Abstract
Overweight and obesity are associated with increased risk of developing metabolic disorders such as diabetes and cardiovascular diseases. However, besides these metabolic diseases, excess body weight is also associated with different cancers, including gastrointestinal cancers, such as liver, pancreatic and colon cancers. Inflammation is a common feature of both obesity and cancer; however, the origin of this inflammation has been largely debated. Over the past decade, growing evidence has shown that the composition of the gut microbiota and its activity might be associated not only with the onset of inflammation but also with metabolic disorders and cancer. Here, we review the links between the gut microbiota, gut barrier function and the onset of low-grade inflammation in the development of gastrointestinal cancer. We also describe the mechanisms by which specific microorganism-associated molecular patterns crosstalk with the immune system and how the metabolic activity of bacteria induces specific signalling pathways beyond the gut that eventually trigger carcinogenesis.
Key points
-
Gut microorganisms produce a myriad of metabolites and factors that affect host metabolism and immunity.
-
Obesity and gastrointestinal cancer are characterized by inflammation and common molecular mechanisms contributing to the onset of these diseases.
-
Specific gut bacteria are undeniably associated with the development of gastrointestinal cancers.
-
Targeting the composition of the intestinal microbiota and eventually the metabolites produced might constitute an interesting strategy to tackle obesity and cancers.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Lauby-Secretan, B. et al. Body fatness and cancer — viewpoint of the IARC working group. N. Engl. J. Med. 375, 794–798 (2016).
Arnold, M. et al. Global burden of cancer attributable to high body-mass index in 2012: a population-based study. Lancet Oncol. 16, 36–46 (2015).
Clevers, H. At the crossroads of inflammation and cancer. Cell 118, 671–674 (2004).
Gupta, R. A. & Dubois, R. N. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat. Rev. Cancer 1, 11–21 (2001).
Balkwill, F. & Coussens, L. M. Cancer: an inflammatory link. Nature 431, 405–406 (2004).
Pikarsky, E. et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461–466 (2004).
Greten, F. R. et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004).
Vogtmann, E. & Goedert, J. J. Epidemiologic studies of the human microbiome and cancer. Br. J. Cancer 114, 237–242 (2016).
Dzutsev, A., Goldszmid, R. S., Viaud, S., Zitvogel, L. & Trinchieri, G. The role of the microbiota in inflammation, carcinogenesis, and cancer therapy. Eur. J. Immunol. 45, 17–31 (2015).
Erdman, S. E. & Poutahidis, T. The microbiome modulates the tumor macroenvironment. Oncoimmunology 3, e28271 (2014).
Schwabe, R. F. & Jobin, C. The microbiome and cancer. Nat. Rev. Cancer 13, 800–812 (2013).
Fulbright, L. E., Ellermann, M. & Arthur, J. C. The microbiome and the hallmarks of cancer. PLoS Pathog. 13, e1006480 (2017).
Li, J. et al. An integrated catalog of reference genes in the human gut microbiome. Nat. Biotechnol. 32, 834–841 (2014).
Bindels, L. B., Delzenne, N. M., Cani, P. D. & Walter, J. Towards a more comprehensive concept for prebiotics. Nat. Rev. Gastroenterol. Hepatol. 12, 303–310 (2015).
Gibson, G. R. et al. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat. Rev. Gastroenterol. Hepatol. 14, 491–502 (2017).
Cani, P. D. & de Vos, W. M. Next-generation beneficial microbes: the case of Akkermansia muciniphila. Front. Microbiol. 8, 1765 (2017).
Hoek, M. & Merks, R. M. H. Emergence of microbial diversity due to cross-feeding interactions in a spatial model of gut microbial metabolism. BMC Syst. Biol. 11, 56 (2017).
Ze, X., Le Mougen, F., Duncan, S. H., Louis, P. & Flint, H. J. Some are more equal than others: the role of “keystone” species in the degradation of recalcitrant substrates. Gut Microbes 4, 236–240 (2013).
Louis, P. & Flint, H. J. Formation of propionate and butyrate by the human colonic microbiota. Environ. Microbiol. 19, 29–41 (2017).
Donohoe, D. R. et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 13, 517–526 (2011).
Byndloss, M. X. et al. Microbiota-activated PPAR-gamma signaling inhibits dysbiotic Enterobacteriaceae expansion. Science 357, 570–575 (2017).
Cani, P. D. Gut cell metabolism shapes the microbiome. Science 357, 548–549 (2017).
