PRESENTATION
Diet, Microbiota, and Colorectal Cancer Hakan Akın, MD* and Nurdan To¨zu¨n, MD, FRCPw
Abstract: Colorectal cancer (CRC) is the third most common cancer in the world causing nearly 500,000 deaths every year. In addition to genetic background, environmental factors including diet and lifestyle are accepted as major contributors to adenoma and CRC development. Lifestyle factors include high BMI, obesity, and reduced physical activity. Growing interest and accumulating data on human microbiota implicate that host-microbe interplay has an important role in the development of metabolic, neoplastic, and inflammatory diseases. Findings from recent studies suggest that colon cancer risk is determined by the interaction between diet and gut microbiota. Dietary changes affect gut microbiota and conversely microbiota mediates the generation of dietary factors triggering colon cancer. Identification of the microbial communities associated with carcinogenesis is of crucial importance. Nowadays, with the evolvement of culture-independent molecular techniques, it has become possible to identify main bacterial species in healthy individuals, inflammatory conditions, and CRC. Some recent studies have shown the differences in intestinal microbiota between colon cancer patients and healthy individuals. Animal studies have provided a better understanding of interaction between pathobionts and symbionts in the development of colon cancer. There is no single causative organism identified in CRC; however, there is strong evidence that reduction of protective bacteria, increase in some bacteria (ie, fusobacterium members; Bacteroides/Prevotella), and age-related changes in microbiota have an impact on adenoma or cancer development. Future studies will enable us to understand procarcinogenic and anticarcinogenic mechanisms and give insights to rational manipulation of the microbiota with prebiotics, probiotics, or dietary modifications. Key Words: colorectal cancer, microbiota, diet, dysbiosis, probiotics
(J Clin Gastroenterol 2014;48:S67–S69)
T
he gastrointestinal microbiota has become the major focus of interest as a determinant of healthy life, as well as a Pandora’s Box of many diseases including inflammatory bowel diseases (IBD), obesity, and cancer. The aphorism attributed to Socrates: “The unexamined life is not worth living.” seems to have been updated by Venter,1 a pioneer in the world of genomic research as “Without understanding the environment in which cells or species exist, life cannot be understood.” Normal human body contains >100 trillion bacteria in the gastrointestinal tract. This dense gastrointestinal microbial population called microbiota has numerous physiological From the *Department of Gastroenterology, Marmara University School of Medicine, Marmara University Institute of Gastroenterology; and wDepartment of Gastroenterology, Acibadem University School of Medicine, Acibadem Kozyatagi Hospital, Istanbul, Turkey. The authors declare that they have nothing to disclose. Reprints: Nurdan To¨zu¨n, MD, FRCP, Department of Gastroenterology, Acibadem University School of Medicine, Acibadem Kozyatagi Hospital, Inonu Cadd.Okur Sok.No: 20 Kozyatagi 34 742, Istanbul, Turkey (e-mails: [email protected]; [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
J Clin Gastroenterol
functions such as gastrointestinal immune stimulation, essential nutrient production, control of pathogenic microorganisms, modulation of gastrointestinal epithelial cell proliferation and differentiation, and management of bioactive foods and chemical components. It is now clear that gut microbiome has a central place in host physiology, metabolism, and nutrition.2–4 The microbiota is subject to change with dietary habits, cultural differences, the environment, and many other factors. Besides different diseases, physical and psychological stress, age, diet, surgery, medications, radiation, and chemicals were shown to affect both the number and the diversity of microbiota.5 Our ecosystem is not only a new platform to explain the pathophysiology of many disorders but also a new target for drug development on the way to personalized medicine. However, it is well established that diet is the most important modifier of the microbiota in health. A well-balanced diet corresponds with a well-composed microbial community. Better understanding of the interplay between host microbiota and diet, and their influence on inflammatory and/or metabolic pathways will enable us to ensure a healthy state and tailor the treatment of many diseases in the near future.4 Colorectal cancer (CRC) is a common, worldwide cancer causing nearly 500,000 deaths every year. Its incidence is higher in developed western countries.6 The marked difference in the epidemiology of CRC reflects different dietary patterns, namely high consumption of animal protein (Western diet) versus plant-based diets and the Mediterranean diet. There is a strong genetic component favoring the development of colorectal adenomas or CRCs. Of all CRC cases, 5% to 15% can be attributed to hereditary CRC syndromes such as Lynch syndrome (hereditary nonpolyposis CRC, familial