Die intestinale Mikrobiota in der Onkologie

Zusammenfassung

Das physiologische intestinale Mikrobiom (Bakterien des Darmes) ist wesentlich für Funktion und Integrität des Darmes. Mikrobiom-Abweichungen können für die onkologische Therapie wichtige Hinweise liefern: Ein vermehrtes Auftreten des als invasiv bekannten Sulfatreduzierers Fusobacterium nucleatum (FN) im Mikrobiom zeigt eine hohe Korrelation mit dem Auftreten des kolorektalen Karzinoms. Hintergrund ist die Eigenschaft von FN, am Darmepithel ein entzündliches Mikroklima zu erzeugen, das den Darm schädigt und die Tumorprogression ebenso fördert wie die durch FN erzeugte Freisetzung des Transkriptionsfaktors NF-κB über die Expression von Onkogenen und weiteren proinflammatorischen Genprodukten. Darüber hinaus lässt FN die T-Zell-Dichte und -Aktivität sinken und hemmt so die Tumorabwehr. Weiterhin aktivieren proentzündliche Zytokine den Abbau der Aminosäure Tryptophan (TRP) zu Kynurenin. Damit wird einerseits TRP der Proteinbio- und der Serotoninsynthese entzogen. Andererseits sind erhöhte Kynurenin-Spiegel mit verringerten Überlebensraten assoziiert, da Kynurenin immunsuppressiv wirkt. Eine Therapie, die auf den Darm, seine Mikrobiota und das Eindämmen der Entzündung abzielt, kann die negativen Auswirkungen eingrenzen und die Regeneration und Remission des Patienten unterstützen.

Abstract

The physiological intestinal microbiome (bacteria of the intestine) is essential for function and integrity of the intestine. Microbial deviations can provide important indications for oncological therapy: high frequency of the Fusobacterium nucleatum (FN), known as an invasive sulfate reducer, shows a high correlation with the occurrence of colorectal cancer. The background is that FN generates an inflammatory microclimate at the intestinal epithelium which damages the intestine and increases the tumor progression as well as the release of the transcription factor NF-κB via expression of oncogenes and other proinflammatory gene products. In addition, FN reduces T-cell density and activity and therefore inhibits the tumor defence. Furthermore, pro-inflammatory cytokines activate the degradation of the amino acid tryptophan (TRP) to kynurenine. Hence TRP lacks for the protein biosynthesis and serotonin synthesis. On the other hand, elevated kynurenine levels are associated with reduced survival rates as kynurenine has an immunsuppressive effect. A therapy targeting the intestine, its microbiota and diminishing of inflammation can inhibit those negative effects and support the regeneration and remission of the patient.

Schlüsselwörter

Mikrobiom - kolorektales Karzinom - Fusobacterium nucleatum - Entzündung - Tryptophan

Key words

Microbiome - colorectal carcinoma - Fusobacterium nucleatum - inflammation - tryptophan

