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Kenneth Simpson, Principal Investigator
Professor of Small Animal Medicine
Director, Simpson Gastroenterology Research Laboratory
Department of Clinical Sciences
kws5@cornell.edu

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Department of Clinical Sciences
Simpson Gastroenterology Research Lab

 

Inflammation Takes Center Stage

cartilage"Today, remission is our mission."

For as long as people have suffered with Crohn’s, scientists have wondered about the role of bacteria in the disease. Recent studies have shown marked changes in the composition of the intestinal bacteria in people with Crohn’s disease, leading researchers to ask: Are microbial abnormalities a direct consequence of genetic abnormalities linked to Crohn’s and do they precede and initiate inflammation, or does intestinal inflammation bring on the bugs?

Announced in a recent issue of PLoS, findings from Cornell researchers show that inflammation drives microbial imbalances (dysbiosis) and proliferation of a specific type of E.coli that is adherent, invasive, and found in the ileum. In addition, this collaborative research project showed that genetics do play a role in determining the threshold and magnitude of dysbiosis in response to acute inflammation induced by environmental triggers. This study also discovered that a current mainstay of Crohn’s disease therapy directed against intestinal inflammation decreases dysbioisis. Finally, the study found that deletion of a receptor that helps to recruit T cells, which are needed for cell-mediated immunity, to the gut also decreases inflammation and dysbiosis, offering a new option for therapeutic intervention.

“Today, remission is our mission,” said Dr. Kenneth Simpson, professor of small animal medicine at Cornell’s College of Veterinary Medicine and principal investigator. “Crohn’s disease is a highly complex condition that finds its strength in the combination of negatives: environmental factors, genetic mutations, and immune system malfunctions. Ultimately, there may be a cure. Until then, we need to find ways to relieve suffering and to make living with Crohn’s disease bearable.”

Crohn’s disease is a chronic debilitating inflammatory bowel disease that involves a complex interaction of host genes, the immune system, the intestinal microbiome, and the environment. Afflicting more than half a million people in North America, Crohn’s disease results in symptoms that range from mild to severe and include diarrhea, fever, fatigue, anemia, reduced appetite, and weight loss.

To mirror the complex nature of the disease, Simpson’s team designed a study that incorporated inflammatory triggers related to relapse of Crohn’s disease and ileal inflammation. Although many previous studies have focused on colonic or fecal dysbiosis, Simpson and his team focused this study on ileal dysbiosis, the location involved in 70 percent of Crohn’s disease cases. Also novel to this study, the research team fused a variety of contemporary techniques, including genome sequencing, gene deletion, and PCR testing, with the more commonly used culture based method to generate a comprehensive picture of the composition and spatial distribution of the ileal microbiome. Particular attention was paid to pinpointing the number, pathotype and location of E.coli that is associated with intestinal inflammation in people, dogs, and mice.

“The results furthered our understanding of the interplay between genetic susceptibility, the microbiome, the environment, and the immune system, knowledge that is essential for developing optimal therapeutic strategies,” Dr. Simpson said.

“Our findings clearly demonstrate that inflammation drives ileal dysbiosis and proliferation of CD-associated adherent invasive E.Coli. Further, in the context of a patient with Crohn’s, we found that the host genotype and therapeutically blocking inflammation both impact the onset and extent of ileal dysbiosis. These novel findings are of high relevance to Crohn’s disease.”

The investigation leveraged the knowledge and resources of researchers in Drs. Eric Denker’s, Dwight Bowman’s, and Sean McDonough’s labs. Building on findings in patients with Crohn’s disease evaluated by Dr. Ellen Scherl’s group at Weill Cornell Medical College, this collaboration shed new light on this debilitating disease.

This work was supported by grants from NY Presbyterian/Weill Cornell Medical College, the Jill Roberts Center for Inflammatory Bowel Disease, and the National Institutes of Health. These organizations and the Crohn’s and Colitis Foundation of America are supporting future research.

"Although not a one-man show, inflammation rather than genetic susceptibility drives the growth of intestinal bacteria and invasive E.coli linked to Crohn’s disease " Chrone

(This article can be found in SCOPES MAGAZINE OCTOBER 2012)