adenomatous polyposis, and MUTYH-associated polyposis). Lifestyle factors increasing the risks for CRC include elevated body mass index, obesity, and reduced physical activity.7,8 Diet has always been considered as a major actor, playing sometimes the “good,” sometimes the “bad” character in the development of CRC. The westerntype diet rich in red and processed meat, refined grains, sweets, fat, and alcohol was associated with high risks for CRC, whereas a Mediterranean-type diet rich in fruits, vegetables, dairy products, fiber, fish, and olive oil with less red meat was reported beneficial in preventing cardiovascular diseases and cancer.9,10 A better understanding of the various mechanisms including microbiota-host interaction will enable the implementation of a better strategy for the prevention of CRC, especially in high-risk groups, and reduce the costs of morbidities associated with the disease.
ASSOCIATION OF CRC WITH CHANGES IN MICROBIOTA: WHERE DOES IT COME FROM? An association between bacteria and colon cancer has long been recognized in previous studies. McCoy and Mason11 published a case report of “enterococcal”
Volume 48, Supp. 1, November/December 2014
www.jcge.com |
S67
Akın and To¨zu¨n
J Clin Gastroenterol
endocarditis associated with a carcinoma of the cecum as early as 1951. The gut microbiota guides both development and function of the gut immune system. In addition, it has a major role in keeping the integrity of the mucosal barrier, ensuring nutrient digestion, absorption, and angiogenesis.12 The shift from normal microbiota colonized by commensals (tolerated by the immune system) to dysbiosis causes an increase of the so-called pathobionts (organisms with pathogenic potential). This shift in turn leads to the induction of an inflammatory state that becomes chronic and significantly increases the risk for CRC. Gut bacteria such as Bacteroides fragilis and Streptococcus bovis have been linked to CRC because of their ability to activate immune cells. CRCs can be initiated by some bacteria called “Drivers” and promoted by some bacteria called “Passengers.”13 The slow progression of studies for the identification of bacteria comprising the microbiota in health and disease states comes from the difficulty in cultivating the bacterial population. It has not always been possible to create optimal medium for the growth of gut bacteria. Although >80% of intestinal bacteria cannot be cultured, identification of all bacteria has become possible by using high technology to perform whole DNA genome sequencing. With the evolvement of culture-independent molecular techniques (phylogenetic analysis of bacterial 16 S rRNA genes) this goal has been achievable. Some studies disclosed main bacterial species in healthy individuals, IBD patients, and CRC.14,15 Recently, Sobhani and colleagues were able to show that the stools of patients with colon cancer harbored a different group of bacteria compared with those of matched individuals with normal colonoscopy; this result has been confirmed by other studies. Furthermore, these researchers were able to demonstrate by real-time quantitative polymerase chain reaction technique that stool Bacteroides/Prevotella group density level was higher in patients with CRC compared with normals independent from age, BMI, the reason for the colonoscopy, and the previous history of polyps or of cancer in their family.14 In another study, patients with adenomas were compared with nonadenoma subjects. At the genus level, the adenoma group had an increased number of Dorea spp. and Faecalibacterium spp. and decreased number of Bacteroides spp. and Coprococcus spp.16 In a recent study, genomic analysis revealed a “significant enrichment” of Fusobacterium in colorectal carcinoma.17 Firmicutes (62%), Bacteroidetes (26%), and Proteobacteria (11%) were reported as the most dominant phyla in bacteria adherent to precancerous adenomatous polyps in other studies. Although some studies have suggested an association of CRC with the Fusobacterium genus, it is likely that this microorganism is a passenger rather than being a driver. Animal studies have also supported the effect of microbiota on colonic neoplasm development. In the study of Kado et al,18 there was no development of adenocarcinoma of the colon among the germ-free mice, whereas in the conventionalized group, adenocarcinomas of the ileocecum and cecum were detected in 70% of animals. Likewise, fresh stool samples were collected from individuals with colon cancer and healthy individuals and transferred to the colons of healthy germ-free mice by gavages, and the animals were followed up to 6 weeks. The composition of bacteria in mice’s stools was of human type and remained stable over time. However, cell proliferation, an early
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Volume 48, Supp. 1, November/December 2014
cancer marker, and aberrant crypt foci, an equivalent in mice to adenomatous polyps in humans, increased in the colons of mice given the cancerous stools.19 These studies are promising on the path to proving the contribution of intestinal microbiota on the development of CRC in susceptible individuals.