Husted, A. S., Trauelsen, M., Rudenko, O., Hjorth, S. A. & Schwartz, T. W. GPCR-mediated signaling of metabolites. Cell Metab. 25, 777–796 (2017).
Spanogiannopoulos, P., Bess, E. N., Carmody, R. N. & Turnbaugh, P. J. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat. Rev. Microbiol. 14, 273–287 (2016).
Kang, M. J. et al. The effect of gut microbiota on drug metabolism. Expert Opin. Drug Metab. Toxicol. 9, 1295–1308 (2013).
Haiser, H. J. & Turnbaugh, P. J. Is it time for a metagenomic basis of therapeutics? Science 336, 1253–1255 (2012).
Koppel, N., Maini Rekdal, V. & Balskus, E. P. Chemical transformation of xenobiotics by the human gut microbiota. Science 356, eaag2770 (2017).
Qin, Y. & Wade, P. A. Crosstalk between the microbiome and epigenome: messages from bugs. J. Biochem. 163, 105–112 (2018).
Cortese, R., Lu, L., Yu, Y., Ruden, D. & Claud, E. C. Epigenome-microbiome crosstalk: a potential new paradigm influencing neonatal susceptibility to disease. Epigenetics 11, 205–215 (2016).
Maudet, C. et al. Functional high-throughput screening identifies the miR-15 microRNA family as cellular restriction factors for Salmonella infection. Nat. Commun. 5, 4718 (2014).
Staedel, C. & Darfeuille, F. MicroRNAs and bacterial infection. Cell. Microbiol. 15, 1496–1507 (2013).
Yu, T. et al. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell 170, 548–563.e16 (2017).
Reigstad, C. S. et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J. 29, 1395–1403 (2015).
Brooks, L. et al. Fermentable carbohydrate stimulates FFAR2-dependent colonic PYY cell expansion to increase satiety. Mol. Metab. 6, 48–60 (2017).
Cani, P. D. et al. Endocannabinoids - at the crossroads between the gut microbiota and host metabolism. Nat. Rev. Endocrinol. 12, 133–143 (2016).
Cani, P. D. & Knauf, C. How gut microbes talk to organs: the role of endocrine and nervous routes. Mol. Metab. 5, 743–752 (2016).
Cani, P. D., Everard, A. & Duparc, T. Gut microbiota, enteroendocrine functions and metabolism. Curr. Opin. Pharmacol. 13, 935–940 (2013).
Everard, A. & Cani, P. D. Gut microbiota and GLP-1. Rev. Endocr. Metab. Disord. 15, 189–196 (2014).
Cani, P. D., Dewever, C. & Delzenne, N. M. Inulin-type fructans modulate gastrointestinal peptides involved in appetite regulation (glucagon-like peptide-1 and ghrelin) in rats. Br. J. Nutr. 92, 521–526 (2004).
Cani, P. D., Neyrinck, A. M., Maton, N. & Delzenne, N. M. Oligofructose promotes satiety in rats fed a high-fat diet: involvement of glucagon-like Peptide-1. Obes. Res. 13, 1000–1007 (2005).
Wichmann, A. et al. Microbial modulation of energy availability in the colon regulates intestinal transit. Cell Host Microbe 14, 582–590 (2013).
Cani, P. D. et al. Improvement of glucose tolerance and hepatic insulin sensitivity by oligofructose requires a functional glucagon-like peptide 1 receptor. Diabetes 55, 1484–1490 (2006).
Batterham, R. L. et al. Gut hormone PYY(3–36) physiologically inhibits food intake. Nature 418, 650–654 (2002).
Cani, P. D. et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 58, 1091–1103 (2009).
Chen, B. D. et al. Effect of the GLP-1 analog exendin-4 and oxaliplatin on intrahepatic cholangiocarcinoma cell line and mouse model. Int. J. Mol. Sci. 14, 24293–24304 (2013).
Zhou, M. et al. The anti-diabetic drug exenatide, a glucagon-like peptide-1 receptor agonist, counteracts hepatocarcinogenesis through cAMP-PKA-EGFR-STAT3 axis. Oncogene 36, 4135–4149 (2017).
Kosowska, A. et al. Exenatide modulates tumor-endothelial cell interactions in human ovarian cancer cells. Endocr. Connect. 6, 856–865 (2017).
Fidan-Yaylali, G., Dodurga, Y., Secme, M. & Elmas, L. Antidiabetic exendin-4 activates apoptotic pathway and inhibits growth of breast cancer cells. Tumour Biol. 37, 2647–2653 (2016).
