Keeping colon cancer at bay
Gut feelings

Colon Cancer Prevention Study 
Mouse colon stained with Alcian blue, showing outer and inner mucus layers.

The average person is made up of many cells: 10 trillion or thereabouts. But given that the multitude of microbes living on and within us add roughly 100 trillion more cells to the mix, we are – by one measure, at least – only 10 percent human. Small wonder that this resident community of bacteria, fungi and viruses, called the microbiome, has garnered increasing scientific interest amid growing recognition that not all microbes are bad for us.

The key, says Shahid Umar, Ph.D., of Cancer Prevention, is figuring out how to maintain the balance so microbes that are our essential allies aren’t hampered in their cause. Umar’s research zeroes in on the human gut, particularly how its microbiota – defined as bacterial species only – might influence colon cancer. To get a better handle on bacterial affairs of the gut, he’s teamed up with Allen Greiner, M.D., of Cancer Control and Population Health, with funding from a KU Cancer Center pilot grant, to collect and analyze tissue samples from colonoscopies alongside one of the more intimate subject matters around: human feces. 

Umar waxes eloquent on the “beautiful process” that normally keeps our gut bacteria in check. The colon contains a series of crypts, each with goblet cells that, as they divide, move along the crypt walls in conveyor belt fashion toward the top, where they secrete mucin before getting sloughed off. Mucin’s sugar components provide much-needed fuel for gut bacteria, which are distributed all over the colon’s lumen, or interior space. It also forms a protective mucus layer in which these bacteria are suspended and thereby barred from interacting directly with gut cells or entering the bloodstream. 

This turnover of goblet cells, with mucin as a byproduct, takes approximately five days and requires its own fuel in the form of butyrate, a short-chain fatty acid generated by gut bacteria as they feed on dietary fiber. Diets high in fat and red meat with little to no fibrous intake eventually rob a person of butyrate, affecting not only a variety of metabolic processes like energy production and cell proliferation, but also the colon’s ability to counteract inflammation. 

Colon cancer’s sporadic form, which comprises about 80 percent of cases and is often pinpointed to lifestyle factors, including poor dietary habits, is very rare among Africans. But the odds aren’t similarly favorable for African Americans, who are at much greater risk of getting and dying from this disease than Caucasians. Umar’s hunch is that levels of beneficial short-chain fatty acids like butyrate are different – likely lower – in African Americans, compared to the rest of their ethnicity. By studying colon tissue and stool samples from volunteers between 50 to 75 years of age, recruited by Greiner through the likes of phone calls and flyers, he’s on track to find out if this is true. 

 Colon Cancer Prevention Study KU Cancer Center 
 Electron microscopy image of a mouse colon infected with bacteria
(magnification 8,000x).

“To their knowledge, they’re completely healthy,” Umar says of these volunteers, “which allows us to follow them longitudinally, obtaining samples at various time points. We can’t make concrete observations from a single round of samples, because our gut microbiota are in a constant state of flux.” It’s laborious, but he’s amassed data on approximately 40 volunteers to date and, while not at liberty to elaborate because a peer-reviewed publication is still in the works, notes that preliminary findings look “quite promising” in terms of bolstering his hypothesis that different short-chain fatty acid levels in African Americans might influence their susceptibility to the sporadic form of colon cancer.  

Umar and Greiner are also collaborating with Haribabu Bodduluri, Ph.D., from the University of Louisville in Kentucky, who is ferreting out 16S ribosomal RNA sequences from the tissue and fecal samples – essentially, genetic “signatures” identifying different kinds of gut bacteria in any one volunteer. Just as a small fraction of these healthy recruits wound up discovering, post-colonoscopy, polyps (abnormal growths) in the colon that they hadn’t been aware of, Umar postulates that some will also have “more interesting” microbiota worth closer inspection. Such bacterial species – not found in the majority of volunteers, or known types observed to be somehow dysregulated – are what he’ll focus on, with the aid of gnotobiology. 

“It involves using mice raised in an environment completely free of germs,” he explains, “so we can study the precise impact of, say, human gut bacteria type X on these gnotobiotic animals – for instance, how it might or might not affect tumor development in the colon.”

While there’s greater appreciation of gut bacteria’s potential culpability in diseases like colon cancer – through chronic inflammation and the production of carcinogenic metabolites – Umar acknowledges that separating cause from correlation remains tricky, albeit crucial. Like many other elements of cancer research, the microbiome’s role could otherwise be oversold. “I maintain, however, that instead of declaring war on cancer back in 1971, if we’d signed a peace treaty emphasizing prevention through lifestyle changes and better environmental regulations, we’d be a lot further along today,” he says. “It’s clichéd to say that you are what you eat, and you only live once, but both are still true. We need to be better about proactively caring for not only the health of our gut, but our whole body.”

Supporting funds for this research

  • NIH RO1 CA131413: “β-catenin/NF-κB in Hyperplasia/Neoplasia of Colonic Crypts: Chemoprevention”

  • 2012–2013 Pilot Award, The University of Kansas Cancer Center: “Colon Microbes and Metabolites: Exploring African American Health Disparities”

Relevant publications

  • Chandrakesan P, Roy B, Jakkula LU, Ahmed I, Ramamoorthy P, Tawfik O, Papineni R, Houchen C, Anant S, Umar S, “Utility of a bacterial infection model to study epithelial-mesenchymal transition, mesenchymal-epithelial transition or tumorigenesis.” Oncogene (Jun 2013).
  • Chandrakesan P, Ahmed I, Chinthalapally A, Singh P, Awasthi S, Anant S, Umar S, “Distinct compartmentalization of Nuclear Factor-κB activity in the crypt and crypt-denuded lamina propria precede and accompany hyperplasia and/or colitis following bacterial infection,” Infection and Immunity (Feb 2012). 
  • Ahmed I, Chandrakesan P, Tawfik O, Xia L, Anant S, Umar S, “Critical roles of Notch and Wnt/-catenin pathways in the regulation of hyperplasia and/or colitis in response to bacterial infection,” Infection and Immunity (Sept 2012).