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Hopkins Medicine Magazine - Bad Bugs

Hopkins Medicine Winter 2013

Bad Bugs

By: Douglas Birch
Date: February 1, 2013


Bad bugs
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It's a dark place, rank and teeming with bugs, the kind of unsavory neighborhood where killers lurk. And there, deep in the sloshing recess of the human digestive system, Cynthia L. Sears is stalking the Alpha-bugs.

Sears, professor of medicine and oncology at the Johns Hopkins School of Medicine, suspects that certain bacteria not only release toxins or chemicals that can trigger cancer of the colon, a leading cause of death worldwide. These culprits may also recruit other bacteria to help them do it.

Over the years, medical researchers have found a strong link between the chronic inflammation caused by infectious diseases and cancers. As many as one-third of all cancers—including those of the liver, bladder, and stomach—have now been tied to infection with a specific microbe.

In the hunt for the cause of colon cancer, a number of bacteria have been named as suspects. But researchers haven’t been able to make the case against any of them stick.

So what is the solution to this bacterial whodunit? According to Sears, the evidence suggests that the microbes colonizing the colon may include what she calls Alpha-bugs—bacteria capable of causing colon cells to change their DNA and manipulating other bacteria into promoting colon cancer, especially in people with cancer-prone diets (heavy on fat and calories, low on fruits and vegetables).

Sears suspects that the toxin-producing Alpha-bugs not only make cancer-causing chemicals themselves, but somehow alter the colon’s ecosystem to promote other harmful groups of bacteria and crowd out helpful ones.

“As such, the Alpha-bug does not act alone but, rather, co-opts the microbial community to aid in its nefarious undertaking,” Sears wrote, with Hopkins oncologist and immunologist Drew Pardoll in the Journal of Infectious Diseases in 2010.

The work is gaining traction—and the attention of the National Cancer Institute, which last summer awarded Sears one of its first “Provocative Questions” grants, with $236,480 in first-year funding, to study the Alpha-bug hypothesis.

Sears’ ultimate goal is to help find new methods for detection or prevention of colon cancer, the second leading cause of cancer-related deaths in the United States. The disease claims about 52,000 lives a year in this country and more than 600,000 worldwide, according to the World Health Organization.

The Body’s Crowded Zoo

Hundreds of different species of bacteria make their homes in the human body, in habitats that range from armpits and belly buttons to bladders and nasal passages. On average our bodies play host to 100 trillion of these tiny organisms, which outnumber our body’s cells by an order of magnitude. This internal biosphere, meanwhile, accounts on average for about two pounds of our body weight.

Microbes, of course, don’t always peacefully coexist with their human hosts. But neither are all bugs threats to health—not by a long shot. Some are believed to promote health by aiding everything from the metabolism of plant carbohydrates to mother’s milk, or by reducing the toxicity of environmental poisons like arsenic and mercury.

“There’s really no question that we wouldn’t be very functional without our various microbiotas,” Sears says. “And the data suggesting that these are important to health are very strong.”

All of which has led some researchers to view our diverse and distinctive microbiomes, together with our bodies, as forming a larger super-organism. It’s an increasingly popular view that has been explored recently in scientific publications like Science and Nature, as well as The New York Times and The Economist.

Unfortunately, our portable microbiomes aren’t always peaceable kingdoms. Sometimes, one of our erstwhile microbial friends breaks bad—as may be the case, Sears posits, with colon cancer.

Wherever the body has a surface, inside and out, it provides an ecological niche for bacteria. But the colon stands out as a particularly hospitable place. In their Alpha-bug paper, Sears and Pardoll wrote that the surface of the colon is home to “one of the most dense and diverse communities of bacteria in the body,” a kind of miniature rainforest of biological diversity.

And lurking in this teeming place is a toxin-producing strain of a bug called B. fragilis. In its non-toxic form, the bacterium appears to be benign, even helpful to us. But toxin-producing B. fragilis is often implicated in blood infections and abscess formation. It’s also a major cause of diarrhea worldwide, and can trigger the kind of chronic inflammation that’s been linked to tumor growth.