Iyengar, N. M., Gucalp, A., Dannenberg, A. J. & Hudis, C. A. Obesity and cancer mechanisms: tumor microenvironment and inflammation. J. Clin. Oncol. 34, 4270–4276 (2016).
Jordan, B. F., Gourgue, F. & Cani, P. D. Adipose tissue metabolism and cancer progression: novel insights from gut microbiota? Curr. Pathobiol. Rep. 5, 315–322 (2017).
Deng, T., Lyon, C. J., Bergin, S., Caligiuri, M. A. & Hsueh, W. A. Obesity, inflammation, and cancer. Annu. Rev. Pathol. 11, 421–449 (2016).
Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).
Gomes, J. M., Costa, J. A. & Alfenas, R. C. Metabolic endotoxemia and diabetes mellitus: a systematic review. Metabolism 68, 133–144 (2017).
Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat. Immunol. 2, 675–680 (2001).
Shi, H. et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 116, 3015–3025 (2006).
Cai, D. et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat. Med. 11, 183–190 (2005).
Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).
Creely, S. J. et al. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 292, E740–E747 (2007).
Mantovani, A. Molecular pathways linking inflammation and cancer. Curr. Mol. Med. 10, 369–373 (2010).
Neal, M. D. et al. Enterocyte TLR4 mediates phagocytosis and translocation of bacteria across the intestinal barrier. J. Immunol. 176, 3070–3079 (2006).
Ghoshal, S., Witta, J., Zhong, J., de, V. W. & Eckhardt, E. Chylomicrons promote intestinal absorption of lipopolysaccharides. J. Lipid Res. 50, 90–97 (2009).
Guerville, M. & Boudry, G. Gastrointestinal and hepatic mechanisms limiting entry and dissemination of lipopolysaccharide into the systemic circulation. Am. J. Physiol. Gastrointest. Liver Physiol. 311, G1–G15 (2016).
Cani, P. D. et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57, 1470–1481 (2008).
Amar, J. et al. Energy intake is associated with endotoxemia in apparently healthy men. Am. J. Clin. Nutr. 87, 1219–1223 (2008).
Lassenius, M. I. et al. Bacterial endotoxin activity in human serum is associated with dyslipidemia, insulin resistance, obesity, and chronic inflammation. Diabetes Care 34, 1809–1815 (2011).
Pussinen, P. J., Havulinna, A. S., Lehto, M., Sundvall, J. & Salomaa, V. Endotoxemia is associated with an increased risk of incident diabetes. Diabetes Care 34, 392–397 (2011).
Wells, J. M. et al. Homeostasis of the gut barrier and potential biomarkers. Am. J. Physiol. Gastrointest. Liver Physiol. 312, G171–G193 (2017).
Derrien, M. et al. Mucin-bacterial interactions in the human oral cavity and digestive tract. Gut Microbes. 1, 254–268 (2010).
Everard, A. et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl Acad. Sci. USA 110, 9066–9071 (2013).
Li, J., Lin, S., Vanhoutte, P. M., Woo, C. W. & Xu, A. Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in Apoe−/− mice. Circulation 133, 2434–2446 (2016).
Chassaing, B., Raja, S. M., Lewis, J. D., Srinivasan, S. & Gewirtz, A. T. Colonic microbiota encroachment correlates with dysglycemia in humans. Cell. Mol. Gastroenterol. Hepatol. 4, 205–221 (2017).
de Vos, W. M. Microbe Profile: Akkermansia muciniphila: a conserved intestinal symbiont that acts as the gatekeeper of our mucosa. Microbiology 163, 646–648 (2017).
Plovier, H. et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat. Med. 23, 107–113 (2017).
Derrien, M., Vaughan, E. E., Plugge, C. M. & de Vos, W. M. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int. J. Syst. Evol. Microbiol. 54, 1469–1476 (2004).
Everard, A. et al. Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes 60, 2775–2786 (2011).
Grander, C. et al. Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. Gut 67, 891–901 (2018).
Hanninen, A. et al. Akkermansia muciniphila induces gut microbiota remodelling and controls islet autoimmunity in NOD mice. Gut https://doi.org/10.1136/gutjnl-2017-314508 (2017).
Shin, N. R. et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63, 727–735 (2014).
Bevins, C. L. & Salzman, N. H. Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat. Rev. Microbiol. 9, 356–368 (2011).
Pott, J. & Hornef, M. Innate immune signalling at the intestinal epithelium in homeostasis and disease. EMBO Rep. 13, 684–698 (2012).
