Portal de Periódicos da CAPES

Agaro-oligosaccharides: a new frontier in the fight against colon cancer?

2016; American Physiological Society; Volume: 310; Issue: 6 Linguagem: Inglês

10.1152/ajpgi.00049.2016

1522-1547

Yogesh Bhattarai, Purna Kashyap,

Enterobacteriaceae and Cronobacter Research

Editorial FocusAgaro-oligosaccharides: a new frontier in the fight against colon cancer?Yogesh Bhattarai and Purna C. KashyapYogesh BhattaraiEnteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota; and Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota and Purna C. KashyapEnteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota; and Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MinnesotaPublished Online:15 Mar 2016https://doi.org/10.1152/ajpgi.00049.2016This is the final version - click for previous versionMoreSectionsPDF (40 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat the human gut represents one of the most diverse bacterial ecosystems. These bacteria live in a mutualistic state with the host; however, when this homeostatic balance is perturbed by an alteration in bacterial community composition and function (dysbiosis), it can lead to disruption of normal host physiology. A role for gut microbiota has been suggested in pathogenesis of colorectal cancer based on recent mouse and human studies. In a mouse model of colitis-associated colorectal cancer, Uronis et al. (24) found that risk for tumorigenesis was lower in germ-free conditions than with a conventional microbiome. In another study Kostic et al. (11) found that Fusobacterium species were enriched in colorectal cancer patients. They attributed this enrichment to the strong adhesive and invasive abilities of Fusobacterium for epithelial cells, which allows them to take up residence in tumor environment. Kostic et al. also showed that introduction of Fusobacterium species in the ApcMin/+ mouse model, a genetic mouse model of colon cancer, accelerates colonic tumorigenesis (11). These studies support a role for gut microbiota in the pathogenesis of colorectal cancer, but there is little known about factors that promote dysbiosis leading to colorectal cancer and how preventing dysbiosis might be protective. The present study by Higashimura et al. (10a) helps answer this question by investigating effects of high-fat diet (HFD) on gut microbiota and host function and supplementing HFD with a prebiotic to prevent changes in gut microbiota.An important determinant of gut microbiota composition and function is diet. HFD consumption in particular is associated with alterations in gut microbiota and can lead to diseases including obesity and colon cancer (20, 23). Alterations in gut microbiota seen with HFD consumption that might be associated with colon cancer include decrease in Bifidobacteria and Lactobacillus spp. and increase in Firmicutes such as Clostridium and Enterococcus spp. (5). Although HFD-induced alteration in gut microbiota are associated with colon cancer, it remains unclear how these alterations promote colon cancer and whether prevention of these changes can halt progression to colon cancer.There are several ways to target gut microbiota, one of which is a prebiotic, defined as "a non-digestible compound that through its metabolism by microorganisms in the gut, modulates composition and/or activity of the gut microbiota thus conferring beneficial physiological effects to the host" (4). Agarose, a major food ingredient in East Asia obtained from seaweed, can be considered a prebiotic given its effect on gut microbiota. In the present study Higashimura et al. (10a) utilized agarose-derived oligosaccharide (agaro-oligosaccharide; AGO) to determine whether AGO protects against HFD induced gut dysbiosis and colon tumorigenesis. The authors show that HFD-fed mice over 8 wk have a significant increase in body weight as well as alterations in gut microbiota characterized specifically by a decrease in taxa within Lactobacillales, and increase within Bacteroides and Clostridium subcluster XIVa as measured by terminal restriction fragment length polymorphism analysis. These findings are similar to previous studies on the effect of HFD on gut microbiota and consistent with negative effects on the host (6, 21, 23). Enterotoxigenic Bacteroides have been implicated in tumorigenesis via activation of T helper cell 17 (TH17) (25). Lactobacilli, a