Blocking Activin Receptor Ligands Is Not Sufficient to Rescue Cancer-Associated Gut Microbiota—A Role for Gut Microbial Flagellin in Colorectal Cancer and Cachexia?
Abstract
:1. Introduction
2. Results
2.1. Experimental C26 Cancer Increased the Diversity of the Gut Microbiota Compared to Healthy Mice without Consistent Effects of Blocking Activin Receptor Ligands
2.2. C26 Cancer, but Not the Alleviation of Cachexia by sACVR Administration, Modulated the Gut Microbiota Composition
2.3. Association of the Gut Microbiota with Cancer Cachexia-Associated Features
2.4. Gut Microbiota-Derived Flagellin Increased Inflammation in C26 Colon Cancer Cells In Vitro
2.5. Flagellin Inhibited Caspase-1 but Not Caspase-8 Activity, Increased Cytotoxicity Independent of Receptor-Interacting Protein (RIP) Kinases, and Decreasedreactive Oxygen Species (ROS) Levels in C26 Cancer Cells In Vitro
2.6. The Conditioned Media of Flagellin-Treated C26 Cells Appeared to Deteriorate Murine C2C12 Myotubes and Decreased Their Number
2.7. Myeloid-Derived Suppressor Cells, M2-Type Macrophage Markers, Cancer, Cachexia, and Flagellin
3. Discussion
4. Materials and Methods
4.1. Animals and Experimental Design
4.2. Human Tumor Samples
4.3. The Production of sACVR
4.4. Fecal DNA Extraction, 16S rRNA Sequencing and Analysis of the Gut Microbiota Composition
4.5. C26 and Thp-1 Cell Cultures, Flagellin Exposure, and Receptor Blockage Using Anti-CCL2 and TH1020 Antagonist
4.6. Measurement of IL6 Excretion, Caspase-1 and -8 Activity, Reactive Oxygen Species Production, and Cytotoxicity
4.7. C2C12 Myotubes, Treatment with Conditioned Media from C26 Cells, and Analysis of Myotube Sizes and Numbers
4.8. RNA Extraction, Quantitative Real-Time PCR, Protein Extraction from Cells and Human Tumors, and Western Blot
4.9. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Brennan, C.A.; Garrett, W.S. Gut Microbiota, Inflammation, and Colorectal Cancer. Annu. Rev. Microbiol. 2016, 70, 395–411. [Google Scholar] [CrossRef] [PubMed]
- Sender, R.; Fuchs, S.; Milo, R. Revised Estimates for the Number of Human and Bacteria Cells in the Body. PLoS Biol. 2016, 14, e1002533. [Google Scholar] [CrossRef] [PubMed]
- Qin, J.; Li, R.; Raes, J.; Arumugam, M.; Burgdorf, K.S.; Manichanh, C.; Nielsen, T.; Pons, N.; Levenez, F.; Yamada, T.; et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010, 464, 59–65. [Google Scholar] [CrossRef] [PubMed]
- Jahani-Sherafat, S.; Alebouyeh, M.; Moghim, S.; Ahmadi Amoli, H.; Ghasemian-Safaei, H. Role of gut microbiota in the pathogenesis of colorectal cancer; a review article. Gastroenterol. Hepatol. Bed Bench. 2018, 11, 101–109. [Google Scholar] [PubMed]
- Argiles, J.M.; Stemmler, B.; Lopez-Soriano, F.J.; Busquets, S. Inter-tissue communication in cancer cachexia. Nat. Rev. Endocrinol. 2018, 15, 9–20. [Google Scholar] [CrossRef]
- Bindels, L.B.; Neyrinck, A.M.; Claus, S.P.; Le Roy, C.I.; Grangette, C.; Pot, B.; Martinez, I.; Walter, J.; Cani, P.D.; Delzenne, N.M. Synbiotic approach restores intestinal homeostasis and prolongs survival in leukaemic mice with cachexia. ISME J. 2016, 10, 1456–1470. [Google Scholar] [CrossRef]