WHAT IS THE MECHANISM BEHIND THE TUMORIGENESIS LINKED TO MICROBIOTA? The development of CRC is a multistep process known as the “adenoma-carcinoma sequence.” CRCs develop on preexisting polyps, the progression of which to cancer is dependent on many genetic, dietary, environmental, and unknown factors. As stated above, many studies have suggested that intestinal carcinogenesis can be a result of dysbiosis in the colonic microbiota with an increased proportion of bacteria whose metabolism elaborates cytotoxic or genotoxic compounds (eg, sulfate-reducing bacteria) or bacteria that cause DNA damage either through production of free radicals (eg, reactive oxygen intermediates) or through abnormal activation of resident immune cells (eg, macrophages). It is generally accepted that chronic inflammation is a major trigger for the start of cellular proliferation and neoplastic changes in a susceptible host.
Impact of Diet A diet rich in red meat and animal fat and higher counts of 7a dehydroxylating colonic bacteria will generate high levels of secondary bile acids in the bowel, which are cytotoxic to colonic epithelial cells, as well as mutagenic with antiapoptotic properties. Bacterial activities and enzymes that have been linked to increased risk for CRC were described as glucuronidases, H2S generation, azoreductases, nitroreductases, alcohol dehydrogenases, arylsulfatases, and reactive oxygen intermediates–generating enzymes.12 In contrast to red meat and animal fat, carbohydrate residues such as fiber stimulate saccharolytic fermentation and the production of the health-promoting short-chain fatty acids acetate, propionate, and butyrate. These are absorbed by colonocytes and used as a primary source of energy and all 3 shortchain fatty acids have anti-inflammatory and antiproliferative properties.20 The higher risk for CRC in African Americans compared with native Africans has been attributed to their chronically lower consumption of fiber and resistant starch and their higher consumption of dietary fat. Microbial composition was fundamentally different in these groups, with predominance of Prevotella in native Africans and of Bacteroides in African Americans.21
Impact of Age Age is another important factor for CRC pathogenesis and also reported to be effective on human microbiota content. With age, the total number of bacteria decreases and the composition of the microbiota changes with lower numbers of Firmicutes and increased proportion of Bacteroidetes.22 Another study reported that with increasing age, Escherichia coli and Enterococci spp. are consistently and significantly increased in the human microbiota. But more studies are needed to reach firm conclusions.23 Finally, it is still too early to conclude that bacteria might directly cause CRC. However, changes in energy uptake, metabolic disorders, stimulation of epithelial cells, r
2014 Lippincott Williams & Wilkins
J Clin Gastroenterol
Volume 48, Supp. 1, November/December 2014
and reduction of protective bacteria are possible ways through which carcinogenesis might be facilitated in humans. Evidence accumulating from the studies on microbiota and inflammatory/neoplastic diseases suggest that by manipulating microbiota in different ways we could be able to prevent, treat, or halt the progression of diseases such as IBDs, obesity, and CRC. Could replacing the “bad bacteria” with the “good bacteria” influence the cross-talk between immune system and microbiota and be beneficial to cease the inflammation and halt the progression to neoplasia? Could prebiotics or probiotics, by reinforcing the natural defenses of the organism, be useful in this matter?12 Animal studies have suggested a favorable role for Bifidobacterium and Lactobacillus, specifically