• Literatur

• 1 Arumuggam N, Bhowmick NA, Rupasinghe HP. A review: phytochemicals targeting JAK/STAT signaling and IDO expression in cancer. Phytother Res 2015; 29: 805-817
• 2 Bashir A, Miskeen AY, Hazari YM. et al. Fusobacterium nucleatum, inflammation, and immunity: the fire within human gut. Tumour Biol 2016; 37: 2805-2810
• 3 Borsini A, Alboni S, Horowitz MA. et al. Rescue of IL-1β-induced reduction of human neurogenesis by omega-3 fatty acids and antidepressants. Brain Behav Immun 2017; 65: 230-238
• 4 Castellarin M, Warren RL, Freeman JD. et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res 2012; 22: 299-306
• 5 Cavia-Saiz M, Muñiz Rodríguez P, Llorente Ayala B. et al. The role of plasma IDO activity as a diagnostic marker of patients with colorectal cancer. Mol Biol Rep 2014; 41: 2275-2279
• 6 Chen W, Liu F, Ling Z. et al. Human intestinal lumen and mucosa-associated microbiota in patients with colorectal cancer. PLoS One 2012; 7: e39743
• 7 Creelan BC, Antonia S, Bepler G. et al. Indoleamine 2,3-dioxygenase activity and clinical outcome following induction chemotherapy and concurrent chemoradiation in Stage III non-small cell lung cancer. Oncoimmunology 2013; 2: e23428
• 8 Folgiero V, Goffredo BM, Filippini P. et al. Indoleamine 2,3-dioxygenase 1 (IDO1) activity in leukemia blasts correlates with poor outcome in childhood acute myeloid leukemia. Oncotarget 2014; 5: 2052-2064
• 9 Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 2012; 12: 253-268
• 10 Gill SR, Pop M, Deboy RT. et al. Metagenomic analysis of the human distal gut microbiome. Science 2006; 312: 1355-1359
• 11 Gulubova MV, Ananiev JR, Vlaykova TI. et al. Role of dendritic cells in progression and clinical outcome of colon cancer. Int J Colorectal Dis 2012; 27: 159-169
• 12 Hitti J, Hillier SL, Agnew KJ. et al. Vaginal indicators of amniotic fluid infection in preterm labor. Obstet Gynecol 2001; 97: 211-219
• 13 Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 2012; 30: 531-564
• 14 Kostic AD, Chun E, Robertson L. et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 2013; 14: 207-215
• 15 Li YY, Ge QX, Cao J. et al. Association of Fusobacterium nucleatum infection with colorectal cancer in Chinese patients. World J Gastroenterol 2016; 22: 3227-3233
• 16 Liu W, Mi S, Ruan Z. et al. Dietary tryptophan enhanced the expression of tight junction protein ZO-1 in intestine. J Food Sci 2017; 82: 562-567
• 17 Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 2010; 22: 231-237
• 18 Mehta RS, Nishihara R, Cao Y. et al. Association of dietary patterns with risk of colorectal cancer subtypes classified by Fusobacterium nucleatum in tumor tissue. JAMA Oncol 2017; 3: 921-927
• 19 Mima K, Nishihara R, Qian ZR. et al. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut 2016; 65: 1973-1980
• 20 Mima K, Sukawa Y, Nishihara R. et al. Fusobacterium nucleatum and T cells in colorectal carcinoma. JAMA Oncol 2015; 1: 653-661
• 21 Nguyen NT, Nakahama T, Le DH. et al. Aryl hydrocarbon receptor and kynurenine: recent advances in autoimmune disease research. Front Immunol 2014; 5: 551
• 22 Prince AL, Antony KM, Chu DM, Aagaard KM. The microbiome, parturition, and timing of birth: more questions than answers. J Reprod Immunol 2014; 104-105: 12-19
• 23 Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F. et al. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 2004; 118: 229-241
• 24 Rothwell PM, Wilson M, Elwin CE. et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 2010; 376: 1741-1750
• 25 Rubinstein MR, Wang X, Liu W. et al. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe 2013; 14: 195-206
• 26 Shenker BJ, Datar S. Fusobacterium nucleatum inhibits human T-cell activation by arresting cells in the mid-G1 phase of the cell cycle. Infect Immun 1995; 63: 4830-4836
• 27 Shenker BJ, DiRienzo JM. Suppression of human peripheral blood lymphocytes by Fusobacterium nucleatum. J Immunol 1984; 132: 2357-2362
• 28 Sugimoto S, Naganuma M, Kanai T. Indole compounds may be promising medicines for ulcerative colitis. J Gastroenterol 2016; 51: 853-861
• 29 Sun HL, Zhou X, Xue YF. et al. Increased frequency and clinical significance of myeloid-derived suppressor cells in human colorectal carcinoma. World J Gastroenterol 2012; 18: 3303-3309
• 30 Tomé D. The roles of dietary glutamate in the intestine. Ann Nutr Metab 2018; 73 (Suppl. 05) 15-20
• 31 van Baren N, Van den Eynde BJ. Tryptophan-degrading enzymes in tumoral immune resistance. Front Immunol 2015; 6: 34
• 32 Wang HF, Li LF, Guo SH. et al. Evaluation of antibody level against Fusobacterium nucleatum in the serological diagnosis of colorectal cancer. Sci Rep 2016; 6: 33440
• 33 Yu CJ, Zheng MF, Kuang CX. et al. Oren-gedoku-to and its constituents with therapeutic potential in Alzheimer's disease inhibit indoleamine 2, 3-dioxygenase activity in vitro. J Alzheimers Dis 2010; 22: 257-266