- Bindels, L.B.; Neyrinck, A.M.; Loumaye, A.; Catry, E.; Walgrave, H.; Cherbuy, C.; Leclercq, S.; Van Hul, M.; Plovier, H.; Pachikian, B.; et al. Increased gut permeability in cancer cachexia: Mechanisms and clinical relevance. Oncotarget 2018, 9, 18224–18238. [Google Scholar] [CrossRef]
- Fukui, H. Increased Intestinal Permeability and Decreased Barrier Function: Does It Really Influence the Risk of Inflammation? Inflamm. Intest. Dis. 2016, 1, 135–145. [Google Scholar] [CrossRef]
- Jemal, A.; Bray, F.; Center, M.M.; Ferlay, J.; Ward, E.; Forman, D. Global cancer statistics. CA Cancer J. Clin. 2011, 61, 69–90. [Google Scholar] [CrossRef]
- Stintzing, S.; Tejpar, S.; Gibbs, P.; Thiebach, L.; Lenz, H.J. Understanding the role of primary tumour localisation in colorectal cancer treatment and outcomes. Eur. J. Cancer 2017, 84, 69–80. [Google Scholar] [CrossRef]
- Patel, M.; McSorley, S.T.; Park, J.H.; Roxburgh, C.S.D.; Edwards, J.; Horgan, P.G.; McMillan, D.C. The relationship between right-sided tumour location, tumour microenvironment, systemic inflammation, adjuvant therapy and survival in patients undergoing surgery for colon and rectal cancer. Br. J. Cancer 2018, 118, 705–712. [Google Scholar] [CrossRef] [PubMed]
- Dejea, C.M.; Wick, E.C.; Hechenbleikner, E.M.; White, J.R.; Mark Welch, J.L.; Rossetti, B.J.; Peterson, S.N.; Snesrud, E.C.; Borisy, G.G.; Lazarev, M.; et al. Microbiota organization is a distinct feature of proximal colorectal cancers. Proc. Natl. Acad. Sci. USA 2014, 111, 18321–18326. [Google Scholar] [CrossRef] [PubMed]
- Xu, J.; Ye, Y.; Zhang, H.; Szmitkowski, M.; Makinen, M.J.; Li, P.; Xia, D.; Yang, J.; Wu, Y.; Wu, H. Diagnostic and Prognostic Value of Serum Interleukin-6 in Colorectal Cancer. Medicine 2016, 95, e2502. [Google Scholar] [CrossRef] [PubMed]
- McClellan, J.L.; Davis, J.M.; Steiner, J.L.; Enos, R.T.; Jung, S.H.; Carson, J.A.; Pena, M.M.; Carnevale, K.A.; Berger, F.G.; Murphy, E.A. Linking tumor-associated macrophages, inflammation, and intestinal tumorigenesis: Role of MCP-1. Am. J. Physiol. Gastrointest. Liver Physiol. 2012, 303, G1087–G1095. [Google Scholar] [CrossRef] [PubMed]
- Talbert, E.E.; Lewis, H.L.; Farren, M.R.; Ramsey, M.L.; Chakedis, J.M.; Rajasekera, P.; Haverick, E.; Sarna, A.; Bloomston, M.; Pawlik, T.M.; et al. Circulating monocyte chemoattractant protein-1 (MCP-1) is associated with cachexia in treatment-naive pancreatic cancer patients. J. Cachexia Sarcopenia Muscle 2018, 9, 358–368. [Google Scholar] [CrossRef] [PubMed]
- Belas, R. Biofilms, flagella, and mechanosensing of surfaces by bacteria. Trends Microbiol. 2014, 22, 517–527. [Google Scholar] [CrossRef]
- Kong, S.Y.; Tran, H.Q.; Gewirtz, A.T.; McKeown-Eyssen, G.; Fedirko, V.; Romieu, I.; Tjonneland, A.; Olsen, A.; Overvad, K.; Boutron-Ruault, M.C.; et al. Serum Endotoxins and Flagellin and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) Cohort. Cancer Epidemiol. Biomark. Prev. 2016, 25, 291–301. [Google Scholar] [CrossRef]