Hooper, L. V. & Macpherson, A. J. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat. Rev. Immunol. 10, 159–169 (2010).
Everard, A. et al. Microbiome of prebiotic-treated mice reveals novel targets involved in host response during obesity. ISME J. 8, 2116–2130 (2014).
Macpherson, A. J., Geuking, M. B., Slack, E., Hapfelmeier, S. & McCoy, K. D. The habitat, double life, citizenship, and forgetfulness of IgA. Immunol. Rev. 245, 132–146 (2012).
Vereecke, L., Beyaert, R. & van Loo, G. Enterocyte death and intestinal barrier maintenance in homeostasis and disease. Trends Mol. Med. 17, 584–593 (2011).
Kitazawa, H. et al. Intectin, a novel small intestine-specific glycosylphosphatidylinositol-anchored protein, accelerates apoptosis of intestinal epithelial cells. J. Biol. Chem. 279, 42867–42874 (2004).
Muccioli, G. G. et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol. Syst. Biol. 6, 392 (2010).
Moreno-Navarrete, J. M., Sabater, M., Ortega, F., Ricart, W. & Fernandez-Real, J. M. Circulating zonulin, a marker of intestinal permeability, is increased in association with obesity-associated insulin resistance. PLoS ONE 7, e37160 (2012).
Casselbrant, A., Elias, E., Fandriks, L. & Wallenius, V. Expression of tight-junction proteins in human proximal small intestinal mucosa before and after Roux-en-Y gastric bypass surgery. Surg. Obes. Relat. Dis. 11, 45–53 (2015).
Telle-Hansen, V. H., Christensen, J. J., Ulven, S. M. & Holven, K. B. Does dietary fat affect inflammatory markers in overweight and obese individuals?-a review of randomized controlled trials from 2010 to 2016. Genes Nutr. 12, 26 (2017).
Schulz, O. & Pabst, O. Antigen sampling in the small intestine. Trends Immunol. 34, 155–161 (2013).
Luck, H. et al. Regulation of obesity-related insulin resistance with gut anti-inflammatory agents. Cell Metab. 21, 527–542 (2015).
Wang, K. & Karin, M. Common flora and intestine: a carcinogenic marriage. Cell Logist. 3, e24975 (2013).
Monteiro-Sepulveda, M. et al. Jejunal T cell inflammation in human obesity correlates with decreased enterocyte insulin signaling. Cell Metab. 22, 113–124 (2015).
Magalhaes, I. et al. Mucosal-associated invariant T cell alterations in obese and type 2 diabetic patients. J. Clin. Invest. 125, 1752–1762 (2015).
Dahal, L. N. The dichotomy of T helper 17 cells in cancer. Nat. Rev. Immunol. 17, 592 (2017).
Stockinger, B. & Omenetti, S. The dichotomous nature of T helper 17 cells. Nat. Rev. Immunol. 17, 535–544 (2017).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).
Schetter, A. J., Heegaard, N. H. & Harris, C. C. Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis 31, 37–49 (2010).
Hussain, S. P., Hofseth, L. J. & Harris, C. C. Radical causes of cancer. Nat. Rev. Cancer 3, 276–285 (2003).
Mittal, M., Siddiqui, M. R., Tran, K., Reddy, S. P. & Malik, A. B. Reactive oxygen species in inflammation and tissue injury. Antioxid. Redox Signal 20, 1126–1167 (2014).
Galon, J., Angell, H. K., Bedognetti, D. & Marincola, F. M. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity 39, 11–26 (2013).
Li, T. T., Ogino, S. & Qian, Z. R. Toll-like receptor signaling in colorectal cancer: carcinogenesis to cancer therapy. World J. Gastroenterol. 20, 17699–17708 (2014).
Oke, S. & Martin, A. Insights into the role of the intestinal microbiota in colon cancer. Therap. Adv. Gastroenterol. 10, 417–428 (2017).
Pradere, J. P., Dapito, D. H. & Schwabe, R. F. The Yin and Yang of Toll-like receptors in cancer. Oncogene 33, 3485–3495 (2014).
Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012).
Li, Y. et al. Gut microbiota accelerate tumor growth via c-jun and STAT3 phosphorylation in APCMin/+ mice. Carcinogenesis 33, 1231–1238 (2012).
Pimentel-Nunes, P. et al. Functional polymorphisms of Toll-like receptors 2 and 4 alter the risk for colorectal carcinoma in Europeans. Dig. Liver Dis. 45, 63–69 (2013).
