NEWS & VIEWS GUT MICROBIOTA
Microbiota organisation—a key to understanding CRC development Georgina L. Hold and Wendy S. Garrett
The gut microbiota has an important role in colorectal cancer (CRC). Dejea and colleagues have demonstrated that particular bacterial biofilms are associated with proximal CRC, correlating with changes in tissue biology associated with oncogenesis. These findings provide a fresh perspective on the microbiota in cancer: microbial organization might provide critical insight into understanding CRC development. Hold, G. L. & Garrett, W. S. Nat. Rev. Gastroenterol. Hepatol. advance online publication 17 February 2015; doi:10.1038/nrgastro.2015.25
Colorectal cancer (CRC) is the second most deadly cancer in both men and women, with more than 600,000 deaths annually.1 Gut bacteria drive inflammation within the colon and such inflammation is strongly linked to CRC. 2 Howe ver, the precise mechanisms through which this process happens are still not fully elucidated. The gut microbiota potentially contributes to host cancer risk via three major routes: altering host cell proliferation or turn over; influencing immune function; and metabolizing ingested and host-derived products.3 Numerous studies now highlight that it is critical to delve beyond microbial community composition and shift focus towards the metabolic function of the microbiota to further our understanding of disease development. In a recent article by Dejea et al.,4 further insights into the links between bacterial biofilms and CRC have been elucidated. The researchers studied microbial communities associated with colorectal tumours (adenomas and adenocarcinomas) and compared these with paired normal (pathologically tumour-free) mucosa from the same individuals.4 Invasive polymicro bial bacterial biofilms, which are a known driver of tissue inflammation, were seen in almost all right-sided tumours (89%) but in only 12% of left-sided tumours. Biofilm-positive tumours were also associ ated with the presence of biofilm-positive normal mucosa distant from the tumour site, indicating a global or field defect rather than a local tumour-specific phenomenon. These biofilms included bacteria that have
been previously associated with colorectal adenomas and adenocarcinomas in human and mouse studies, such as enterotoxigenic Bacteroides fragilis and Fusobacterium nucleatum. Whether from tumour or normal mucosa communities, biofilm-positive tissues exhibited enhanced pro-oncogenic epithelial permeability and increased epi thelial IL‑6 levels, suggesting that there might be underlying features related to biofilm assembly in certain individuals that increases their risk of developing CRC.4 Enhanced epithelial permeability facili tates bacterial antigen translocation and promotes proinflammatory cytokine production. But what drives a biofilm to assemble and why are certain individuals susceptible to colonic biofilm formation whilst others are potentially refractory? Substantial overlap in bacterial diversity has been repeatedly demonstrated between tumour and healthy tissues, emphasiz ing the possibility that the gut microbiota is capable of altering its metabolism in response to the environment in which it finds itself. Perhaps biofilm function as well as community structure can be at least partly influenced by the host?
Biofilms are defined as polymicrobial communities. The bacterial communi ties of the human gut are predominantly anaerobic and are comprised of hundreds of different species. The bacteria that live in biofilm communities greatly influence each other’s existence through nutrient sharing and/or scavenging and cell-tocell communications (quorum sensing).5 The complex structural and functional capabilities of bacterial biofilms have led to the analogy that biofilms func tion organizationally like tissues from higher organisms.5 A number of chronic bacterial infections involve bacterial bio films. Bacteria function differently within mixed communities compared to in isola tion, with predetermined signals triggered at specific cell densities or in response to certain metabolites. These signals can influence biofilm maturation and differ entiation, which in turn influences host– bacterial communications.6,7 Evidence that biofilms can modify epithelial cell biology, especially within a subset of colorectal tumours, presents a fascinating opportu nity to further unravel the basis of host– microbial interactions and is consistent with the concept of tumour on:tumour off bacterial communities reported previously.
NPG
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY © 2015 Macmillan Publishers Limited. All rights reserved
ADVANCE ONLINE PUBLICATION | 1
NEWS & VIEWS Several bacterial species have been impli cated in CRC due to their ability to either directly or indirectly damage DNA.2 Other microbes possess proteins that can interfere with host pathways, which favour carcino genesis. Putting aside the need to attribute specific metabolic capabilities to defined community members and embracing the concept that a bacterial community might dictate whether it is procarcinogenic not only requires careful consideration but, if correct, lends itself to potential manipula tion wherein it could be rewired to drive an anticarcinogenic environment.