- Rhee, S.H.; Im, E.; Pothoulakis, C. Toll-like receptor 5 engagement modulates tumor development and growth in a mouse xenograft model of human colon cancer. Gastroenterology 2008, 135, 518–528. [Google Scholar] [CrossRef]
- Sfondrini, L.; Rossini, A.; Besusso, D.; Merlo, A.; Tagliabue, E.; Menard, S.; Balsari, A. Antitumor activity of the TLR-5 ligand flagellin in mouse models of cancer. J. Immunol. 2006, 176, 6624–6630. [Google Scholar] [CrossRef]
- Cho, H.Y.; Lee, S.W. TLR5 activation by flagellin induces doxorubicin resistance via interleukin-6 (IL-6) expression in two multiple myeloma cells. Cell. Immunol. 2014, 289, 27–35. [Google Scholar] [CrossRef]
- Qu, Y.; Misaghi, S.; Newton, K.; Maltzman, A.; Izrael-Tomasevic, A.; Arnott, D.; Dixit, V.M. NLRP3 recruitment by NLRC4 during Salmonella infection. J. Exp. Med. 2016, 213, 877–885. [Google Scholar] [CrossRef] [PubMed]
- Cen, X.; Liu, S.; Cheng, K. The Role of Toll-Like Receptor in Inflammation and Tumor Immunity. Front. Pharmacol. 2018, 9, 878. [Google Scholar] [CrossRef] [PubMed]
- Su, Z.; Yang, Z.; Xu, Y.; Chen, Y.; Yu, Q. Apoptosis, autophagy, necroptosis, and cancer metastasis. Mol. Cancer 2015, 14, 48. [Google Scholar] [CrossRef] [PubMed]
- Dajon, M.; Iribarren, K.; Petitprez, F.; Marmier, S.; Lupo, A.; Gillard, M.; Ouakrim, H.; Victor, N.; Vincenzo, D.B.; Joubert, P.E.; et al. Toll like receptor 7 expressed by malignant cells promotes tumor progression and metastasis through the recruitment of myeloid derived suppressor cells. Oncoimmunology 2019, 8, e1505174. [Google Scholar] [CrossRef] [PubMed]
- Aulino, P.; Berardi, E.; Cardillo, V.M.; Rizzuto, E.; Perniconi, B.; Ramina, C.; Padula, F.; Spugnini, E.P.; Baldi, A.; Faiola, F.; et al. Molecular, cellular and physiological characterization of the cancer cachexia-inducing C26 colon carcinoma in mouse. BMC Cancer 2010, 10, 363. [Google Scholar] [CrossRef]
- Nissinen, T.A.; Hentila, J.; Penna, F.; Lampinen, A.; Lautaoja, J.H.; Fachada, V.; Holopainen, T.; Ritvos, O.; Kivela, R.; Hulmi, J.J. Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses. J. Cachexia Sarcopenia Muscle 2018, 9, 514–529. [Google Scholar] [CrossRef]
- Benny Klimek, M.E.; Aydogdu, T.; Link, M.J.; Pons, M.; Koniaris, L.G.; Zimmers, T.A. Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia. Biochem. Biophys. Res. Commun. 2010, 391, 1548–1554. [Google Scholar] [CrossRef]
- Robertson, B.R.; O’Rourke, J.L.; Neilan, B.A.; Vandamme, P.; On, S.L.; Fox, J.G.; Lee, A. Mucispirillum schaedleri gen. nov., sp. nov., a spiral-shaped bacterium colonizing the mucus layer of the gastrointestinal tract of laboratory rodents. Int. J. Syst Evol Microbiol. 2005, 55, 1199–1204. [Google Scholar] [CrossRef]
- Ferreira, J.L.; Gao, F.Z.; Rossmann, F.M.; Nans, A.; Brenzinger, S.; Hosseini, R.; Wilson, A.; Briegel, A.; Thormann, K.M.; Rosenthal, P.B.; et al. Gamma-proteobacteria eject their polar flagella under nutrient depletion, retaining flagellar motor relic structures. PLoS Biol. 2019, 17, e3000165. [Google Scholar] [CrossRef]
- Duck, L.W.; Walter, M.R.; Novak, J.; Kelly, D.; Tomasi, M.; Cong, Y.; Elson, C.O. Isolation of flagellated bacteria implicated in Crohn’s disease. Inflamm. Bowel Dis. 2007, 13, 1191–1201. [Google Scholar] [CrossRef]