Lu, C. C. et al. Upregulation of TLRs and IL-6 as a marker in human colorectal cancer. Int. J. Mol. Sci. 16, 159–177 (2014).
Fukata, M. et al. Constitutive activation of epithelial TLR4 augments inflammatory responses to mucosal injury and drives colitis-associated tumorigenesis. Inflamm. Bowel Dis. 17, 1464–1473 (2011).
Fukata, M. et al. Innate immune signaling by Toll-like receptor-4 (TLR4) shapes the inflammatory microenvironment in colitis-associated tumors. Inflamm. Bowel Dis. 15, 997–1006 (2009).
Fukata, M. & Abreu, M. T. Pathogen recognition receptors, cancer and inflammation in the gut. Curr. Opin. Pharmacol. 9, 680–687 (2009).
Rakoff-Nahoum, S. & Medzhitov, R. Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science 317, 124–127 (2007).
Salcedo, R. et al. MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. J. Exp. Med. 207, 1625–1636 (2010).
Li, Y. et al. Constitutive TLR4 signalling in intestinal epithelium reduces tumor load by increasing apoptosis in APC(Min/+) mice. Oncogene 33, 369–377 (2014).
Yu, L. X. et al. Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents. Hepatology 52, 1322–1333 (2010).
Ochi, A. et al. MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells. J. Exp. Med. 209, 1671–1687 (2012).
Everard, A. et al. Intestinal epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional status. Nat. Commun. 5, 5648 (2014).
Chen, G. Y., Shaw, M. H., Redondo, G. & Nunez, G. The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis. Cancer Res. 68, 10060–10067 (2008).
Couturier-Maillard, A. et al. NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J. Clin. Invest. 123, 700–711 (2013).
Denou, E. et al. Defective NOD2 peptidoglycan sensing promotes diet-induced inflammation, dysbiosis, and insulin resistance. EMBO Mol. Med. 7, 259–274 (2015).
Ikebe, M. et al. Lipopolysaccharide (LPS) increases the invasive ability of pancreatic cancer cells through the TLR4/MyD88 signaling pathway. J. Surg. Oncol. 100, 725–731 (2009).
Velcich, A. et al. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science 295, 1726–1729 (2002).
Huang, L. C. & Merchea, A. Dysplasia and cancer in inflammatory bowel disease. Surg. Clin. North Am. 97, 627–639 (2017).
Li, X. Y. et al. Lipopolysaccharide promotes tumorigenicity of hepatic progenitor cells by promoting proliferation and blocking normal differentiation. Cancer Lett. 386, 35–46 (2017).
Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013).
Ogrendik, M. Periodontal pathogens in the etiology of pancreatic cancer. Gastrointest. Tumors 3, 125–127 (2017).
Marchesi, J. R. et al. Towards the human colorectal cancer microbiome. PLoS ONE 6, e20447 (2011).
Tjalsma, H., Boleij, A., Marchesi, J. R. & Dutilh, B. E. A bacterial driver-passenger model for colorectal cancer: beyond the usual suspects. Nat. Rev. Microbiol. 10, 575–582 (2012).
Yu, J. et al. Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer. Gut 66, 70–78 (2017).
Andoh, A. et al. Comparison of the gut microbial community between obese and lean peoples using 16S gene sequencing in a Japanese population. J. Clin. Biochem. Nutr. 59, 65–70 (2016).
Kostic, A. D. et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res. 22, 292–298 (2012).
Kostic, A. D. et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 14, 207–215 (2013).
Rubinstein, M. R. et al. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/beta-catenin signaling via its FadA adhesin. Cell Host Microbe 14, 195–206 (2013).
Mima, K. et al. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut 65, 1973–1980 (2016).
Abed, J. et al. Fap2 mediates Fusobacterium nucleatum colorectal adenocarcinoma enrichment by binding to tumor-expressed Gal-GalNAc. Cell Host Microbe 20, 215–225 (2016).
Yamaoka, Y. et al. Fusobacterium nucleatum as a prognostic marker of colorectal cancer in a Japanese population. J. Gastroenterol. 53, 517–524 (2018).
Ramos, A. & Hemann, M. T. Drugs, bugs, and cancer: Fusobacterium nucleatum promotes chemoresistance in colorectal cancer. Cell 170, 411–413 (2017).
Yang, Y. et al. Fusobacterium nucleatum increases proliferation of colorectal cancer cells and tumor development in mice by activating Toll-like receptor 4 signaling to nuclear factor-kappaB, and up-regulating expression of MicroRNA-21. Gastroenterology 152, 851–866.e24 (2017).