B. lactis, Blongum, L. acidophilus, L. casei, and L. rhamnosus in reducing the number of aberrant crypt foci in mice. Probiotic bacteria (Lactobacillus spp. and Bifidobacterium spp.) exert anticarcinogenic effects, in part by inactivating microbial enzymes. Thus, modulating the gut microbiota should be considered as a therapeutic strategy to treat chronic disease. This can be achieved by the use of prebiotics, supplementation with probiotics, reconstitution of bacterial populations by fecal transplantation, by the administration of antimicrobials to eliminate pathogens or manipulate the gut microbiota in favor of the host. However, we should bear in mind that current oral probiotic doses do not provide sufficient microbial numbers to fully influence the populations of the colon. Regarding the fecal transplantation, which proved to be effective in resistant Clostridium difficile infections, there is still much to learn about its effectiveness in other situations including CRC. In conclusion, studies on gut microbiota and CRC are exciting and give insights on the understanding and management of colorectal neoplasia. However, there is still a need for larger studies and animal experiments to elucidate the interplay of microbiota, innate immune system, genetic factors, diet, and CRC before moving to targeted therapies by manipulation of microbiota.2 The rapidly evolving “omics” technologies will help us provide with more information regarding selection of beneficial organisms capable of survival, persistence, and delivery of a wide range of bioactive compounds in the prevention and control of CRC and many other diseases. REFERENCES 1. Venter G. A Life Decoded: My Genome: My Life. London: Penguin Allen Lane; 2007. 2. Guinane CM, Cotter PD. Role of the gut microbiota in health and chronic gastrointestinal disease. Understanding a hidden metabolic organ. Ther Adv Gastroenterol. 2013;6:295–308. 3. Korecka A, Arulampalam V. The gut microbiome: scourge, sentinel or spectator? J Oral Microbiol. 2012;4:9367–9381.
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Microbiota and Colorectal Cancer
4. Shanahan F. The gut microbiota—a clinical perspective on lessons learned. Nat Rev Gastroenterol Hepatol. 2012;9:609–614. 5. Tennyson CA, Friedman G. Microecology, obesity, and probiotics. Curr Opin Endocrinol Diabetes Obes. 2008;15:422–427. 6. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108. 7. Johnson IT, Lund EK. Nutrition, obesity and colorectal cancer. Aliment Pharmacol Ther. 2007;26:161–181. 8. Marshall JR. Prevention of colorectal cancer: diet, chemo prevention, and lifestyle. Gastroenterol Clin North Am. 2008;37:73–82. 9. Arvanitakis C, Tozun N. Mediterranean diet – Health and culture. Int J Anthropol. 2013;28:207–235. 10. Estruch R, Ras E, Salas-Salvado J, et al. Primary prevention of cardiovascular disease with a mediterranean diet. N Engl J Med. 2013;368:1279–1290. 11. McCoy WC, Mason JM III. Enterococcal endocarditis associated with carcinoma of the sigmoid: report of a case. J Med Assoc State Ala. 1951;21:162–166. 12. Azca´rate-Peril MA, Sikes M, Bruno-Ba´rcena JM. The intestinal microbiota, gastrointestinal environment and colorectal cancer: a putative role for probiotics in prevention of colorectal cancer? Am J Physiol Gastrointest Liver Physiol. 2011;301:G401–G424. 13. Tjalsma H, Boleij A, Marchesi J, et al. A bacterial driverpassenger model for colorectal cancer: beyond the usual suspects. Nat Rev Microbiol. 2012;10:575–582. 14. Sobhani I, Tap J, Roudot-Thoraval F, et al. Microbial dysbiosis in colorectal cancer (CRC) patients. PLoS One. 2011;6:e16393. 15. Scanlan PD, Shanahan F, Clune Y, et al. Culture-independent analysis of the gut microbiota in colorectal cancer and polyposis. Environ Microbiol. 