- Turner, L.; Ping, L.; Neubauer, M.; Berg, H.C. Visualizing Flagella while Tracking Bacteria. Biophys. J. 2016, 111, 630–639. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zafar, H.; Saier, M.H., Jr. Comparative genomics of transport proteins in seven Bacteroides species. PLoS ONE 2018, 13, e0208151. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, X.; Das, A.M.; Seideman, J.; Griswold, D.; Afuh, C.N.; Kobayashi, T.; Abe, S.; Fang, Q.; Hashimoto, M.; Kim, H.; et al. The CC chemokine ligand 2 (CCL2) mediates fibroblast survival through IL-6. Am. J. Respir. Cell Mol. Biol. 2007, 37, 121–128. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yan, L.; Liang, J.; Yao, C.; Wu, P.; Zeng, X.; Cheng, K.; Yin, H. Pyrimidine Triazole Thioether Derivatives as Toll-Like Receptor 5 (TLR5)/Flagellin Complex Inhibitors. ChemMedChem 2016, 11, 822–826. [Google Scholar] [CrossRef]
- Ziegler, T.R.; Luo, M.; Estivariz, C.F.; Moore, D.A., 3rd; Sitaraman, S.V.; Hao, L.; Bazargan, N.; Klapproth, J.M.; Tian, J.; Galloway, J.R.; et al. Detectable serum flagellin and lipopolysaccharide and upregulated anti-flagellin and lipopolysaccharide immunoglobulins in human short bowel syndrome. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2008, 294, R402R410. [Google Scholar] [CrossRef]
- Kumari, N.; Dwarakanath, B.S.; Das, A.; Bhatt, A.N. Role of interleukin-6 in cancer progression and therapeutic resistance. Tumour. Biol. 2016, 37, 11553–11572. [Google Scholar] [CrossRef]
- Rajanbabu, V.; Galam, L.; Fukumoto, J.; Enciso, J.; Tadikonda, P.; Lane, T.N.; Bandyopadhyay, S.; Parthasarathy, P.T.; Cho, Y.; Cho, S.H.; et al. Genipin suppresses NLRP3 inflammasome activation through uncoupling protein-2. Cell. Immunol. 2015, 297, 40–45. [Google Scholar] [CrossRef] [Green Version]
- Banic, B.; Nipic, D.; Suput, D.; Milisav, I. DMSO modulates the pathway of apoptosis triggering. Cell. Mol. Biol. Lett. 2011, 16, 328–341. [Google Scholar] [CrossRef]
- Zhang, L.; Yu, J. Role of apoptosis in colon cancer biology, therapy, and prevention. Curr. Colorectal Cancer Rep. 2013, 9, 331–340. [Google Scholar] [CrossRef] [Green Version]
- Feltham, R.; Vince, J.E.; Lawlor, K.E. Caspase-8: Not so silently deadly. Clin. Transl. Immunol. 2017, 6, e124. [Google Scholar] [CrossRef]
- Liu, W.J.; Ye, L.; Huang, W.F.; Guo, L.J.; Xu, Z.G.; Wu, H.L.; Yang, C.; Liu, H.F. p62 links the autophagy pathway and the ubiqutin-proteasome system upon ubiquitinated protein degradation. Cell. Mol. Biol. Lett. 2016, 21, 29. [Google Scholar] [CrossRef] [Green Version]
- Cuenca, A.G.; Cuenca, A.L.; Winfield, R.D.; Joiner, D.N.; Gentile, L.; Delano, M.J.; Kelly-Scumpia, K.M.; Scumpia, P.O.; Matheny, M.K.; Scarpace, P.J.; et al. Novel role for tumor-induced expansion of myeloid-derived cells in cancer cachexia. J. Immunol. 2014, 192, 6111–6119. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Porporato, P.E. Understanding cachexia as a cancer metabolism syndrome. Oncogenesis 2016, 5, e200. [Google Scholar] [CrossRef] [Green Version]