member of Lactobacillales, on the other hand have previously been shown to be protective against proliferation of pathogenic bacteria (14, 17). AGO supplementation did not have an effect on weight gain but significantly suppressed the HFD-related changes in Lactobacillales and Clostridium subcluster XIVa. Although microbial compositional changes seen with AGO support its protective effects, the physiological effects on the host and changes in microbial community function in response to AGO are more relevant.To determine whether AGO protects against colon tumorigenesis, the authors analyzed the effects of AGO supplementation on azoxymethane (AOM)-induced development of aberrant crypt foci (ACF) in HFD-fed mice. They found that AGO supplementation significantly suppressed the development of ACF in AOM-administered HFD mice. Furthermore, AGO also suppressed mRNA expression of tumorigenic factor cyclooxygenase-1 (COX-1) and increased anti-tumorigenic factor 8-oxoguanine DNA-glycosylase 1 (OGG1) in HFD-fed mice.The authors in the present study also correlated changes in microbial composition to changes in microbial function to identify potential mechanisms by which AGO is protective. They found that lactic acid concentration was elevated in the cecum of HFD-fed mice that were supplemented with AGO, consistent with an increase in Lactobacillales. Succinic acid, a major by-product of Bacteroides metabolism, was also increased following HFD but suppressed by AGO supplementation. It is unclear whether these fermentative products directly influence colon tumorigenesis or are just reflective of changes in community function as a result of AGO supplementation.In the present study, AGO supplementation prevented the decrease in cytoprotective ω-muricholic acid (MCA) and increased the ratio of MCA to deoxycholic acid (DCA), providing a potential mechanism for anti-tumorigenic effect of AGO. A high physiological level of a secondary bile acid, particularly DCA, as seen with HFD consumption (15), has been reported to be a risk factor for colon cancer in humans (2, 3). DCA increases tyrosine phosphorylation of β-catenin, a member of the cadherin family of transmembrane cell-cell adhesion receptors and a key component of adherens junctions, which leads to enhanced colon cancer cell proliferation and invasiveness (13). A recent study has also shown that DCA levels are significantly higher in the sera of patients with colorectal adenomas (1), suggesting a link between DCA and colon tumorigenesis (16, 19). Since Clostridium spp. harbor a gene for 7 alpha dehydroxylation enzymatic activity (7, 18), decreased Clostridium spp. levels seen with AGO supplementation may in part be responsible for diminished DCA levels.Apart from the prebiotic effects of AGO on microbial composition and bile acid production, AGO-mediated anti-tumorigenic activity might also occur via modulation of hemeoxygenase-1 expression (HO-1) and polyamine (PA) production. Recent studies have shown that AGO increases HO-1 expression in the macrophages (8, 10). Because increased HO-1 expression suppresses TH17 immune responses, inflammatory cytokines, and tumorigenic factors including TNF-α and COX-1 in mice (8, 26), it is possible that anti-tumorigenic effects of AGO and other oligosaccharides are in part HO-1 mediated. Evidence supporting this hypothesis is observed in the present study, in which COX-1 expression is suppressed by AGO in HFD-fed mice. Besides HO-1, AGO might have anti-tumorigenic effects by potentially reducing PA production in the intestine. PAs are a regulator of epithelial cell division and high PA levels have been linked to tumorigenesis (9). PAs in the human intestine can be produced by microbial species belonging to the Clostridium subcluster XIVa, which are suppressed by AGO (12, 22).The present paper helps advance our understanding on beneficial physiological effects of prebiotics on the host in regards to colon cancer. The authors provide data to show that AGO, a prebiotic, suppresses HFD-induced dysbiosis, change microbial community function, and prevent colonic tumorigenesis in a HFD mouse model. Future studies investigating molecular mechanisms by which a prebiotic induces microbiota changes exerting protective effects on the host will allow development of new microbiota-targeted therapies.GRANTSThis work was made possible by funding from NIH K08 