.
JUser Object ( [isRoot:protected] => [id] => 0 [name] => [username] => [email] => [password] => [password_clear] => [usertype] => [block] => [sendEmail] => 0 [registerDate] => [lastvisitDate] => [activation] => [params] => [groups] => Array ( ) [guest] => 1 [lastResetTime] => [resetCount] => [_params:protected] => JRegistry Object ( [data:protected] => stdClass Object ( ) ) [_authGroups:protected] => Array ( [0] => 1 ) [_authLevels:protected] => Array ( [0] => 1 [1] => 1 ) [_authActions:protected] => [_errorMsg:protected] => [_errors:protected] => Array ( ) [aid] => 0 )
Subscribe rss-microbe
Article Begin Here

Colon Cancer and IBD: Potential Links to Race, Microbiota

Microbiota might vary with race, perhaps accounting for differences in rates of inflammatory bowel disease and colon cancer

Courtney J. Robinson, Edward L. Lee, Broderick E. Eribo, Hassan Ashktorab, and Hassan Brim

AUTHOR PROFILE--Robinson: Mentors and Family Members as Important Motivators

SUMMARY
➤ Dysbiosis, or a shift in gut flora community membership and/or abundance, might contribute to IBD.
➤ Caucasians have the highest incidence of IBD, which appears to be increasing across all populations, whereas minority populations, such as African Americans, face a greater risk for colon cancer, a disease that is highly preventable.
➤ More than 99 genetic loci are associated with IBD, yet they account for only an estimated 25% of predicted heritability.
➤ Understanding the effects of race on microbiota and disease will require many more studies, including participants from different genetic and ethnic backgrounds.


Some diseases affect particular racial groups at higher rates than others. For example, African-American males develop colorectal cancer (CRC) at a signifıcantly higher frequency than do European- American males. Likewise, Caucasians are more likely to develop inflammatory bowel diseases (IBD) than any other racial group worldwide, but the number of cases in non-whites appears to be increasing. While several factors contribute to IBD and colon cancer, here we focus on how the microbiota and racial backgrounds might intersect in these two diseases. The microbiota contributes a number of key functions to its host. For example, the intestinal microbial community helps to repair the gut epithelium after infection, plays roles in enteric nerve function, produces vitamins and amino acids, and primes the immune system through a continuous exposure to antigens.

Members of the Firmicutes and Bacteroidetes phyla are typically dominant among the human gut microbiota. Although phylum-level and genus-level components are shared among most individuals, species- and strain-level variations occur in response to factors such as diet, microbemicrobe interactions within the community, and host genetics. Variations in microbiota are also associated with various diseases. For example, fecal transplants from healthy individuals have been successfully used to reestablish “healthy” microbiota and reduce symptoms in patients with recalcitrant Clostridium diffıcile infections and IBD.

Disease and the Microbiota

The microbes that live with us shape many important physiological and metabolic processes, particularly in the gastrointestinal (GI) system. When disturbed, the microbial community is thought to contribute to several gastrointestinal diseases, including IBD, which is characterized by unusual and sustained inflammation. The two most common forms of IBD are ulcerative colitis (UC) and Crohn’s disease (CD). Although the etiology of IBD is not known, abnormal interactions between the host immune system and the microbiota are key to disease development. Treatments for IBD include immunomodulation, changes in diet, antibiotics, and probiotics, all of which are consistent with microbiotaimmune system interactions playing an important role in IBD.