- Potgens, S.A.; Brossel, H.; Sboarina, M.; Catry, E.; Cani, P.D.; Neyrinck, A.M.; Delzenne, N.M.; Bindels, L.B. Klebsiella oxytoca expands in cancer cachexia and acts as a gut pathobiont contributing to intestinal dysfunction. Sci. Rep. 2018, 8, 12321. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Puppa, M.J.; White, J.P.; Sato, S.; Cairns, M.; Baynes, J.W.; Carson, J.A. Gut barrier dysfunction in the Apc(Min/+) mouse model of colon cancer cachexia. Biochim. Biophys. Acta 2011, 1812, 1601–1606. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cani, P.D.; Amar, J.; Iglesias, M.A.; Poggi, M.; Knauf, C.; Bastelica, D.; Neyrinck, A.M.; Fava, F.; Tuohy, K.M.; Chabo, C.; et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007, 56, 1761–1772. [Google Scholar] [CrossRef] [Green Version]
- Bindels, L.B.; Neyrinck, A.M.; Salazar, N.; Taminiau, B.; Druart, C.; Muccioli, G.G.; Francois, E.; Blecker, C.; Richel, A.; Daube, G.; et al. Non Digestible Oligosaccharides Modulate the Gut Microbiota to Control the Development of Leukemia and Associated Cachexia in Mice. PLoS ONE 2015, 10, e0131009. [Google Scholar] [CrossRef] [Green Version]
- Lautaoja, J.H.; Lalowski, M.; Nissinen, T.A.; Hentila, J.; Shi, Y.; Ritvos, O.; Cheng, S.; Hulmi, J.J. Muscle and serum metabolomes are dysregulated in colon-26 tumor-bearing mice despite amelioration of cachexia with activin receptor type 2B ligand blockade. Am. J. Physiol. Endocrinol. Metab. 2019, 316, E852–E865. [Google Scholar] [CrossRef]
- Peddareddigari, V.G.; Wang, D.; Dubois, R.N. The tumor microenvironment in colorectal carcinogenesis. Cancer Microenviron. 2010, 3, 149–166. [Google Scholar] [CrossRef] [Green Version]
- Roca, H.; Varsos, Z.S.; Sud, S.; Craig, M.J.; Ying, C.; Pienta, K.J. CCL2 and interleukin-6 promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-type macrophage polarization. J. Biol. Chem. 2009, 284, 34342–34354. [Google Scholar] [CrossRef] [Green Version]
- Nakamura, K.; Deyama, Y.; Yoshimura, Y.; Suzuki, K.; Morita, M. Toll like receptor 5 ligand induces monocyte chemoattractant protein-1 in mouse osteoblastic cells. Biomed Res 2012, 33, 39–44. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jeon, J.H.; Ahn, K.B.; Kim, S.K.; Im, J.; Yun, C.H.; Han, S.H. Bacterial flagellin induces IL-6 expression in human basophils. Mol. Immunol. 2015, 65, 168–176. [Google Scholar] [CrossRef] [PubMed]
- He, Q.; Fu, Y.; Tian, D.; Yan, W. The contrasting roles of inflammasomes in cancer. Am. J. Cancer Res. 2018, 8, 566–583. [Google Scholar] [PubMed]
- Dupaul-Chicoine, J.; Arabzadeh, A.; Dagenais, M.; Douglas, T.; Champagne, C.; Morizot, A.; Rodrigue-Gervais, I.G.; Breton, V.; Colpitts, S.L.; Beauchemin, N.; et al. The Nlrp3 Inflammasome Suppresses Colorectal Cancer Metastatic Growth in the Liver by Promoting Natural Killer Cell Tumoricidal Activity. Immunity 2015, 43, 751–763. [Google Scholar] [CrossRef] [Green Version]
- Celardo, I.; Grespi, F.; Antonov, A.; Bernassola, F.; Garabadgiu, A.V.; Melino, G.; Amelio, I. Caspase-1 is a novel target of p63 in tumor suppression. Cell Death Dis. 2013, 4, e645. [Google Scholar] [CrossRef]
