Gut Microbiome and Colon Cancer: Role of Bacterial Metabolites and Their Molecular Targets in the Host

Current Colorectal Cancer Reports

Volumn 13, Issue 2, 2017, Pages 111-118

  Bhutia, Yangzom D ^a   Ogura, Jiro ^a   Sivaprakasam, Sathish ^a   Ganapathy, Vadivel ^a  

^a TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER SCHOOL OF MEDICINE   (United States)

Author keywords

Bacteria host symbiosis; Bacterial metabolites; Cell surface receptors; Colon cancer; Colonic inflammation; Epigenetics; HIF1 prolylhydroxylases; Histone deacetylases; NDRG3; Nuclear receptors; TET DNA demethylases

Indexed keywords

CELL SURFACE RECEPTOR; G PROTEIN COUPLED RECEPTOR; G PROTEIN COUPLED RECEPTOR 109A; G PROTEIN COUPLED RECEPTOR 41; G PROTEIN COUPLED RECEPTOR 43; G PROTEIN COUPLED RECEPTOR 81; G PROTEIN COUPLED RECEPTOR 91; HISTONE DEACETYLASE; LACTIC ACID; SHORT CHAIN FATTY ACID; SUCCINIC ACID; TRYPTOPHAN; UNCLASSIFIED DRUG;

BACTERIAL CELL WALL; BACTERIAL METABOLISM; COLON CANCER; COLON EPITHELIUM; DNA METHYLATION; ENZYME INHIBITION; EPITHELIUM CELL; GENE EXPRESSION; HISTONE ACETYLATION; HOST PATHOGEN INTERACTION; HUMAN; IMMUNOCOMPETENT CELL; INTESTINE FLORA; MOLECULAR GENETICS; NONHUMAN; REVIEW; SIGNAL TRANSDUCTION;

EID: 85013427506     PISSN: 15563790     EISSN: 15563804     Source Type: Journal    
DOI: 10.1007/s11888-017-0362-9     Document Type: Review

References (86)