2008;10:789–798. 16. Shen XJ I, Rawls JF, Randall T, et al. Molecular characterization of mucosal adherent bacteria and associations with colorectal adenomas. Gut Microbes. 2010;1:138–147. 17. Kostic AD, Gevers D, Pedamallu CS, et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res. 2012;22:292–298. 18. Kado S, Uchida K, Funabashi H, et al. Intestinal microflora are necessary for development of spontaneous adenocarcinoma of the large intestine in T-cell receptor beta chain and p53 double-knockout mice. Cancer Res. 2001;61:2395–2398. 19. Sobhani I, Jarrousse V, Guilemeau S, et al. Colon cancer patients’ microbiome induces intestinal precancerous change in germ-free mice. Abstract presented at the UEGW 2011, Stockholm, Sweden. Gut. 2011;60(suppl 3):A1. 20. Waldecker M, Kautenburger T, Daumann H, et al. Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon. J Nutr Biochem. 2008;19:587–593. 21. Ou J, Carbonero F, Zoetendal EG, et al. Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans. Am J Clin Nutr. 2013;98:111–120. 22. Ma¨kivuokko H, Tiihonen K, Tynkkynen S, et al. The effect of age and non-steroidal anti-inflammatory drugs on human intestinal microbiota composition. Br J Nutr. 2010;103:227–234. 23. Enck P, Zimmermann K, Rusch K, et al. The effects of ageing on the colonic bacterial microflora in adults. Z Gastroenterol. 2009;47:653–658.
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Diet, Microbiota, and Colorectal Cancer Hakan Akın, MD* and Nurdan To¨zu¨n, MD, FRCPw
Abstract: Colorectal cancer (CRC) is the third most common cancer in the world causing nearly 500,000 deaths every year. In addition to genetic background, environmental factors including diet and lifestyle are accepted as major contributors to adenoma and CRC development. Lifestyle factors include high BMI, obesity, and reduced physical activity. Growing interest and accumulating data on human microbiota implicate that host-microbe interplay has an important role in the development of metabolic, neoplastic, and inflammatory diseases. Findings from recent studies suggest that colon cancer risk is determined by the interaction between diet and gut microbiota. Dietary changes affect gut microbiota and conversely microbiota mediates the generation of dietary factors triggering colon cancer. Identification of the microbial communities associated with carcinogenesis is of crucial importance. Nowadays, with the evolvement of culture-independent molecular techniques, it has become possible to identify main bacterial species in healthy individuals, inflammatory conditions, and CRC. Some recent studies have shown the differences in intestinal microbiota between colon cancer patients and healthy individuals. Animal studies have provided a better understanding of interaction between pathobionts and symbionts in the development of colon cancer. There is no single causative organism identified in CRC; however, there is strong evidence that reduction of protective bacteria, increase in some bacteria (ie, fusobacterium members; Bacteroides/Prevotella), and age-related changes in microbiota have an impact on adenoma or cancer development. Future studies will enable us to understand procarcinogenic and anticarcinogenic mechanisms and give insights to rational manipulation of the microbiota with prebiotics, probiotics, or dietary modifications. Key Words: colorectal cancer, microbiota, diet, dysbiosis, probiotics
(J Clin Gastroenterol 2014;48:S67–S69)
T