- Lee, S.Y.; Ju, M.K.; Jeon, H.M.; Jeong, E.K.; Lee, Y.J.; Kim, C.H.; Park, H.G.; Han, S.I.; Kang, H.S. Regulation of Tumor Progression by Programmed Necrosis. Oxid. Med. Cell. Longev. 2018, 2018, 3537471. [Google Scholar] [CrossRef] [Green Version]
- Pollheimer, M.J.; Kornprat, P.; Lindtner, R.A.; Harbaum, L.; Schlemmer, A.; Rehak, P.; Langner, C. Tumor necrosis is a new promising prognostic factor in colorectal cancer. Hum. Pathol. 2010, 41, 1749–1757. [Google Scholar] [CrossRef]
- Lage, S.L.; Buzzo, C.L.; Amaral, E.P.; Matteucci, K.C.; Massis, L.M.; Icimoto, M.Y.; Carmona, A.K.; D’Imperio Lima, M.R.; Rodrigues, M.M.; Ferreira, L.C.; et al. Cytosolic flagellin-induced lysosomal pathway regulates inflammasome-dependent and -independent macrophage responses. Proc. Natl. Acad. Sci. USA 2013, 110, E3321–E3330. [Google Scholar] [CrossRef] [Green Version]
- Kumari, S.; Badana, A.K.; Gavara, M.M.; Gugalavath, S.; Malla, R. Reactive Oxygen Species: A Key Constituent in Cancer Survival. Biomark Insights 2018, 13. [Google Scholar] [CrossRef] [Green Version]
- Talbert, E.E.; Guttridge, D.C. Impaired regeneration: A role for the muscle microenvironment in cancer cachexia. Semin. Cell Dev. Biol. 2016, 54, 82–91. [Google Scholar] [CrossRef] [Green Version]
- De Sire, R.; Rizzatti, G.; Ingravalle, F.; Pizzoferrato, M.; Petito, V.; Lopetuso, L.; Graziani, C.; de Sire, A.; Mentella, M.C.; Mele, M.C.; et al. Skeletal muscle-gut axis: Emerging mechanisms of sarcopenia for intestinal and extra intestinal diseases. Minerva Gastroenterol. Dietol. 2018, 64, 351–362. [Google Scholar] [CrossRef] [PubMed]
- Bloise, E.; Ciarmela, P.; Dela Cruz, C.; Luisi, S.; Petraglia, F.; Reis, F.M. Activin A in Mammalian Physiology. Physiol. Rev. 2019, 99, 739–780. [Google Scholar] [CrossRef] [PubMed]
- Choi, S.S.; Kim, Y.; Han, K.S.; You, S.; Oh, S.; Kim, S.H. Effects of Lactobacillus strains on cancer cell proliferation and oxidative stress in vitro. Lett. Appl. Microbiol. 2006, 42, 452–458. [Google Scholar] [CrossRef] [PubMed]
- Maroof, H.; Hassan, Z.M.; Mobarez, A.M.; Mohamadabadi, M.A. Lactobacillus acidophilus could modulate the immune response against breast cancer in murine model. J. Clin. Immunol. 2012, 32, 1353–1359. [Google Scholar] [CrossRef]
- Jaffar, N.; Ishikawa, Y.; Mizuno, K.; Okinaga, T.; Maeda, T. Mature Biofilm Degradation by Potential Probiotics: Aggregatibacter actinomycetemcomitans versus Lactobacillus spp. PLoS ONE 2016, 11, e0159466. [Google Scholar] [CrossRef]
- Li, B.; Zhou, X.; Zhou, X.; Wu, P.; Li, M.; Feng, M.; Peng, X.; Ren, B.; Cheng, L. Effects of different substrates/growth media on microbial community of saliva-derived biofilm. FEMS Microbiol. Lett. 2017, 364. [Google Scholar] [CrossRef]
- Lima, H.R.; Gelani, V.; Fernandes, A.P.; Gasparoto, T.H.; Torres, S.A.; Santos, C.F.; Garlet, G.P.; da Silva, J.S.; Campanelli, A.P. The essential role of toll like receptor-4 in the control of Aggregatibacter actinomycetemcomitans infection in mice. J. Clin. Periodontol. 2010, 37, 248–254. [Google Scholar] [CrossRef]