The abundances of tissue- or mucosa-associated microbiota members in Crohn’s disease, ulcerative colitis, and colorectal cancer patients are altered as compared to healthy controls. The population sizes of some members, such as Clostridium spp. vary in diseased subjects. Interestingly, population sizes for members of the Enterobacteriaceae family (e.g. Escherichia coli, Klebsiella, and Shigella), which are commonly associated with inflammation, increase in all three diseases. Additionally, there are several other community members that seem not to be impacted by health status.Dysbiosis, a shift in gut flora community membership and/or abundance, might contribute to IBD. The microbiota of IBD patients differs from that of healthy controls, according to a recent review by Nabeetha Nagalingam and Susan Lynch at the University of California San Francisco (Fig. 1). For example, Proteobacteria populations, including Escherichia coli and other Enterobacteriaceae, expand, whereas Firmicutes and Bacteroidetes decrease. Furthermore, patients with ileal CD contain more E. coli and other Proteobacteria than do subjects with colonic CD. Also, abundance of E. coli correlates with ileitis severity. However, because the microbiota typically is not evaluated until after onset of the disease, we do not know whether shifts in the microbiota cause IBD or merely result from inflammation associated with the disease.

IBD patients are at elevated risk of colitis-associated colorectal cancer (CRC). Chronic inflammation is likely important to the genesis of gastrointestinal cancers and is estimated to contribute to at least 30% of IBD-associated CRC. As with IBD, the microbiota is suspected to play a role in colon carcinogenesis, and according to Weiguang Chen and colleagues at Zhejiang University there are shifts in the microbiota associated with CRC (Fig. 1).

The microbiota of the colon can convert dietary components into DNA-damaging molecules, or mutagens. Despite considerable efforts, no one has directly linked the metabolic activities of these bacteria with CRC. The strongest evidence that commensal microbiota contribute to CRC comes from studies of genetically engineered mice. Thus, under germ-free conditions, injecting mice with individual bacteria has a causal effect on colon cancer development. For example, a single commensal bacterial species of the microbiota, Bacteroides thetaiotamicron, induces colonic mucosal gene expression, angiogenesis, and immune responses revealing a broad extent of microbe-mucosal communication and cross-regulation. Meanwhile, the enterotoxigenic Bacteroides fragilis (ETBF) intimately associates with the colonic mucosa adjacent to CRC and secretes a mutagen. The gene encoding the toxin (BFT) that this bacterium secretes might be the ancestral origin of human matrix metalloproteases, and the toxin might act by usurping a eukaryotic signaling pathway, according to Cynthia Sears and colleagues from Johns Hopkins University in Baltimore, Md. BFT is a potent proliferative and proinflammatory toxin that contributes to chronic subclinical colitis in mice that eventually develop colon cancer. Thus, by secreting its toxin, ETBF promotes CRC development.

Race and Disease

Although the global magnitude of IBD is not known in detail due to a paucity of studies that include diverse racial populations in both developing and developed countries, it is clear that Caucasians have the highest incidence, and IBD appears to be increasing across all populations. For instance, rates have increased in two nonwhite populations, one in Atlanta, Ga., and the other in Ponce, Puerto Rico, according to Sesi Ogunbi, formerly at Emory University in Atlanta, and Caroline Appleyard at the Ponce School of Medicine, respectively. Furthermore, epidemiologists in Europe, China, and Brazil note increases in IBD within nonwhite populations during the past three decades.

While approximately 60–65% of African Americans and European Americans with IBD develop Crohn’s disease (CD), Hispanic Americans with IBD tend to develop UC in comparable proportions. Furthermore, age at diagnosis, anatomic location of disease, extraintestinal involvement, and disease severity can differ among racial groups.

Minority populations face a greater risk for colon cancer, a disease that is highly preventable and for which incentives to participate in screening programs are well established. However, African Americans are more prone to develop aggressive forms of CRC than is the general U.S. population, and much more so than their African counterparts with whom they share the same genetic background. Other features of this disease are associated with gender and race. For example, in white males the disease tends to be found at distal sites, whereas in women and African American males it occurs more at proximal sites. Differences in risk and cancer location could be due to either genetic or environmental factors, including colonic microbiota, as the proximal colon is the site for high bacterial metabolic activity.