he gastrointestinal microbiota has become the major focus of interest as a determinant of healthy life, as well as a Pandora’s Box of many diseases including inflammatory bowel diseases (IBD), obesity, and cancer. The aphorism attributed to Socrates: “The unexamined life is not worth living.” seems to have been updated by Venter,1 a pioneer in the world of genomic research as “Without understanding the environment in which cells or species exist, life cannot be understood.” Normal human body contains >100 trillion bacteria in the gastrointestinal tract. This dense gastrointestinal microbial population called microbiota has numerous physiological From the *Department of Gastroenterology, Marmara University School of Medicine, Marmara University Institute of Gastroenterology; and wDepartment of Gastroenterology, Acibadem University School of Medicine, Acibadem Kozyatagi Hospital, Istanbul, Turkey. The authors declare that they have nothing to disclose. Reprints: Nurdan To¨zu¨n, MD, FRCP, Department of Gastroenterology, Acibadem University School of Medicine, Acibadem Kozyatagi Hospital, Inonu Cadd.Okur Sok.No: 20 Kozyatagi 34 742, Istanbul, Turkey (e-mails: [email protected]; [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
J Clin Gastroenterol
functions such as gastrointestinal immune stimulation, essential nutrient production, control of pathogenic microorganisms, modulation of gastrointestinal epithelial cell proliferation and differentiation, and management of bioactive foods and chemical components. It is now clear that gut microbiome has a central place in host physiology, metabolism, and nutrition.2–4 The microbiota is subject to change with dietary habits, cultural differences, the environment, and many other factors. Besides different diseases, physical and psychological stress, age, diet, surgery, medications, radiation, and chemicals were shown to affect both the number and the diversity of microbiota.5 Our ecosystem is not only a new platform to explain the pathophysiology of many disorders but also a new target for drug development on the way to personalized medicine. However, it is well established that diet is the most important modifier of the microbiota in health. A well-balanced diet corresponds with a well-composed microbial community. Better understanding of the interplay between host microbiota and diet, and their influence on inflammatory and/or metabolic pathways will enable us to ensure a healthy state and tailor the treatment of many diseases in the near future.4 Colorectal cancer (CRC) is a common, worldwide cancer causing nearly 500,000 deaths every year. Its incidence is higher in developed western countries.6 The marked difference in the epidemiology of CRC reflects different dietary patterns, namely high consumption of animal protein (Western diet) versus plant-based diets and the Mediterranean diet. There is a strong genetic component favoring the development of colorectal adenomas or CRCs. Of all CRC cases, 5% to 15% can be attributed to hereditary CRC syndromes such as Lynch syndrome (hereditary nonpolyposis CRC, familial adenomatous polyposis, and MUTYH-associated polyposis). Lifestyle factors increasing the risks for CRC include elevated body mass index, obesity, and reduced physical activity.7,8 Diet has always been considered as a major actor, playing sometimes the “good,” sometimes the “bad” character in the development of CRC. The westerntype diet rich in red and processed meat, refined grains, sweets, fat, and alcohol was associated with high risks for CRC, whereas a Mediterranean-type diet rich in fruits, vegetables, dairy products, fiber, fish, and olive oil with less red meat was reported beneficial in preventing cardiovascular diseases and cancer.9,10 A better understanding of the various mechanisms including microbiota-host interaction will enable the implementation of a better strategy for the prevention of CRC, especially in high-risk groups, and reduce the costs of morbidities associated with the disease.