1. Luckey T. Introduction to intestinal microecology. Am J Clin Nutr. 1972;25:1292–4.
2. •• Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacterial cells in the body. PLoS Biol. 2016;14:e1002533. This paper questions one of the most commonly cited value for the ratio of bacterial cells to human cells and provides a revised estimate of this ratio as ∼1:1 instead of the previous assumed ∼10:1.
3. Havenaar R. Intestinal health functions of colonic microbial metabolites: a review. Benefic Microbes. 2011;2:103–14.
4. Macfarlane GT, Macfarlane S. Bacteria, colonic fermentation, and gastrointestinal health. J AOAC Int. 2012;95:50–60.
5. Ramakrishna BS. Role of the gut microbiota in human nutrition and metabolism. J Gastroenterol Hepatol. 2013;28 Suppl 4:9–17.
6. Zeng H, Chi H. Metabolic control of regulatory T cell development and function. Trends Immunol. 2015;36:3–12.
7. Vipperla K, O’Keefe SJ. The microbiota and its metabolites in colonic mucosal health and cancer risk. Nutr Clin Pract. 2012;27:624–35.
8. Shanahan F. The colonic microbiota in health and disease. Curr Opin Gastroenterol. 2013;29:49–54.
9. Kovatcheva-Datchary P, Arora T. Nutrition, the gut microbiome and the metabolic syndrome. Best Pract Res Clin Gastroenterol. 2013;27:59–72.
10. Fukuda S, Ohno H. Gut microbiome and metabolic diseases. Semin Immunopathol. 2014;36:103–14.
11. • Schroeder BO, Backhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med. 2016;22:1079–89. This is an outstanding review of the literature summarizing the signals from the gut bacteria that travel to distant organs and influence their function in health and disease.
12. Bhutia YD, Ganapathy V. Short, but smart: SCFAs train T cells in the gut to fight autoimmunity in the brain. Immunity. 2015;43:629–31.
13. •• Haghikia A, Jorg S, Duscha A, et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity. 2015;43:817–29. This study demonstrates that dietary fatty acids, by modulating gut microbiota and their metabolism, regulate immune cells in the gut, which then travel to the periphery to impact systemic immunity.
14. Kuhn KA, Stappenbeck TS. Peripheral education of the immune system by the colonic microbiota. Semin Immunol. 2013;25:364–9.
15. Selkrig J, Wong P, Zhang X, Pettersson S. Metabolic tinkering by the gut microbiome: implications for brain development and function. Gut Microbes. 2014;5:369–80.
16. Tang WH, Hazen SL. The contributory role of gut microbiota in cardiovascular disease. J Clin Invest. 2014;124:4204–11.
17. Vamanu E, Pelinescu D, Sarbu I. Compartive fingerprinting of the human microbiota in diabetes and cardiovascular disease. J Med Food. 2016. doi:10.1089/jmf.2016.0085.
18. Blandino G, Inturri R, Lazzara F, et al. Impact of gut microbiota on diabetes mellitus. Diabetes Metab. 2016. doi:10.1016/j.diabet.2016.04.004.
19. Kraneveld AD, Szklany K, de Theije CG, Garssen J. Gut-to-brain axis in autism spectrum disorders: central role for the microbiome. Int Rev Neurobiol. 2016;131:263–87.
20. Vinolo MA, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short-chain fatty acids. Nutrients. 2011;3:858–76.
21. Felice C, Lewis A, Armuzzi A, Lindsay JO, Silver A. Review article: selective histone deacetylase isoforms as potential therapeutic targets in inflammatory bowel diseases. Aliment Pharmacol Ther. 2015;41:26–38.
22. Thangaraju M, Gopal E, Martin PM, et al. SLC5A8 triggers tumor cell apoptosis through pyruvate-dependent inhibition of histone deacetylases. Cancer Res. 2006;66:11560–4.
23. Singh N, Thangaraju M, Prasad PD, et al. Blockade of dendritic cell development by bacterial fermentation products butyrate and propionate through a transporter (Slc5a8)-dependent inhibition of histone deacetylases. J Biol Chem. 2010;285:27601–8.
24. Thangaraju M, Cresci GA, Liu K, et al. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res. 2009;69:2826–32.
25. Tazoe H, Otomo Y, Kaji I, et al. Roles of short-chain fatty acids receptors, GPR41 and GPR43 on colonic functions. J Physiol Pharmacol. 2008;59 Suppl 2:252–62.
26. Ganapathy V, Thangaraju M, Prasad PD, Martin PM, Singh N. Transporters and receptors for short-chain fatty acids as the molecular link between colonic bacteria and the host. Curr Opin Pharmacol. 2013;13:869–74.
27. Tan J, McKenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L. The role of short-chain fatty acids in health and disease. Adv Immunol. 2014;121:91–119.
28. Ganapathy V, Thangaraju M, Gopal E, et al. Sodium-coupled monocarboxylate transporters in normal tissues and in cancer. AAPS J. 2008;10:193–9.
29. + symporters. J Mol Med. 2016;94:155–71.
30. Ganapathy V, Thangaraju M, Prasad PD. Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond. Pharmacol Ther. 2009;121:29–40.
31. Bhutia YD, Babu E, Ramachandran S, Yang S, Thangaraju M, Ganapathy V. SLC transporters as a novel class of tumour suppressors: identity, function and molecular mechanisms. Biochem J. 2016;473:1113–24.
32. Li H, Myeroff L, Smiraglia D, et al. SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci U S A. 2003;100:8412–7.