‘‘
Gut bacteria drive inflammation within the colon and such inflammation is strongly linked to CRC
’’
In the context of CRC, tumorigenesis happens over many years. On the basis of a number of potential modifiers of the gut microbiota, including diet, environmental factors and health status,8 it is understand able how different species might play dif fering parts over time. As with malignancy induced by Helicobacter pylori, by the time CRC is detected, initiating microbial trig gers might no longer remain within the tumour environment. 3 The interesting proposition from the study by Dejea et al.,4 however, is that certain individuals seem to be programmed to form these bacterial biofilms that are capable of driving onco genic transformation of the healthy colon, offering an early opportunity to intervene.
Historically, the greater proportion of CRC were considered to be distal to the splenic flexure, although a 30-year analy sis of CRC trends in the USA between 1976 and 2005 showed a decrease in all subsite CRC incidence except for rightsided CRC.9 Clear molecular pathological differences exist between left-sided and right-sided CRC, with proximal tumours more frequently displaying microsatellite instability and the presence of tumourinfiltrating lymphocytes, whereas distal tumours more commonly arise from the conventional adenoma–carcinoma sequence and demonstrate chromosomal instability.10 Environmental differences are also relevant for the microbiota in proxi mal and distal CRC. The distal colon has a higher bacterial load—which results in markedly more fermentation (short-chain fatty acid production)—than the proximal colon. Exposure to mutagenic metabo lites also differs; levels of these products are higher in the distal colon than in the proximal colon, although this difference is balanced by increased bile acid exposure in the proximal colon. What is evident is that consideration of the metabolic capabilities of the gut micro biota in situ is in its infancy. These results also suggest that further research is needed into the bioactive molecules generated in these biofilm microbial communities. Understanding this microbial metabolism and its effects on colonic health, as well as CRC development, adds another thera peutic and diagnostic angle for offering precision health care.
2 | ADVANCE ONLINE PUBLICATION
School of Medicine & Dentistry, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK (G.L.H.). Department of Immunology and Infectious Disease, Harvard School of Public Health, Boston, MA 02115, USA (W.S.G.) Correspondence to: G.L.H. [email protected] Competing interests The authors declare no competing interests. 1.
Ferlay, J. et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer 127, 2893–2917 (2010). 2. Louis, P., Hold, G. L. & Flint, H. J. The gut microbiota, bacterial metabolites and colorectal cancer. Nat. Rev. Microbiol. 12, 661–672 (2014). 3. Sears, C. L. & Garrett, W. S. Microbes, microbiota and colon cancer. Cell Host Microbe 15, 317–328 (2014). 4. Dejea, C. M. et al. Microbiota organization is a distinct feature of proximal colorectal cancers. Proc. Natl Acad. Sci. USA 111, 18321–18326 (2014). 5. Costerton, J. W., Stewart, P. S. & Greenberg, E. P. Bacterial biofilms: a common cause of persistent infections. Science 284, 1318–1322 (1999). 6. Fuqua, C., Winans, S. C. & Greenberg, E. P. Census and consensus in bacterial ecosystems: The LuxR-Luxl family of quorum-sensing transcriptional regulators. Ann. Rev. Micro. 50, 727–751 (1996). 7. Davies, D. G. et al. The involvement of cell‑to‑cell signals in the development of a bacterial biofilm. Science 280, 295–298 (1998). 8. Hold, G. L. Western lifestyle: a ‘master’ manipulator of the intestinal microbiota? Gut 63, 5–6 (2014). 9. Cheng, L., Eng, C., Nieman, L. Z., Kapadia, A. S. & Du, X. L. Trends in colorectal cancer incidence by anatomic site and disease stage in the United States from 1976 to 2005. Am. J. Clin. Oncol. 34, 573–580 (2011). 10. Yamauchi, M. et al. Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut 61, 847–854 (2012).