Chen, Y. et al. Invasive Fusobacterium nucleatum activates beta-catenin signaling in colorectal cancer via a TLR4/P-PAK1 cascade. Oncotarget 8, 31802–31814 (2017).
Yu, L. X. & Schwabe, R. F. The gut microbiome and liver cancer: mechanisms and clinical translation. Nat. Rev. Gastroenterol. Hepatol. 14, 527–539 (2017).
Brahe, L. K., Astrup, A. & Larsen, L. H. Is butyrate the link between diet, intestinal microbiota and obesity-related metabolic diseases? Obes. Rev. 14, 950–959 (2013).
Hartstra, A. V., Bouter, K. E., Backhed, F. & Nieuwdorp, M. Insights into the role of the microbiome in obesity and type 2 diabetes. Diabetes Care 38, 159–165 (2015).
Qin, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012).
Ilhan, Z. E. et al. Distinctive microbiomes and metabolites linked with weight loss after gastric bypass, but not gastric banding. ISME J. 11, 2047–2058 (2017).
Fernandes, J., Su, W., Rahat-Rozenbloom, S., Wolever, T. M. & Comelli, E. M. Adiposity, gut microbiota and faecal short chain fatty acids are linked in adult humans. Nutr. Diabetes 4, e121 (2014).
O’Keefe, Diet, S. J. microorganisms and their metabolites, and colon cancer. Nat. Rev. Gastroenterol. Hepatol. 13, 691–706 (2016).
Thangaraju, M. 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. 69, 2826–2832 (2009).
Jobin, C. GPR109a: the missing link between microbiome and good health? Immunity 40, 8–10 (2014).
Singh, N. et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40, 128–139 (2014).
Rubtsov, Y. P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546–558 (2008).
Bardhan, K. et al. IFNγ induces DNA methylation-silenced GPR109A expression via pSTAT1/p300 and H3K18 acetylation in colon cancer. Cancer Immunol. Res. 3, 795–805 (2015).
Sivaprakasam, S. 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 5, e238 (2016).
Sivaprakasam, S., Prasad, P. D. & Singh, N. Benefits of short-chain fatty acids and their receptors in inflammation and carcinogenesis. Pharmacol. Ther. 164, 144–151 (2016).
Boursi, B., Mamtani, R., Haynes, K. & Yang, Y. X. Recurrent antibiotic exposure may promote cancer formation — another step in understanding the role of the human microbiota? Eur. J. Cancer 51, 2655–2664 (2015).
Zackular, J. P. et al. The gut microbiome modulates colon tumorigenesis. mBio 4, e00692–00613 (2013).
Tang, Y., Chen, Y., Jiang, H., Robbins, G. T. & Nie, D. G-protein-coupled receptor for short-chain fatty acids suppresses colon cancer. Int. J. Cancer 128, 847–856 (2011).
Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T cell generation. Nature 504, 451–455 (2013).
Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).
Winer, S. et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15, 921–929 (2009).
Zeng, H. & Chi, H. Metabolic control of regulatory T cell development and function. Trends Immunol. 36, 3–12 (2015).
Ilan, Y. et al. Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice. Proc. Natl Acad. Sci. USA 107, 9765–9770 (2010).
Rudolph, U. et al. Ulcerative colitis and adenocarcinoma of the colon in G alpha i2-deficient mice. Nat. Genet. 10, 143–150 (1995).
Belcheva, A., Irrazabal, T. & Martin, A. Gut microbial metabolism and colon cancer: can manipulations of the microbiota be useful in the management of gastrointestinal health? Bioessays 37, 403–412 (2015).
Howe, G. R. et al. Dietary intake of fiber and decreased risk of cancers of the colon and rectum: evidence from the combined analysis of 13 case-control studies. J. Natl Cancer Inst. 84, 1887–1896 (1992).
Chirakkal, H. et al. Upregulation of BAK by butyrate in the colon is associated with increased Sp3 binding. Oncogene 25, 7192–7200 (2006).
Xiao, M., Liu, Y. G., Zou, M. C. & Zou, F. Sodium butyrate induces apoptosis of human colon cancer cells by modulating ERK and sphingosine kinase 2. Biomed. Environ. Sci. 27, 197–203 (2014).
Donohoe, D. R. et al. The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol. Cell 48, 612–626 (2012).
Belcheva, A. et al. Gut microbial metabolism drives transformation of MSH2-deficient colon epithelial cells. Cell 158, 288–299 (2014).
