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:: By Carrie Golus, AB’91, AM’93

:: Photography by Dan Dry

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Investigations ::

One-tract mind

Gastroenterologist Stephen Hanauer has spent decades studying inflammatory bowel disease—and changing the way it’s treated.

photo:  Stephen Hanauer
Ten years ago there were few options for treating IBD. Thanks in part to Stephen Hanauer, that’s no longer the case.

Stephen Hanauer, professor of medicine and codirector of the Inflammatory Bowel Research Center, is one of those rare doctors who haven’t grown blasé from his day-to-day dealings with one human body after another. Discussing his years of pioneering research into inflammatory bowel disease (IBD), he demonstrates both a poet’s flair for metaphor and an eight-year-old’s love of disgusting factoids.

The intestinal tract is “a sewer,” he says. “There are more bacteria living in your colon than there are human cells in your body. You’re more bacteria than you are human cells.” Another believe-it-or-not tidbit: the intestinal tract “has more immune tissue than there is in the rest of the body combined,” Hanauer says. “The intestine is a tunnel through the body.” Before a substance is absorbed into the body, it has to pass muster with the immune cells lining the gut, or else it’s “excluded,” he says euphemistically, “and flushed down the toilet.”

In IBD—which has two main types, ulcerative colitis and Crohn’s disease—something goes wrong with these intestinal immune cells, and the result is inflammation. The inflammation in ulcerative colitis is usually superficial and limited to the colon, or large intestine. In Crohn’s disease, the inflammation can affect any part of the intestine and runs much deeper. (Inflammatory bowel disease is not the same as irritable bowel syndrome [IBS], though the two are often confused, Hanauer says. Like IBD, IBS is marked by diarrhea, constipation, and abdominal pain, but the intestines look normal—there’s no inflammation—and pain is relieved with a bowel movement.)

Ten years ago there were few options for treating IBD, a chronic, incurable condition that generally sets in between ages ten and 30. About 1 million Americans suffer from IBD, divided equally between Crohn’s disease and ulcerative colitis. Hanauer and his colleagues have come so far in understanding and treating IBD that their work may become a model for treating other immune-mediated inflammatory disorders (IMIDs), such as rheumatoid arthritis, psoriasis, eczema, lupus, and asthma.

These diseases are “the opposite of HIV,” he says: instead of the immune system shutting down it goes into overdrive, attacking things it shouldn’t. “Most of the medicines [for IMIDs] are overlapping.” Skin rashes, asthma, and intestinal inflammation all can be treated with corticosteroids, for example, which suppress the immune system. The trick is to deliver the steroid so that it hits the affected area and then breaks down without producing side effects.

Hanauer is testing several newer drugs, known as biologic therapies, that could someday replace steroids, whose long-term use can cause osteoporosis, diabetes, mood swings, and dependency. One alternative is infliximab (marketed as Remicade), which interferes with tumor necrosis factor, a substance that helps produce an inflammatory response. Hanauer ran the world’s first large-scale trial of infliximab, reporting in the May 4, 2002, Lancet that the drug can prolong remission in patients with moderate to severe Crohn’s, offering a way to treat the disease over time rather than simply responding to flare-ups.

Another approach Hanauer is investigating for Crohn’s is apheresis, a process that slows the immune system by filtering out particular subsets of activated white blood cells. In his trial patients take a drug absorbed by these cells. Then the patient is hooked up to an apheresis device, similar to a dialysis machine, that removes blood from the body and runs it past a UV light. The light activates the drug, killing only the marked white blood cells. Though the treatment sounds drastic, it’s actually “non-medicinal,” Hanauer says, so it has no side effects; patients usually tolerate it well.

One of Hanauer’s earliest attempts to conquer IBD was simply by keeping good records. In 1982, when he became a fellow in Chicago’s gastroenterology department, he established a database of IBD sufferers. More than 20 years later, it’s among the world’s largest, with detailed information on 5,000 patients.

Using the database, Hanauer and his colleagues discovered patterns of disease within families. That information helped them to identify the first gene associated with IBD. Pinpointing new genes is an ongoing process that, he says, is “nowhere near finished.”

The system also keeps track of environmental factors that influence IBD prevalence, such as cigarette smoking. For example, Hanauer’s group found that while smoking worsens Crohn’s, it actually protects against ulcerative colitis. In a family prone to IBD, he notes, “the smokers get Crohn’s, nonsmokers get ulcerative colitis.”

Genes can determine how IBD should be treated. Because people break down medications according to genetically programmed enzymes, Hanauer explains, depending on the amount of an enzyme patients have, they may need a tiny dose or a huge dose. In other words, the same level of drug that could be toxic for one person could be ineffective for another. Understanding this genetic effect, he says, will help physicians prescribe IBD drugs in optimal ways.

Despite wide media coverage of both IBD and IBS, neither condition is on the rise. There’s simply more openness about previously “closet disorders,” Hanauer says, and pharmaceutical companies have developed new medications that they can now market on television.

There is no typical IBD patient—in the United States the disease cuts across race, age, gender, and economic lines—but it’s one of the “diseases of cleanliness,” he points out, all but unknown in third-world countries. This phenomenon is the basis for the so-called “hygiene hypothesis”: third-world children, routinely exposed to pathogens, develop a tolerant immune system not prone to autoimmune disorders.

“It used to be that 90 percent of the children living in the South had worms,” Hanauer says. Now that they don’t, the incidence of immune-mediated diseases in the region has risen sharply. Hanauer doesn’t go as far as one University of Iowa gastroenterologist, who recently achieved excellent results in IBD patients by introducing pig whipworm ova into their digestive systems, but he has thought about trying bacteria. “Maybe if we give back healthy bacteria,” Hanauer says, “that will actually help position our bodies’ immune system to be tolerant, to be less reactive.”