33. +-coupled transporter for short-chain fatty acids. J Biol Chem. 2004;279:13293–6.
34. Frank H, Groger N, Diener M, Becker C, Braun T, Boettger T. Lactaturia and loss of sodium-dependent lactate uptake in the colon of SLC5A8-deficient mice. J Biol Chem. 2008;283:24729–37.
35. +-coupled high-affinity transporter for short-chain fatty acids, is a conditional tumour suppressor in colon that protects against colitis and colon cancer under low-fibre dietary conditions. Biochem J. 2015;469:267–78. This study demonstrated a link between the tumor-suppressive function of the short-chain fatty acid transporter SLC5A8 and the dietary fiber content and provided a reasonable explanation as to why Slc5a8-null mice do not show increased risk for colitis and colon cancer under normal dietary conditions.
36. Cresci GA, Thangaraju M, Mellinger JD, Liu K, Ganapathy V. Colonic gene expression in conventional and germ-free ice with a focus on the butyrate receptor GPR109A and the butyrate transporter SLC5A8. J Gastrointest Sug. 2010;14:449–61.
37. •• 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;40:128–39. This study demonstrated unequivocally the anti-inflammatory and tumor-suppressive function of the butyrate receptor GPR109A in vivo using Gpr109a-null mice.
38. Taggart AK, Kero J, Gan X, et al. (D)-β-hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J Biol Chem. 2005;280:26649–52.
39. •• Tan J, KcKenzie C, Vuillermin PJ, et al. Dietary fiber and bacterial SCFA enhance oral tolerance and protect against food allergy through diverse cellular pathways. Cell Rep. 2016;15:2809–24. Here, the authors showed that a high-fiber content in the diet improved oral tolerance and offered protection against food allergy and that deletion of Gpr43 or Gpr109a in mice exacerbated food allergy.
40. Ang Z, Ding JL. GPR41 and GPR43 in obesity and inflammation—protective or causative? Front Immunol. 2016;7:28.
41. Tazoe H, Otomo Y, Karaki S, et al. Expression of short-chain fatty acid receptor GPR41 in the human colon. Biomed Res. 2009;30:149–56.
42. Karaki S, Mitsui R, Hayashi H, et al. Short-chain fatty acid receptor, Gpr43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine. Cell Tissue Res. 2006;324:353–60.
43. Karaki S, Tazoe H, Hayashi H, et al. Expression of the short-chain fatty acid receptor, GPR43, in the human colon. J Mol Histol. 2008;39:135–42.
44. Trompette A, Gollwitzer ES, Yadava K, et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med. 2014;20:159–66.
45. Kime MH, Kang SG, Park JH, Yanagisawa M, Kim CH. Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology. 2013;145:396–406.
46. Maslowski KM, Vieira AT, Ng A, et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009;461:1282–6.
47. Smith PM, Howitt MR, Panikov N, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013;341:569–73.
48. Masui R, Sasaki M, Funaki Y, et al. G protein-coupled receptor 43 moderates gut inflammation through cytokine regulation from mononuclear cells. Inflamm Bowel Dis. 2013;19:2848–56.
49. Macia L, Tan J, Vieira AT, et al. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat Commun. 2015;6:6734.
50. Sivaprakasam S, Gurav V, Paschall AV, et al. An essential role of Ffar2 (Gpr43) in dietary fibre-mediated promotion of healthy composition of gut microbiota and suppression of intestinal carcinogenesis. Oncogenesis. 2016;5:e238.
51. Sina C, Gavrilova O, Forster M, et al. G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation. J Immunol. 2009;183:7514–22.
52. Choi SY, Collins CC, Gout PW, Wang Y. Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite? J Pathol. 2013;230:350–5.
53. Liu C, Wu J, Zhu J, et al. Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor. J Biol Chem. 2009;284:2811–22.
54. Lee DC, Sohn HA, Park ZY, et al. A lactate-induced response to hypoxia. Cell. 2015;161:595–609.
55. Jakobsdottir G, Xu J, Molin G, Ahme S, Nyman M. High-fat diet reduces the formation of butyrate, but increases succinate, inflammation, liver fat and cholesterol in rats, while dietary fibre counteracts these effects. PLoS One. 2013;8:e80476.
56. Yang M, Pollard PJ. Succinate: a new epigenetic hacker. Cancer Cell. 2013;23:709–11.
57. Boulahbel H, Duran RV, Gottlieb E. Prolyl hydroxylases as regulators of cell metabolism. Biochem Soc Trans. 2009;37:291–4.
58. He W, Miao FJ, Lin DC, et al. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature. 2004;429:188–93.
59. Hubbard TD, Murray IA, Perdew GH. Indole and tryptophan metabolism: endogenous and dietary routes to Ah receptor activation. Drug Metab Dispos. 2015;43:1522–35.
60. Jin UH, Lee SO, Sridharan G, et al. Microbiome-derived tryptophan metabolites and their aryl hydrocarbon receptor-dependent agonist and antagonist activities. Mol Pharmacol. 2014;85:777–88.
61. Wikoff WR, Anfora AT, Liu J, et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci U S A. 2009;106:3698–703.
62. Venkatesh M, Mukherjee S, Wang H, et al. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity. 2014;41:296–310.