DK100638, Global Probiotics Council (P. C. Kashyap), and Center for Individualized Medicine (CIM; Mayo Clinic, P. C. Kashyap).DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author(s).AUTHOR CONTRIBUTIONSY.B. drafted manuscript; Y.B. and P.C.K. edited and revised manuscript.REFERENCES1. Ajouz H, Mukherji D, Shamseddine A. Secondary bile acids: an underrecognized cause of colon cancer. World J Surg Oncol 12: 164, 2014.Crossref | PubMed | ISI | Google Scholar2. Bernstein C, Holubec H, Bhattacharyya AK, Nguyen H, Payne CM, Zaitlin B, Bernstein H. Carcinogenicity of deoxycholate, a secondary bile acid. Arch Toxicol 85: 863–871, 2011.Crossref | PubMed | ISI | Google Scholar3. Bernstein H, Bernstein C, Payne CM, Dvorakova K, Garewal H. Bile acids as carcinogens in human gastrointestinal cancers. Mutat Res 589: 47–65, 2005.Crossref | PubMed | ISI | Google Scholar4. Bindels LB, Delzenne NM, Cani PD, Walter J. Towards a more comprehensive concept for prebiotics. Nat Rev Gastroenterol Hepatol 12: 303–310, 2015.Crossref | PubMed | ISI | Google Scholar5. Brown K, DeCoffe D, Molcan E, Gibson DL. Diet-induced dysbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients 4: 1095–1119, 2012.Crossref | PubMed | ISI | Google Scholar6. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57: 1470–1481, 2008.Crossref | PubMed | ISI | Google Scholar7. Doerner KC, Takamine F, LaVoie CP, Mallonee DH, Hylemon PB. Assessment of fecal bacteria with bile acid 7 alpha-dehydroxylating activity for the presence of bai-like genes. Appl Environ Microbiol 63: 1185–1188, 1997.Crossref | PubMed | ISI | Google Scholar8. Enoki T, Okuda S, Kudo Y, Takashima F, Sagawa H, Kato I. Oligosaccharides from agar inhibit pro-inflammatory mediator release by inducing heme oxygenase 1. Biosci Biotechnol Biochem 74: 766–770, 2010.Crossref | PubMed | ISI | Google Scholar9. Gerner EW, Meyskens FL. Polyamines and cancer: old molecules, new understanding. Nat Rev Cancer 4: 781–792, 2004.Crossref | PubMed | ISI | Google Scholar10. Higashimura Y, Naito Y, Takagi T, Mizushima K, Hirai Y, Harusato A, Ohnogi H, Yamaji R, Inui H, Nakano Y, Yoshikawa T. Oligosaccharides from agar inhibit murine intestinal inflammation through the induction of heme oxygenase-1 expression. J Gastroenterol 48: 897–909, 2013.Crossref | PubMed | ISI | Google Scholar10a. Higashimura Y, Naito Y, Takagi T, Uchiyama K, Mizushima K, Ushiroda C, Ohnogi H, Kudo Y, Yasui M, Inui S, Hisada T, Honda A, Matsuzaki Y, Yoshikawa T. Protective effect of agaro-oligosaccharides on gut dysbiosis and colon tumorigenesis in high-fat diet-fed mice. Am J Physiol Gastrointest Liver Physiol (January 14, 2016). doi:10.1152/ajpgi.00324.2015.Link | ISI | Google Scholar11. Kostic AD, Chun E, Robertson L, Glickman JN, Gallini CA, Michaud M, Clancy TE, Chung DC, Lochhead P, Hold GL, El-Omar EM, Brenner D, Fuchs CS, Meyerson M, Garrett WS. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 14: 207–215, 2013.Crossref | PubMed | ISI | Google Scholar12. Matsumoto M, Benno Y. The relationship between microbiota and polyamine concentration in the human intestine: a pilot study. Microbiol Immunol 51: 25–35, 2007.Crossref | PubMed | ISI | Google Scholar13. Pai R, Tarnawski AS, Tran T. Deoxycholic acid activates beta-catenin signaling pathway and increases colon cell cancer growth and invasiveness. Mol Biol Cell 15: 2156–2163, 2004.Crossref | PubMed | ISI | Google Scholar14. Qiang X, YongLie C, QianBing W. Health benefit application of functional oligosaccharides. Carbohydrate Polymers 77: 435–441, 2009.Crossref | ISI | Google Scholar15. Reddy BS. Diet and excretion of bile acids. Cancer Res 41: 3766–3768, 1981.PubMed | ISI | Google Scholar16. Reddy BS, Hanson D, Mangat S, Mathews L, Sbaschnig M, Sharma C, Simi B. Effect of high-fat, high-beef diet and of mode of cooking of beef in the diet on fecal bacterial enzymes and fecal bile acids and neutral sterols. J Nutr 110: 1880–1887, 1980.Crossref | PubMed | ISI | Google Scholar17. Reid G, Burton J. Use of Lactobacillus to prevent infection by pathogenic bacteria. Microbes Infect 4: 319–324, 2002.Crossref | PubMed | ISI | Google Scholar18. Ridlon JM, Kang DJ, Hylemon PB. Isolation and characterization of a bile acid inducible 7alpha-dehydroxylating operon in Clostridium hylemonae TN271. Anaerobe 16: 137–146, 2010.Crossref | PubMed | ISI | Google Scholar19. Ridlon JM, Kang DJ, Hylemon PB, Bajaj JS. Bile acids and the gut microbiome. Curr Opin Gastroenterol 30: 332–338, 2014.Crossref | PubMed | ISI | Google Scholar20. Schulz MD, Atay C, Heringer J, Romrig FK, Schwitalla S, Aydin B, Ziegler PK, Varga J, Reindl W, Pommerenke C, Salinas-Riester G, Böck A, Alpert C, Blaut M, Polson SC, Brandl L, Kirchner T, Greten FR, Polson SW, Arkan MC. High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity. Nature 514: 508–512, 2014.Crossref | PubMed | ISI | Google Scholar21. Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer 13: 800–812, 2013.Crossref | PubMed | ISI | Google Scholar22. Timmons J, Chang ET, Wang JY, Rao JN. Polyamines and gut mucosal homeostasis. J Gastrointest Dig Syst 2, Suppl 7: 001, 2012.PubMed | Google Scholar23. Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med 1: 6ra14, 2009.Crossref | PubMed | ISI | Google Scholar24. Uronis JM, Mühlbauer M, Herfarth HH, Rubinas TC, Jones GS, Jobin C. Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility. PLoS One 4: e6026, 2009.Crossref | PubMed | ISI | Google Scholar25. Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X, Yen HR, Huso DL, Brancati FL, Wick E, McAllister F, Housseau F, Pardoll DM, Sears CL. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 15: 1016–1022, 2009.Crossref | PubMed | ISI | Google Scholar26. Zhang Y, Zhang L, Wu J, Di C, Xia Z. Heme oxygenase-1 exerts a protective role in ovalbumin-induced neutrophilic airway inflammation by inhibiting Th17 cell-mediated immune response. J Biol Chem 288: 34612–34626, 2013.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: P. C. Kashyap, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905 (e-mail: kashyap.[email protected]edu). Download PDF Back to Top Next FiguresReferencesRelatedInformation CollectionsAJP-GI CollectionsThe Gut Microbiome - Related Articles Cited ByIn vitro human fecal fermentation of agarooligosaccharides from Gracilaria fisheriBioactive Carbohydrates and Dietary Fibre, Vol. 27Macroalgal dietary glycans: potential source for human gut bacteria and enhancing immune system for better health16 November 2020 | Critical Reviews in Food Science and Nutrition, Vol. 62, No. 6Insights into Algal Polysaccharides: A Review of Their Structure, Depolymerases, and Metabolic Pathways7 February 2022 | Journal of Agricultural and Food Chemistry, Vol. 70, No. 6Sulfated Seaweed Polysaccharides1 January 2022Sulfated Seaweed Polysaccharides18 December 2021The Evolution Road of Seaweed Aquaculture: Cultivation Technologies and the Industry 4.08 September 2020 | International Journal of Environmental Research and Public Health, Vol. 17, No. 18Comparative Genomic and Secretomic Analysis Provide Insights Into Unique Agar Degradation Function of Marine Bacterium Vibrio fluvialis A8 Through Horizontal Gene Transfer11 August 2020 | Frontiers in Microbiology, Vol. 11Characterization of a novel alkaline β-agarase and its hydrolysates of agarFood Chemistry, Vol. 295AllergoOncology: Microbiota in allergy and cancer—A European Academy for Allergy and Clinical Immunology position paper6 March 2019 | Allergy, Vol. 74, No. 6Integral Utilization of Red Seaweed for Bioactive Production28 May 2019 | Marine Drugs, Vol. 17, No. 6Simple Preparation of Diverse Neoagaro-Oligosaccharides7 May 2019 | Processes, Vol. 7, No. 5Oligosaccharides Derived from Red Seaweed: Production, Properties, and Potential Health and Cosmetic Applications25 September 2018 | Molecules, Vol. 23, No. 10Quantification of Neoagaro-Oligosaccharide Production through Enzymatic Hydrolysis and Its Anti-Oxidant Activities5 June 2018 | Molecules, Vol. 23, No. 6Protective effect of agaro-oligosaccharides on gut dysbiosis and colon tumorigenesis in high-fat diet-fed miceYasuki Higashimura, Yuji Naito, Tomohisa Takagi, Kazuhiko Uchiyama, Katsura Mizushima, Chihiro Ushiroda, Hiromu Ohnogi, Yoko Kudo, Madoka Yasui, Seina Inui, Takayoshi Hisada, Akira Honda, Yasushi Matsuzaki, and Toshikazu Yoshikawa15 March 2016 | American Journal of Physiology-Gastrointestinal and Liver Physiology, Vol. 310, No. 6 More from this issue > Video Abstract Volume 310Issue 6March 2016Pages G335-G336 Copyright & PermissionsCopyright © 2016 the American Physiological Societyhttps://doi.org/10.1152/ajpgi.00049.2016PubMed26867562History Received 2 February 2016 Accepted 5 February 2016 Published online 15 March 2016 Published in print 15 March 2016 Metrics