White, D. L., Kanwal, F. & El-Serag, H. B. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin. Gastroenterol. Hepatol. 10, 1342–1359.e2 (2012).
Moschen, A. R., Kaser, S. & Tilg, H. Non-alcoholic steatohepatitis: a microbiota-driven disease. Trends Endocrinol. Metab. 24, 537–545 (2013).
Tilg, H., Cani, P. D. & Mayer, E. A. Gut microbiome and liver diseases. Gut 65, 2035–2044 (2016).
Marchesi, J. R. et al. The gut microbiota and host health: a new clinical frontier. Gut 65, 330–339 (2016).
Hsu, D. et al. Toll-like receptor 4 differentially regulates epidermal growth factor-related growth factors in response to intestinal mucosal injury. Lab. Invest. 90, 1295–1305 (2010).
Tomita, K. et al. Epiregulin promotes the emergence and proliferation of adult liver progenitor cells. Am. J. Physiol. Gastrointest. Liver Physiol. 307, G50–57 (2014).
Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).
Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).
Kasai, C. et al. Comparison of the gut microbiota composition between obese and non-obese individuals in a Japanese population, as analyzed by terminal restriction fragment length polymorphism and next-generation sequencing. BMC Gastroenterol. 15, 100 (2015).
Loo, T. M. et al. Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity. Cancer Discov. 7, 522–538 (2017).
Staley, C., Weingarden, A. R., Khoruts, A. & Sadowsky, M. J. Interaction of gut microbiota with bile acid metabolism and its influence on disease states. Appl. Microbiol. Biotechnol. 101, 47–64 (2017).
Payne, C. M. et al. Deoxycholate induces mitochondrial oxidative stress and activates NF-kappaB through multiple mechanisms in HCT-116 colon epithelial cells. Carcinogenesis 28, 215–222 (2007).
Takahashi, A. et al. DNA damage signaling triggers degradation of histone methyltransferases through APC/C(Cdh1) in senescent cells. Mol. Cell 45, 123–131 (2012).
Poutahidis, T. et al. Dietary microbes modulate transgenerational cancer risk. Cancer Res. 75, 1197–1204 (2015).
Nishimura, F. & Murayama, Y. Periodontal inflammation and insulin resistance — lessons from obesity. J. Dent. Res. 80, 1690–1694 (2001).
Genco, R. J., Grossi, S. G., Ho, A., Nishimura, F. & Murayama, Y. A proposed model linking inflammation to obesity, diabetes, and periodontal infections. J. Periodontol. 76, 2075–2084 (2005).
Chitsazi, M. T., Pourabbas, R., Shirmohammadi, A., Ahmadi Zenouz, G. & Vatankhah, A. H. Association of periodontal diseases with elevation of serum C-reactive protein and body mass index. J. Dent. Res. Dent. Clin. Dent. Prospects 2, 9–14 (2008).
Thanakun, S., Pornprasertsuk-Damrongsri, S. & Izumi, Y. Increased oral inflammation, leukocytes, and leptin, and lower adiponectin in overweight or obesity. Oral Dis. 23, 956–965 (2017).
Dursun, E. et al. Oxidative stress and periodontal disease in obesity. Medicine 95, e3136 (2016).
Otomo-Corgel, J., Pucher, J. J., Rethman, M. P. & Reynolds, M. A. State of the science: chronic periodontitis and systemic health. J. Evid. Based Dent. Pract. 12, 20–28 (2012).
Hujoel, P. P., Drangsholt, M., Spiekerman, C. & Weiss, N. S. An exploration of the periodontitis-cancer association. Ann. Epidemiol. 13, 312–316 (2003).
Stolzenberg-Solomon, R. Z. et al. Tooth loss, pancreatic cancer, and Helicobacter pylori. Am. J. Clin. Nutr. 78, 176–181 (2003).
Ahn, J., Segers, S. & Hayes, R. B. Periodontal disease, Porphyromonas gingivalis serum antibody levels and orodigestive cancer mortality. Carcinogenesis 33, 1055–1058 (2012).
Michaud, D. S. & Izard, J. Microbiota, oral microbiome, and pancreatic cancer. Cancer J. 20, 203–206 (2014).
Michaud, D. S. et al. Plasma antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort study. Gut 62, 1764–1770 (2013).
Fan, X. et al. Human oral microbiome and prospective risk for pancreatic cancer: a population-based nested case-control study. Gut 67, 120–127 (2018).