Fewer than 40% of CRC cases present at an early stage, leading public health offıcials to recommend universal screening for all adults older than 50. According to our data, the screening age should be lowered to 45, if not 40, years for African Americans, who have the lowest level of adherence to screening recommendations compared to other ethnic groups. Noninvasive stoolor serum-based approaches linking microbiota components to CRC risk and diagnosis might help to overcome these barriers.

Impact of Genetic and Racial Background

More than 99 genetic loci are associated with IBD, yet they account for only an estimated 25% of predicted heritability. One of these loci, NOD2/CARD15, encodes for a receptor that recognizes the muramyl dipeptide component of peptidoglycan and thus modulates immune responses. Mutations in NOD2/CARD15, which are thought to derive from Europeans, are less common among African Americans. However, one such allele is commonly found among African Americans but not among sub-Saharan Africans with IBD.

Another gene associated with IBD is IRGM, which encodes for immunity-related guanosine triphosphate M. IRGM plays a role in autophagy and innate immune responses to bacteria. Variants of IRGM are associated with CD in white populations, but are more frequent in Asian populations. Remarkably, these IRGM variants are not associated with CD in Asian populations. Several alleles associated with increased risk for IBD might interfere with microbiota-immune system interactions. NOD2/CARD15 is key for maintaining relatively low numbers of bacteria in the ileum.Deleting NOD2/CARD15 in mice leads to increases of several common members of the microbiota, and reduced clearing of Helicobacter hepaticus—a bacterium that induces IBDlike disease in mice. In humans, NOD2/CARD15 alleles are linked to dysbiosis, as are mutations in ATG16L1 that are associated with increased risk of IBD.

Colorectal carcinogenesis proceeds through well-defıned morphological as well as genetic and epigenetic changes. For instance, DNA methylation occurs in distinct regions within the promoters of genes enriched for CpG dinucleotides, called CpG islands, and is mediated by DNA methyltransferases (DNMTs). The ensuing transcriptional silencing is due to the interaction of methylated CpG islands with changes in histones leading to chromatin structural changes and genes’ expression alterations.

Within the gastric mucosa, Helicobacter pylori induces the methylation of genes involved in gastric carcinogenesis; eradicating these bacteria reverses the methylation status of those genes. Other studies link different bacteria to changes in DNA mismatch repair systems in the host, leading to microsatellite unstable types of tumors. Some types of bacteria induce chromosomal instability in the path of tumor formation. We have shown that SLC5A8 gene methylation and microsatellite instability are particularly high among African Americans with CRC. SLC5A8 is responsible for the transport of butyrate, a gut microbiota metabolite that has antiproliferative properties, through the colon mucosa. This gene was silenced by methylation in colonic lesions, thus blocking butyrate access to the colon mucosa. Other examples of host interactions with the gut microbiota include Toll-like receptors and immunity genes.

Race and the Microbiota

High-throughput DNA sequencing reveals considerable dissimilarity among human microbiota but only hints at the potential impact of host genetics, including differences in race, on diseases affecting particular anatomic sites. We still know little about the differences among the microbiota carried by individuals belonging to different racial groups from the same geographic region or who share similar diets.

However, investigators from the Human Microbiome Project (HMP) recently profıled microbial communities in samples from hundreds of individuals living in either St. Louis, Mo., or Houston, Tex., 20% of whom are members of ethnic minorities. The HMP investigators report that the abundance of Bacteroides vulgatus, a bacterium implicated in IBD, varies with race. Metabolic pathways in the North American human microbiome also appear to vary with race. Although only relatively small numbers of microbial communities were analyzed, these apparent race-based differences in microbiota and microbiome suggest a potential link of racial background and microbiota with disease.

While it is encouraging that the HMP and other research groups are studying the potential impact of race on microbiota, understanding the effects of race on microbiota and disease will require many more studies, including those involving nonwhite participants.

Linking Race and Microbiota to IBD and Colon Cancer

Despite the considerable amount of information concerning race, IBD, and CRC, our understanding of the microbiota’s role in these diseases is limited. Ideally, historical data would allow for tracing shifts in the microbiota within racial groups as well as the prevalence and incidence rates of disease in these populations. Because such data are lacking, we need prospective studies to take into account race, shifts in the microbiota, and disease rates.