63. Stockinger B, Di Meglio P, Gialitakis M, Duarte JH. The aryl hydrocarbon receptor: multitasking in the immune system. Annu Rev Immunol. 2014;32:403–32.
64. Xie G, Raufman JP. Role of the aryl hydrocarbon receptor in colon neoplasia. Cancers. 2015;7:1436–46.
65. Goettel JA, Gandhi R, Kenison JE, et al. AHR activation is protective against colitis driven by T cells in humanized mice. Cell Rep. 2016;17:1318–29.
66. Diaz-Diaz CJ, Ronnekleiv-Kelly SM, Nukaya M, Geiger PG, et al. The aryl hydrocarbon receptor is a repressor of inflammation-associated colorectal tumorigenesis in mouse. Ann Surg. 2016;264:429–36.
67. Pondugula SR, Pavek P, Mani S. Pregnane X receptor and cancer: context-specificity is key. Nucl Receptor Res. 2016;3.
68. Jonker JW, Liddle C, Downes M. FXR and PXR: potential therapeutic targets in cholestasis. J Steroid Biochem Mol Biol. 2012;130:147–58.
69. •• Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19:576–85. This was the first report on the generation of trimethylamine (TMA) in the colon by bacterial metabolism of diet-derived carnitine and the subsequent hepatic conversion of TMA into the cardiovascular toxin TMA oxide, thus providing a mechanistic link between high dietary intake of carnitine-rich red meat and risk for cardiovascular disease.
70. • Tang WH, Wang Z, Levison BS, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368:1575–84. This study provides evidence for the association between increased plasma levels of TMAO and risk for cardiovascular disease and also for dietary lipid phosphatidylcholine as the source for colonic bacterial metabolism to generate TMA, the precursor for TMAO.
71. Gregory JC, Buffa JA, Org E, et al. Transmission of atherosclerosis susceptibility with gut microbial transplantation. J Biol Chem. 2015;290:5647–60.
72. Brown JM, Hazen SL. The gut microbial endocrine organ: bacterially derived signals driving cardiometabolic diseases. Annu Rev Med. 2015;66:343–59.
73. Wilson A, McLean C, Kim RB. Trimethylamine-N-oxide: a link between the gut microbiome, bile acid metabolism, and atherosclerosis. Curr Opin Lipidol. 2016;27:148–54.
74. Wallrabenstein I, Kuklan J, Weber L, et al. Human trace amine-associated receptor TAAR5 can be activated by trimethylamine. PLoS One. 2013;8. e54950.
75. Lakhan R, Said M. Lipopolysaccharide inhibits colonic biotin uptake via interference with membrane expression of its transporter: a role for casein kinase 2-mediated pathway. Am J Physiol Cell Physiol. 2017. doi:10.1152/ajpcell.00300.2016.
76. Anitha M, Vijay-Kumar M, Sitaraman SV, Gewirtz AT, Srinivasan S. Gut microbial products regulate murine gastrointestinal motility via Toll-like receptor 4 signaling. Gastroenterology. 2012;143:1006–16.
77. Reichardt F, Chassaing B, Nezami BG, et al. Western diet induces colonic nitrergic myenteric neuropathy and dysmotility in mice via saturated fatty acid- and LPS-induced TLR4 signaling. J Physiol. 2016. doi:10.1113/JP273269.
78. Cario E. Microbiota and innate immunity in intestinal inflammation and neoplasia. Curr Opin Gastroenterol. 2013;29:85–91.
79. Kamba A, Lee IA, Mizoguchi E. Potential association between TLR4 and chitinase 3-like 1 (CHI3L1/YKL40) signaling on colonic epithelial cells in inflammatory bowel disease and colitis-associated cancer. Curr Mol Med. 2013;13:1110–21.
80. Jiang Q, Akashi S, Miake K, Petty HR. Lipopolysaccharide induces physical proximity between CD14 and Toll-like receptor 4 (TLR4) prior to nuclear translocation of NF-κB. J Immunol. 2000;165:3541–4.
81. de Silva Correia J, Soldau K, Christen U, Tobias PS, Ulevitch RJ. Lipopolysaccharide is close proximity to each of the proteins in its membrane receptor complex; transfer from CD14 to TLR4 and MD2. J Biol Chem. 2001;276:21129–35.
82. •• Kuo WT, Lee TC, Yang HY, et al. LPS receptor subunits have antagonistic roles in epithelial apoptosis and colonic carcinogenesis. Cell Death Diff. 2015;22:1590–604. This study provided the molecular rationale for the antagonistic actions of LPS in colonic epithelium via the presence or absence of the co-expression of CD14 with TLR4.
83. Ishida A, Akita K, Mori Y, et al. Negative regulation of Toll-like receptor-4 signaling through the binding of glycosylphosphatidylinositol-anchored glycoprotein, CD14, with the sialic acid-binding lectin, CD33. J Biol Chem. 2014;289:25341–50.
84. Santaolalla R, Sussman DA, Ruiz JR, et al. TLR4 activates the β-catenin pathway to cause intestinal neoplasia. PLoS One. 2013;8:e63298.
85. Munford RS, Hall CL. Detoxification of bacterial lipopolysaccharide (endotoxins) by a human neutrophil enzyme. Science. 1986;234:203–5.
86. • Janelsins BM, Lu M, Datta SK. Altered inactivation of commensal LPS due to acyloxyacyl hydrolase deficiency in colonic dendritic cells impairs mucosal Th17 immunity. Proc Natl Acad Sci U S A. 2014;111:373–8. This study describes the role of chronic exposure of the colon to LPS in the polarization of naïve T cells towards pro-inflammatory Th17-positive T cells or immunosuppressive regulatory T cells (Tregs).