts are novel nonprofessional APCs in the human colonic mucosa. J. Immunol. 177:95968–79
    [Google Scholar]
  169. 169.
    Robinson W, Schischlik F, Gertz EM, Lee JS, Zhu K et al. 2022. CSI-microbes: identifying cell-type specific intracellular microbes from single-cell RNA-seq data. Cancer Res. 82:Suppl. 1282 (Abstr.)
    [Google Scholar]
  170. 170.
    Calon A, Lonardo E, Berenguer-Llergo A, Espinet E, Hernando-Momblona X et al. 2015. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat. Genet. 47:4320–29
    [Google Scholar]
  171. 171.
    Kalluri R. 2016. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16:9582–98
    [Google Scholar]
  172. 172.
    Huynh PT, Beswick EJ, Coronado YA, Johnson P, O'Connell MR et al. 2016. CD90+ stromal cells are the major source of IL-6, which supports cancer stem-like cells and inflammation in colorectal cancer. Int. J. Cancer 138:81971–81
    [Google Scholar]
  173. 173.
    Martin-Gallausiaux C, Béguet-Crespel F, Marinelli L, Jamet A, Ledue F et al. 2018. Butyrate produced by gut commensal bacteria activates TGF-beta1 expression through the transcription factor SP1 in human intestinal epithelial cells. Sci. Rep. 8:9742
    [Google Scholar]
  174. 174.
    Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T et al. 2011. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331:6015337–41
    [Google Scholar]
  175. 175.
    Chen Y, Chen Y, Zhang J, Cao P, Su W et al. 2020. Fusobacterium nucleatum promotes metastasis in colorectal cancer by activating autophagy signaling via the upregulation of CARD3 expression. Theranostics 10:1323–39
    [Google Scholar]
  176. 176.
    Brennan CA, Garrett WS. 2019. Fusobacterium nucleatum—symbiont, opportunist and oncobacterium. Nat. Rev. Microbiol. 17:3156–66
    [Google Scholar]
  177. 177.
    Parhi L, Alon-Maimon T, Sol A, Nejman D, Shhadeh A et al. 2020. Breast cancer colonization by Fusobacterium nucleatum accelerates tumor growth and metastatic progression. Nat. Commun. 11:13259
    [Google Scholar]
  178. 178.
    Mitsuhashi K, Nosho K, Sukawa Y, Matsunaga Y, Ito M et al. 2015. Association of Fusobacterium species in pancreatic cancer tissues with molecular features and prognosis. Oncotarget 6:97209–20
    [Google Scholar]
  179. 179.
    Yamamura K, Baba Y, Nakagawa S, Mima K, Miyake K et al. 2016. Human microbiome Fusobacterium nucleatum in esophageal cancer tissue is associated with prognosis. Clin. Cancer Res. 22:225574–81
    [Google Scholar]
  180. 180.
    Baruch EN, Youngster I, Ben-Betzalel G, Ortenberg R, Lahat A et al. 2021. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science 371:6529602–9
    [Google Scholar]
  181. 181.
    Wang Y, Wiesnoski DH, Helmink BA, Gopalakrishnan V, Choi K et al. 2018. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat. Med. 24:121804–8
    [Google Scholar]
  182. 182.
    Fu D, Calvo JA, Samson LD 2012. Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat. Rev. Cancer 12:12104–20
    [Google Scholar]
/content/journals/10.1146/annurev-physiol-042022-025619
Loading
/content/journals/10.1146/annurev-physiol-042022-025619
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error