Designing such studies is complicated because variations in microbiota and host genetics within a race-based population likely play important roles in disease development. For example, identifying which patients to monitor could prove particularly challenging, although there may be enough data from CRC patients to begin such studies. While these studies lead into controversies over race-based medicine, they also could broaden treatment opportunities for those who were previously ignored or underrepresented in clinical studies.

Conclusion

Although the role of the microbiota in the development of IBD and colon cancer is not yet clearly defıned, it appears that these microbes are important factors along with the immune system, host genetics as a whole, and likely many other factors. Our understanding of the impact that race and other potentially important genetic factors have on the various facets of disease and structure of the microbiota is lacking, and therefore warrants deeper study with appropriately sized sample populations. The limitations of our current knowledge of racial differences in colon cancer, IBD, and microbiota highlight that there is massive room for advances in racial inclusivity in not only how we study the microbiota in disease, but also in health. Studies addressing the community structure of the microbiota and genomic potential (metagenomics) are of particular importance, as are studies of the dynamics of expression in these genomes in time and space (metatranscriptomics and metaproteomics).

Courtney J. Robinson is an Assistant Professor of Biology, Edward L. Lee is the Chair of the Department of Pathology, Broderick E. Eribo is an Associate Professor of Biology, Hassan Ashktorab is a Professor in College of Medicine, and Hassan Brim is an Assistant Professor of Pathology at Howard University, Washington, D.C.

Suggested Reading

Brim, H., K. Kumar, J. Nazarian, Y. Hathout, A. Jafarian, E. Lee,W.Green, D. Smoot, J. Park, M. Nouraie, and H. Ashktorab.
2011. SLC5A8 gene, a transporter of butyrate: a gut flora metabolite, is frequently methylated in African American colon adenomas. PLoS ONE 6:e20216.

Brim, H., E. Lee, M. S. Abu-Asab, M. Chaouchi, H. Razjouyan, H. Namin, A. Goel, A. A. Schäffer, and H. Ashktorab. 2012. Genomic aberrations in an African American colorectal cancer cohort reveals a MSIspecifıc profıle and chromosome X amplifıcation in male patients. PLoS ONE 7:e40392.

Cho, J. H., and S. R. Brant. 2011. Recent insights into the genetics of inflammatory bowel disease. Gastroenterology 140:1704 –1712.

Molodecky, N. A., I. S. Soon, D. M. Rabi, W. A. Ghali, M. Ferris, G. Chernoff, E. I. Benchimol, R. Panaccione, S. Ghosh, H. W. Barkema, and G. G. Kaplan. 2012. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142:46 –54.

Nagalingam, N. A., and S. V. Lynch. 2012. Role of the microbiota in inflammatory bowel diseases. Inflamm. Bowel Dis. 18:968–984.

Robinson, C. J., B. J. M. Bohannan, and V. B. Young. 2010. From structure to function: the ecology of hostassociated microbial communities. Microbiol. Mol. Biol. Rev. 74:453– 476.

Sears, C. L., H. Ashktorab, and H. Brim. 2010. Do the colonic microbial flora serve to trigger colon cancer? AGA Perspectives 6:18 –19.

Sears, C. L., and D. M. Pardoll. 2011. Perspective: alphabugs, their microbial partners, and the link to colon cancer. J. Infect. Dis. 3:306 –311.

The Human Microbiome Project. 2012. Structure, function and diversity of the healthy human microbiome. Nature 486:207–214.

Veluswamy, H., K. Suryawala, A. Sheth, S. Wells, E. Salvatierra, W. Cromer, G. Chaitanya, A. Painter, M. Patel, K. Manas, et al. 2010. African-American inflammatory bowel disease in a Southern U.S. health center. BMC Gastroenterol. 10
:104 –111.

Article End Here