ASSOCIATION OF CRC WITH CHANGES IN MICROBIOTA: WHERE DOES IT COME FROM? An association between bacteria and colon cancer has long been recognized in previous studies. McCoy and Mason11 published a case report of “enterococcal”
Volume 48, Supp. 1, November/December 2014
www.jcge.com |
S67
Akın and To¨zu¨n
J Clin Gastroenterol
endocarditis associated with a carcinoma of the cecum as early as 1951. The gut microbiota guides both development and function of the gut immune system. In addition, it has a major role in keeping the integrity of the mucosal barrier, ensuring nutrient digestion, absorption, and angiogenesis.12 The shift from normal microbiota colonized by commensals (tolerated by the immune system) to dysbiosis causes an increase of the so-called pathobionts (organisms with pathogenic potential). This shift in turn leads to the induction of an inflammatory state that becomes chronic and significantly increases the risk for CRC. Gut bacteria such as Bacteroides fragilis and Streptococcus bovis have been linked to CRC because of their ability to activate immune cells. CRCs can be initiated by some bacteria called “Drivers” and promoted by some bacteria called “Passengers.”13 The slow progression of studies for the identification of bacteria comprising the microbiota in health and disease states comes from the difficulty in cultivating the bacterial population. It has not always been possible to create optimal medium for the growth of gut bacteria. Although >80% of intestinal bacteria cannot be cultured, identification of all bacteria has become possible by using high technology to perform whole DNA genome sequencing. With the evolvement of culture-independent molecular techniques (phylogenetic analysis of bacterial 16 S rRNA genes) this goal has been achievable. Some studies disclosed main bacterial species in healthy individuals, IBD patients, and CRC.14,15 Recently, Sobhani and colleagues were able to show that the stools of patients with colon cancer harbored a different group of bacteria compared with those of matched individuals with normal colonoscopy; this result has been confirmed by other studies. Furthermore, these researchers were able to demonstrate by real-time quantitative polymerase chain reaction technique that stool Bacteroides/Prevotella group density level was higher in patients with CRC compared with normals independent from age, BMI, the reason for the colonoscopy, and the previous history of polyps or of cancer in their family.14 In another study, patients with adenomas were compared with nonadenoma subjects. At the genus level, the adenoma group had an increased number of Dorea spp. and Faecalibacterium spp. and decreased number of Bacteroides spp. and Coprococcus spp.16 In a recent study, genomic analysis revealed a “significant enrichment” of Fusobacterium in colorectal carcinoma.17 Firmicutes (62%), Bacteroidetes (26%), and Proteobacteria (11%) were reported as the most dominant phyla in bacteria adherent to precancerous adenomatous polyps in other studies. Although some studies have suggested an association of CRC with the Fusobacterium genus, it is likely that this microorganism is a passenger rather than being a driver. Animal studies have also supported the effect of microbiota on colonic neoplasm development. In the study of Kado et al,18 there was no development of adenocarcinoma of the colon among the germ-free mice, whereas in the conventionalized group, adenocarcinomas of the ileocecum and cecum were detected in 70% of animals. Likewise, fresh stool samples were collected from individuals with colon cancer and healthy individuals and transferred to the colons of healthy germ-free mice by gavages, and the animals were followed up to 6 weeks. The composition of bacteria in mice’s stools was of human type and remained stable over time. However, cell proliferation, an early
S68 | www.jcge.com
Volume 48, Supp. 1, November/December 2014
cancer marker, and aberrant crypt foci, an equivalent in mice to adenomatous polyps in humans, increased in the colons of mice given the cancerous stools.19 These studies are promising on the path to proving the contribution of intestinal microbiota on the development of CRC in susceptible individuals.
WHAT IS THE MECHANISM BEHIND THE TUMORIGENESIS LINKED TO MICROBIOTA? The development of CRC is a multistep process known as the “adenoma-carcinoma sequence.” CRCs develop on preexisting polyps, the progression of which to cancer is dependent on many genetic, dietary, environmental, and unknown factors. As stated above, many studies have suggested that intestinal carcinogenesis can be a result of dysbiosis in the colonic microbiota with an increased proportion of bacteria whose metabolism elaborates cytotoxic or genotoxic compounds (eg, sulfate-reducing bacteria) or bacteria that cause DNA damage either through production of free radicals (eg, reactive oxygen intermediates) or through abnormal activation of resident immune cells (eg, macrophages). It is generally accepted that chronic inflammation is a major trigger for the start of cellular proliferation and neoplastic changes in a susceptible host.