“The ones that don’t make a toxin are proposed to be good for our health, and the ones that do make a toxin have been clearly shown to be associated with diarrheal disease, at a minimum,” says Sears.

She first became interested in infectious diseases two decades ago while working in a refugee camp for Cambodian refugees in Thailand, where diarrheal illness was a major killer of children. After returning to the U.S., she trained in infectious diseases and worked with R. Bradley Sack, of the Bloomberg School of Public Health.

Sack was among the first to recognize the important role that the toxin-producing strain of B. fragilis plays in diarrheal illness. “He brought it to me and he asked me if I could work with it because they didn’t have a good way to detect the toxin made by the bacteria,” she says. “So we were able to develop a way to detect the toxin and then went on to study it in much more depth.”

As other cancers were linked to infections over the years, Sears came to see B. fragilis as a prime suspect in colon tumors.

One clinical study by the Marmara University School of Medicine in Istanbul, Turkey, published in 2006, found the genetic footprint of the toxin-producing B. fragilis microbe in 38 percent of 73 colorectal cancer patients, compared to 12 percent in a sample of healthy patients.

At Hopkins, laboratory studies are also zeroing in on the bug.

Sears used a mouse model for colon cancer with an altered APC gene that encourages tumor growth and infected the animals with toxin-producing B. fragilis. After a brief bout of diarrhea, the mice developed inflammation in their colons. Within a month, they were riddled with tumors. Meanwhile mice that carried the mutant APC gene but were not infected had far fewer tumors.

Sears and Pardoll suspect that toxin-producing B. fragilis causes inflammation by tricking the body into overproduction of an immune system cell called T-helper 17, or Th17. Chronic inflammation is at least one factor believed to lead to changes in cellular DNA that results in tumor growth.

Importantly, Sears says, the bug may not be acting alone.

A number of cancers have been linked to single organisms: H. pylori and gastric cancer; hepatitis B and C viruses and liver cancer; Schistosoma hematobium and urinary bladder cancer and others.

But in some cases, Sears says, whole communities of bacteria may be responsible for causing the chronic inflammations thought to lead to cancer. She proposes that B. fragilis acts as the ringleader of a gang of other bacteria that work together. And she says that the Alpha-bug hypothesis might apply to other cancers or chronic illnesses, including inflammatory bowel disease.

With her “Provocative Questions” grant, Sears is studying the population of bacteria found in both healthy and cancerous colons. The aim is to see if people with colon cancer have a different mix of gut bacteria than healthy people—as the Alpha-bug hypothesis predicts.

To identify the different species, Sears’ team is sequencing the DNA of the bacteria they find during their hunt. Then they’re matching the sequences against the database of sequences being assembled by the National Institutes of Health’s Human Microbiome Project, an ongoing effort to identify all the bacteria in the normal human microbiomes.

She is about to launch a parallel colon cancer study in Malaysia that will replicate some of the work on B. fragilis being done at Hopkins. Her team will also look for patterns in patient data, in work similar to what was done in Turkey in 2006.

“We’re trying to establish what the ecology is,” Sears says. But the colon is home to an estimated 800 to 1,000 species, and each individual’s population of gut bacteria is different. “Normal is pretty complex, it turns out.”

Finding patterns is likely to prove challenging.

Ultimately, Sears says, it’s clear that colon tumors are caused by damage to the DNA in the cells of the colon lining.  “If you don’t have disease-causing DNA changes, you don’t end up with a tumor,” she says.

Something is causing this damage. Whether in most cases it’s a single organism, like B. fragilis, or a whole gang of them, the ultimate aim is to open doors to new methods of diagnosis, treatment, and prevention.

One goal could be a blood test that can identify people at high risk. The research could also lead to vaccines and drug therapies that block the Alpha-bugs’ toxin. There may even be ways to promote a person’s population of protective bacteria, while reducing the number of nasty bugs.

 “Is there some balance of organisms that is more protective or are more likely to produce health rather than disease?” she says. “We don’t really have many of the answers yet.” *

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