www.nature.com/nrgastro © 2015 Macmillan Publishers Limited. All rights reserved
Microbiota organisation—a key to understanding CRC development Georgina L. Hold and Wendy S. Garrett
The gut microbiota has an important role in colorectal cancer (CRC). Dejea and colleagues have demonstrated that particular bacterial biofilms are associated with proximal CRC, correlating with changes in tissue biology associated with oncogenesis. These findings provide a fresh perspective on the microbiota in cancer: microbial organization might provide critical insight into understanding CRC development. Hold, G. L. & Garrett, W. S. Nat. Rev. Gastroenterol. Hepatol. advance online publication 17 February 2015; doi:10.1038/nrgastro.2015.25
Colorectal cancer (CRC) is the second most deadly cancer in both men and women, with more than 600,000 deaths annually.1 Gut bacteria drive inflammation within the colon and such inflammation is strongly linked to CRC. 2 Howe ver, the precise mechanisms through which this process happens are still not fully elucidated. The gut microbiota potentially contributes to host cancer risk via three major routes: altering host cell proliferation or turn over; influencing immune function; and metabolizing ingested and host-derived products.3 Numerous studies now highlight that it is critical to delve beyond microbial community composition and shift focus towards the metabolic function of the microbiota to further our understanding of disease development. In a recent article by Dejea et al.,4 further insights into the links between bacterial biofilms and CRC have been elucidated. The researchers studied microbial communities associated with colorectal tumours (adenomas and adenocarcinomas) and compared these with paired normal (pathologically tumour-free) mucosa from the same individuals.4 Invasive polymicro bial bacterial biofilms, which are a known driver of tissue inflammation, were seen in almost all right-sided tumours (89%) but in only 12% of left-sided tumours. Biofilm-positive tumours were also associ ated with the presence of biofilm-positive normal mucosa distant from the tumour site, indicating a global or field defect rather than a local tumour-specific phenomenon. These biofilms included bacteria that have
been previously associated with colorectal adenomas and adenocarcinomas in human and mouse studies, such as enterotoxigenic Bacteroides fragilis and Fusobacterium nucleatum. Whether from tumour or normal mucosa communities, biofilm-positive tissues exhibited enhanced pro-oncogenic epithelial permeability and increased epi thelial IL‑6 levels, suggesting that there might be underlying features related to biofilm assembly in certain individuals that increases their risk of developing CRC.4 Enhanced epithelial permeability facili tates bacterial antigen translocation and promotes proinflammatory cytokine production. But what drives a biofilm to assemble and why are certain individuals susceptible to colonic biofilm formation whilst others are potentially refractory? Substantial overlap in bacterial diversity has been repeatedly demonstrated between tumour and healthy tissues, emphasiz ing the possibility that the gut microbiota is capable of altering its metabolism in response to the environment in which it finds itself. Perhaps biofilm function as well as community structure can be at least partly influenced by the host?
Biofilms are defined as polymicrobial communities. The bacterial communi ties of the human gut are predominantly anaerobic and are comprised of hundreds of different species. The bacteria that live in biofilm communities greatly influence each other’s existence through nutrient sharing and/or scavenging and cell-tocell communications (quorum sensing).5 The complex structural and functional capabilities of bacterial biofilms have led to the analogy that biofilms func tion organizationally like tissues from higher organisms.5 A number of chronic bacterial infections involve bacterial bio films. Bacteria function differently within mixed communities compared to in isola tion, with predetermined signals triggered at specific cell densities or in response to certain metabolites. These signals can influence biofilm maturation and differ entiation, which in turn influences host– bacterial communications.6,7 Evidence that biofilms can modify epithelial cell biology, especially within a subset of colorectal tumours, presents a fascinating opportu nity to further unravel the basis of host– microbial interactions and is consistent with the concept of tumour on:tumour off bacterial communities reported previously.
NPG
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY © 2015 Macmillan Publishers Limited. All rights reserved
ADVANCE ONLINE PUBLICATION | 1
NEWS & VIEWS Several bacterial species have been impli cated in CRC due to their ability to either directly or indirectly damage DNA.2 Other microbes possess proteins that can interfere with host pathways, which favour carcino genesis. Putting aside the need to attribute specific metabolic capabilities to defined community members and embracing the concept that a bacterial community might dictate whether it is procarcinogenic not only requires careful consideration but, if correct, lends itself to potential manipula tion wherein it could be rewired to drive an anticarcinogenic environment.