Mitsuhashi, K. et al. Association of Fusobacterium species in pancreatic cancer tissues with molecular features and prognosis. Oncotarget 6, 7209–7220 (2015).
Li, X., Kolltveit, K. M., Tronstad, L. & Olsen, I. Systemic diseases caused by oral infection. Clin. Microbiol. Rev. 13, 547–558 (2000).
Singh, A. et al. The capsule of Porphyromonas gingivalis leads to a reduction in the host inflammatory response, evasion of phagocytosis, and increase in virulence. Infect. Immun. 79, 4533–4542 (2011).
Taxman, D. J. et al. Porphyromonas gingivalis mediates inflammasome repression in polymicrobial cultures through a novel mechanism involving reduced endocytosis. J. Biol. Chem. 287, 32791–32799 (2012).
Palm, E., Khalaf, H. & Bengtsson, T. Porphyromonas gingivalis downregulates the immune response of fibroblasts. BMC Microbiol. 13, 155 (2013).
Farrell, J. J. et al. Variations of oral microbiota are associated with pancreatic diseases including pancreatic cancer. Gut 61, 582–588 (2012).
Torres, P. J. et al. Characterization of the salivary microbiome in patients with pancreatic cancer. PeerJ 3, e1373 (2015).
Ren, Z. et al. Gut microbial profile analysis by MiSeq sequencing of pancreatic carcinoma patients in China. Oncotarget 8, 95176–95191 (2017).
Greenblum, S., Turnbaugh, P. J. & Borenstein, E. Metagenomic systems biology of the human gut microbiome reveals topological shifts associated with obesity and inflammatory bowel disease. Proc. Natl Acad. Sci. USA 109, 594–599 (2012).
Plovier, H. & Cani, P. D. Microbial impact on host metabolism: opportunities for novel treatments of nutritional disorders? Microbiol. Spectr. 5, BAD-0002-2016 (2017).
Wen, L. & Duffy, A. Factors influencing the gut microbiota, inflammation, and type 2 diabetes. J. Nutr. 147, 1468S–1475S (2017).
Li, S., Bostick, J. W. & Zhou, L. Regulation of innate lymphoid cells by aryl hydrocarbon receptor. Front. Immunol. 8, 1909 (2017).
Acknowledgements
B.F.J. and P.D.C. are senior research associates at FRS-FNRS (Fonds de la Recherche Scientifique). P.D.C. is a recipient of grants from FNRS (Projet de Recherche, convention: T.0138.14) and Walloon region DG06-FSO project (Microbes 1510053). This work was supported by FRFS-WELBIO (Fund for Strategic Fundamental Research-Walloon Excellence in Life sciences and Biotechnology) grants, WELBIO-CR-2012S-02 R and WELBIO-CR-2017-C02 (continuation grant 2017), and in part by the Fonds Baillet Latour (Grant for Medical Research 2015). P.D.C. is a recipient of Proof of Concept ERC grant 2016 (European Research Council, Microbes4U_713547) and ERC Starting Grant 2013 (Starting grant 336452-ENIGMO).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
P.D.C. is inventor on patent applications dealing with the use of Akkermansia muciniphila and its components in the treatment of obesity and related disorders. P.D.C. is co-founder of A-Mansia biotech SA. B.F.J. declares no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Cani, P.D., Jordan, B.F. Gut microbiota-mediated inflammation in obesity: a link with gastrointestinal cancer. Nat Rev Gastroenterol Hepatol 15, 671–682 (2018). https://doi.org/10.1038/s41575-018-0025-6
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41575-018-0025-6
This article is cited by
-
Zinc glycine chelate ameliorates DSS-induced intestinal barrier dysfunction via attenuating TLR4/NF-κB pathway in meat ducks
Journal of Animal Science and Biotechnology (2024)
-
The role of gut microbiota in human metabolism and inflammatory diseases: a focus on elderly individuals
Annals of Microbiology (2024)
-
Far-Infrared Therapy Based on Graphene Ameliorates High-Fat Diet-Induced Anxiety-Like Behavior in Obese Mice via Alleviating Intestinal Barrier Damage and Neuroinflammation
Neurochemical Research (2024)
-
Risk of Esophageal Adenocarcinoma After Bariatric Surgery: A Meta-Analysis of Retrospective Studies
Obesity Surgery (2024)
-
Vitamin D3 supplementation shapes the composition of gut microbiota and improves some obesity parameters induced by high-fat diet in mice
European Journal of Nutrition (2024)