- Chen, W.; Liu, F.; Ling, Z.; Tong, X.; Xiang, C. Human intestinal lumen and mucosa-associated microbiota in patients with colorectal cancer. PLoS ONE 2012, 7, e39743. [Google Scholar] [CrossRef]
- Periasamy, S.; Kolenbrander, P.E. Aggregatibacter actinomycetemcomitans builds mutualistic biofilm communities with Fusobacterium nucleatum and Veillonella species in saliva. Infect. Immun. 2009, 77, 3542–3551. [Google Scholar] [CrossRef] [Green Version]
- Amarnani, R.; Rapose, A. Colon cancer and enterococcus bacteremia co-affection: A dangerous alliance. J. Infect. Public Health 2017, 10, 681–684. [Google Scholar] [CrossRef]
- Khan, Z.; Siddiqui, N.; Saif, M.W. Enterococcus Faecalis Infective Endocarditis and Colorectal Carcinoma: Case of New Association Gaining Ground. Gastroenterol. Res. 2018, 11, 238–240. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sedgley, C.; Buck, G.; Appelbe, O. Prevalence of Enterococcus faecalis at multiple oral sites in endodontic patients using culture and PCR. J. Endod. 2006, 32, 104–109. [Google Scholar] [CrossRef] [PubMed]
- Sato, N.; Michaelides, M.C.; Wallack, M.K. Characterization of tumorigenicity, mortality, metastasis, and splenomegaly of two cultured murine colon lines. Cancer Res. 1981, 41, 2267–2272. [Google Scholar] [PubMed]
- Peters, B.A.; Dominianni, C.; Shapiro, J.A.; Church, T.R.; Wu, J.; Miller, G.; Yuen, E.; Freiman, H.; Lustbader, I.; Salik, J.; et al. The gut microbiota in conventional and serrated precursors of colorectal cancer. Microbiome 2016, 4, 69. [Google Scholar] [CrossRef] [Green Version]
- Sokol, H.; Pigneur, B.; Watterlot, L.; Lakhdari, O.; Bermudez-Humaran, L.G.; Gratadoux, J.J.; Blugeon, S.; Bridonneau, C.; Furet, J.P.; Corthier, G.; et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl. Acad. Sci. USA 2008, 105, 16731–16736. [Google Scholar] [CrossRef] [Green Version]
- Mendez-Salazar, E.O.; Ortiz-Lopez, M.G.; Granados-Silvestre, M.L.A.; Palacios-Gonzalez, B.; Menjivar, M. Altered Gut Microbiota and Compositional Changes in Firmicutes and Proteobacteria in Mexican Undernourished and Obese Children. Front. Microbiol. 2018, 9, 2494. [Google Scholar] [CrossRef] [Green Version]
- Hulmi, J.J.; Oliveira, B.M.; Silvennoinen, M.; Hoogaars, W.M.; Ma, H.; Pierre, P.; Pasternack, A.; Kainulainen, H.; Ritvos, O. Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins. Am. J. Physiol. Endocrinol. Metab. 2013, 304, E41–E50. [Google Scholar] [CrossRef]
- Rintala, A.; Riikonen, I.; Toivonen, A.; Pietila, S.; Munukka, E.; Pursiheimo, J.P.; Elo, L.L.; Arikoski, P.; Luopajarvi, K.; Schwab, U.; et al. Early fecal microbiota composition in children who later develop celiac disease and associated autoimmunity. Scand. J. Gastroenterol. 2018, 53, 403–409. [Google Scholar] [CrossRef] [Green Version]
- Caporaso, J.G.; Kuczynski, J.; Stombaugh, J.; Bittinger, K.; Bushman, F.D.; Costello, E.K.; Fierer, N.; Pena, A.G.; Goodrich, J.K.; Gordon, J.I.; et al. QIIME allows analysis of high-throughput community sequencing data. Nat. Methods 2010, 7, 335–336. [Google Scholar] [CrossRef] [Green Version]