‘‘
Gut bacteria drive inflammation within the colon and such inflammation is strongly linked to CRC
’’
In the context of CRC, tumorigenesis happens over many years. On the basis of a number of potential modifiers of the gut microbiota, including diet, environmental factors and health status,8 it is understand able how different species might play dif fering parts over time. As with malignancy induced by Helicobacter pylori, by the time CRC is detected, initiating microbial trig gers might no longer remain within the tumour environment. 3 The interesting proposition from the study by Dejea et al.,4 however, is that certain individuals seem to be programmed to form these bacterial biofilms that are capable of driving onco genic transformation of the healthy colon, offering an early opportunity to intervene.
Historically, the greater proportion of CRC were considered to be distal to the splenic flexure, although a 30-year analy sis of CRC trends in the USA between 1976 and 2005 showed a decrease in all subsite CRC incidence except for rightsided CRC.9 Clear molecular pathological differences exist between left-sided and right-sided CRC, with proximal tumours more frequently displaying microsatellite instability and the presence of tumourinfiltrating lymphocytes, whereas distal tumours more commonly arise from the conventional adenoma–carcinoma sequence and demonstrate chromosomal instability.10 Environmental differences are also relevant for the microbiota in proxi mal and distal CRC. The distal colon has a higher bacterial load—which results in markedly more fermentation (short-chain fatty acid production)—than the proximal colon. Exposure to mutagenic metabo lites also differs; levels of these products are higher in the distal colon than in the proximal colon, although this difference is balanced by increased bile acid exposure in the proximal colon. What is evident is that consideration of the metabolic capabilities of the gut micro biota in situ is in its infancy. These results also suggest that further research is needed into the bioactive molecules generated in these biofilm microbial communities. Understanding this microbial metabolism and its effects on colonic health, as well as CRC development, adds another thera peutic and diagnostic angle for offering precision health care.
2 | ADVANCE ONLINE PUBLICATION
School of Medicine & Dentistry, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK (G.L.H.). Department of Immunology and Infectious Disease, Harvard School of Public Health, Boston, MA 02115, USA (W.S.G.) Correspondence to: G.L.H. [email protected] Competing interests The authors declare no competing interests. 1.
Ferlay, J. et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer 127, 2893–2917 (2010). 2. Louis, P., Hold, G. L. & Flint, H. J. The gut microbiota, bacterial metabolites and colorectal cancer. Nat. Rev. Microbiol. 12, 661–672 (2014). 3. Sears, C. L. & Garrett, W. S. Microbes, microbiota and colon cancer. Cell Host Microbe 15, 317–328 (2014). 4. Dejea, C. M. et al. Microbiota organization is a distinct feature of proximal colorectal cancers. Proc. Natl Acad. Sci. USA 111, 18321–18326 (2014). 5. Costerton, J. W., Stewart, P. S. & Greenberg, E. P. Bacterial biofilms: a common cause of persistent infections. Science 284, 1318–1322 (1999). 6. Fuqua, C., Winans, S. C. & Greenberg, E. P. Census and consensus in bacterial ecosystems: The LuxR-Luxl family of quorum-sensing transcriptional regulators. Ann. Rev. Micro. 50, 727–751 (1996). 7. Davies, D. G. et al. The involvement of cell‑to‑cell signals in the development of a bacterial biofilm. Science 280, 295–298 (1998). 8. Hold, G. L. Western lifestyle: a ‘master’ manipulator of the intestinal microbiota? Gut 63, 5–6 (2014). 9. Cheng, L., Eng, C., Nieman, L. Z., Kapadia, A. S. & Du, X. L. Trends in colorectal cancer incidence by anatomic site and disease stage in the United States from 1976 to 2005. Am. J. Clin. Oncol. 34, 573–580 (2011). 10. Yamauchi, M. et al. Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut 61, 847–854 (2012).
www.nature.com/nrgastro © 2015 Macmillan Publishers Limited. All rights reserved
