Inside Tract
July 5, 2013

A new way of studying an old mouse model of IBD is helping Xuhang Li’s lab decipher the disease’s earliest chemistry.

  

Four years ago, Xuhang Li devised rapid ways to screen the blood serum of patients with inflammatory bowel disease for antibodies—his search for renegade molecules to tie to ulcerative colitis or Crohn’s disease. His lab netted a cache of antibodies not found in healthy children or adults. Now benefits for patients—in diagnosis or prognosis—are closer.

Li expected to find red herrings. But true biomarkers were possible as well. The good antibodies could be tested for in a drop of patient blood and would signal generalized bowel inflammation. The best could distinguish Crohn’s from ulcerative colitis or other bowel conditions. 

Now Li’s lab has patents on three IBD and Crohn’s biomarkers that lean toward “best.” They come from patient immune responses—outpourings of reactive proteins like cytokines or antibodies called forth by yeasts or gut bacteria.  

There’s more. Using both variations on the standard laboratory ELISA assay and new ways of analysis, the group hopes to predict therapeutic benefit. “If we knew beforehand the 30 percent who won’t respond to the current IBD therapy, infliximab, we could save suffering,” says Li. Typically, it takes six weeks for the agent to help any patient. “That’s a long time for a nonresponder to lose.” An NIH grant is helping the researchers single out patients who do improve. 

Li also hasn’t forgotten IBD’s extreme complications. “About 50 percent of patients undergoing IBD-related surgery at Johns Hopkins have painful strictures in the bowel,” he explains. “Fistulas, with their dangerous leakages, are also a concern.” Even a small idea of who’s at risk could prompt earlier, more aggressive treatment. Fortunately, Li’s group has unique biomarkers in hand, candidates to be tested in a larger patient cohort.

The most basic use of their “proteomic nets” aims to reveal IBD’s early biology. By regularly sampling proteins in a standard mouse model of IBD, the researchers revealed molecular activity well before the disease appears. At three months, for example, the IL-10 gene-knockout mouse that mirrors human disease has obvious diarrhea. But early as a month after birth, its proinflammatory cytokines start climbing. 

Both mice and humans generate cytokines from an inflammasome, a “death star” of immune activity activated fast at bodily threats. One of its cytokine products, interleukin-1-beta, is key to the decline that follows.  “How do we know?” asks Li. “We shot down the ‘death star.’ The cytokine disappeared. Mice had a much healthier gut.

“For therapies, you want to go upstream as far as possible. That’s what we believe we’ve done.”