Impact of Diet A diet rich in red meat and animal fat and higher counts of 7a dehydroxylating colonic bacteria will generate high levels of secondary bile acids in the bowel, which are cytotoxic to colonic epithelial cells, as well as mutagenic with antiapoptotic properties. Bacterial activities and enzymes that have been linked to increased risk for CRC were described as glucuronidases, H2S generation, azoreductases, nitroreductases, alcohol dehydrogenases, arylsulfatases, and reactive oxygen intermediates–generating enzymes.12 In contrast to red meat and animal fat, carbohydrate residues such as fiber stimulate saccharolytic fermentation and the production of the health-promoting short-chain fatty acids acetate, propionate, and butyrate. These are absorbed by colonocytes and used as a primary source of energy and all 3 shortchain fatty acids have anti-inflammatory and antiproliferative properties.20 The higher risk for CRC in African Americans compared with native Africans has been attributed to their chronically lower consumption of fiber and resistant starch and their higher consumption of dietary fat. Microbial composition was fundamentally different in these groups, with predominance of Prevotella in native Africans and of Bacteroides in African Americans.21
Impact of Age Age is another important factor for CRC pathogenesis and also reported to be effective on human microbiota content. With age, the total number of bacteria decreases and the composition of the microbiota changes with lower numbers of Firmicutes and increased proportion of Bacteroidetes.22 Another study reported that with increasing age, Escherichia coli and Enterococci spp. are consistently and significantly increased in the human microbiota. But more studies are needed to reach firm conclusions.23 Finally, it is still too early to conclude that bacteria might directly cause CRC. However, changes in energy uptake, metabolic disorders, stimulation of epithelial cells, r
2014 Lippincott Williams & Wilkins
J Clin Gastroenterol
Volume 48, Supp. 1, November/December 2014
and reduction of protective bacteria are possible ways through which carcinogenesis might be facilitated in humans. Evidence accumulating from the studies on microbiota and inflammatory/neoplastic diseases suggest that by manipulating microbiota in different ways we could be able to prevent, treat, or halt the progression of diseases such as IBDs, obesity, and CRC. Could replacing the “bad bacteria” with the “good bacteria” influence the cross-talk between immune system and microbiota and be beneficial to cease the inflammation and halt the progression to neoplasia? Could prebiotics or probiotics, by reinforcing the natural defenses of the organism, be useful in this matter?12 Animal studies have suggested a favorable role for Bifidobacterium and Lactobacillus, specifically B. lactis, Blongum, L. acidophilus, L. casei, and L. rhamnosus in reducing the number of aberrant crypt foci in mice. Probiotic bacteria (Lactobacillus spp. and Bifidobacterium spp.) exert anticarcinogenic effects, in part by inactivating microbial enzymes. Thus, modulating the gut microbiota should be considered as a therapeutic strategy to treat chronic disease. This can be achieved by the use of prebiotics, supplementation with probiotics, reconstitution of bacterial populations by fecal transplantation, by the administration of antimicrobials to eliminate pathogens or manipulate the gut microbiota in favor of the host. However, we should bear in mind that current oral probiotic doses do not provide sufficient microbial numbers to fully influence the populations of the colon. Regarding the fecal transplantation, which proved to be effective in resistant Clostridium difficile infections, there is still much to learn about its effectiveness in other situations including CRC. In conclusion, studies on gut microbiota and CRC are exciting and give insights on the understanding and management of colorectal neoplasia. However, there is still a need for larger studies and animal experiments to elucidate the interplay of microbiota, innate immune system, genetic factors, diet, and CRC before moving to targeted therapies by manipulation of microbiota.2 The rapidly evolving “omics” technologies will help us provide with more information regarding selection of beneficial organisms capable of survival, persistence, and delivery of a wide range of bioactive compounds in the prevention and control of CRC and many other diseases. REFERENCES 1. Venter G. A Life Decoded: My Genome: My Life. London: Penguin Allen Lane; 2007. 2. Guinane CM, Cotter PD. Role of the gut microbiota in health and chronic gastrointestinal disease. Understanding a hidden metabolic organ. Ther Adv Gastroenterol. 2013;6:295–308. 3. Korecka A, Arulampalam V. The gut microbiome: scourge, sentinel or spectator? J Oral Microbiol. 2012;4:9367–9381.
r
2014 Lippincott Williams & Wilkins
Microbiota and Colorectal Cancer
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