- DeSantis, T.Z.; Hugenholtz, P.; Larsen, N.; Rojas, M.; Brodie, E.L.; Keller, K.; Huber, T.; Dalevi, D.; Hu, P.; Andersen, G.L. Greengenes, a chimera-checked 16S rRNA gene database and workbench compatible with ARB. Appl. Environ. Microbiol. 2006, 72, 5069–5072. [Google Scholar] [CrossRef] [Green Version]
Taxon | C26 + PBS vs. CTRL p-Value | C26 + PBS vs. CTRL Direction |
---|---|---|
Phylum | ||
Bacteroidetes | 0.046 | ↓ |
Deferribacteres | 0.046 | ↑ |
Firmicutes | 0.046 | ↑ |
Proteobacteria | 0.046 | ↑ |
Family | ||
Bacteroidaceae | 0.028 | ↑ |
Deferribacteraceae | 0.034 | ↑ |
Lactobacillaceae | 0.005 | ↑ |
Pasteurellaceae | 0.005 | ↑ |
Porphyromonadaceae | 0.005 | ↑ |
Enterococcaceae | 0.007 | ↑ |
Lachnospiraceae | 0.009 | ↑ |
S24-7 | 0.023 | ↓ |
Prevotellaceae | 0.007 | ↓ |
Genus | ||
Bacteroides | 0.030 | ↑ |
Lactobacillus | 0.008 | ↑ |
Enterococcus | 0.011 | ↑ |
Mucispirillum | 0.037 | ↑ |
ud-Lachnospiraceae | 0.012 | ↑ |
ud-S24-7 | 0.024 | ↓ |
Prevotella | 0.011 | ↓ |
Aggregatibacter | 0.008 | ↑ |
Sample | Tumor Location | Gender | Age | Diagnosis | pT | pN | Metastases |
---|---|---|---|---|---|---|---|
12 | Sigma | Female | 58 | Adenocarcinoma | a | pN1b | 3/10 |
15 | Rectum | Female | 65 | Adenocarcinoma | pT4 | pN0 | 0/6 |
24 | Sigma | Male | 78 | Adenocarcinoma | pT4a | pN2b | 15/35 |
27 | Caecum | Male | 84 | Adenocarcinoma | pT4b | pN2a | 4/15 |
29 | Colon (ascendens) | Male | 91 | Adenoma tubulovillosum | |||
31 | Colon (ascendens) | Female | 69 | Adenoma tubulovillosum | |||
32 | Caecum | Female | 59 | Adenocarcinoma | pT3 | pN2b | 8/16 |
34 | Caecum | Male | 79 | Adenoma tubulare | |||
35 | Caecum | Male | 56 | Adenocarcinoma | pT2 | pN0 | 0/22 |
36 | Sigma | Female | 68 | Adenocarcinoma | pT4a | pN0 | 0/13 |
37 | Sigma | Male | 67 | Adenocarcinoma | pT2 | pN0 | 0/13 |
39 | Sigma | Female | 70 | Adenocarcinoma | pT3 | pN0 | 0/13 |
50 | Sigma | Male | 65 | Adenocarcinoma | pT3 | pN2b | 11/38 |
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Share and Cite
Pekkala, S.; Keskitalo, A.; Kettunen, E.; Lensu, S.; Nykänen, N.; Kuopio, T.; Ritvos, O.; Hentilä, J.; Nissinen, T.A.; Hulmi, J.J. Blocking Activin Receptor Ligands Is Not Sufficient to Rescue Cancer-Associated Gut Microbiota—A Role for Gut Microbial Flagellin in Colorectal Cancer and Cachexia? Cancers 2019, 11, 1799. https://doi.org/10.3390/cancers11111799
Pekkala S, Keskitalo A, Kettunen E, Lensu S, Nykänen N, Kuopio T, Ritvos O, Hentilä J, Nissinen TA, Hulmi JJ. Blocking Activin Receptor Ligands Is Not Sufficient to Rescue Cancer-Associated Gut Microbiota—A Role for Gut Microbial Flagellin in Colorectal Cancer and Cachexia? Cancers. 2019; 11(11):1799. https://doi.org/10.3390/cancers11111799
Chicago/Turabian StylePekkala, Satu, Anniina Keskitalo, Emilia Kettunen, Sanna Lensu, Noora Nykänen, Teijo Kuopio, Olli Ritvos, Jaakko Hentilä, Tuuli A. Nissinen, and Juha J. Hulmi. 2019. "Blocking Activin Receptor Ligands Is Not Sufficient to Rescue Cancer-Associated Gut Microbiota—A Role for Gut Microbial Flagellin in Colorectal Cancer and Cachexia?" Cancers 11, no. 11: 1799. https://doi.org/10.3390/cancers11111799