UChicago research team receives $10M grant to study the causes of IBD

A research team based at the University of Chicago has received a $10 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to study the causes of inflammatory bowel disease (IBD).

The new project is a collaboration among researchers at the University of Chicago, the Marine Biological Laboratory (MBL), Argonne National Laboratory, Michigan State University, the University of Michigan and Harvard University. The NIDDK, a division of the National Institutes of Health (NIH), awarded the five-year grant through its Eugene B. Chang, MD, Martin Boyer Professor of Medicine at UChicago and one of the principal investigators for the project. “This may be the only way to gain significant insight to really move the needle in this area.”

Enormous complexity across oceans and the human body

The project is the result of a long collaboration between Chang and microbiologist Mitchell Sogin, PhD, a Distinguished Senior Scientist at MBL in Woods Hole, Mass. Sogin’s work focuses on microbial ecology, studying how microbes evolve within their community and their relationship to the environment. Many of the tools Sogin has developed over the years to analyze the genetic sequence data of millions of microbes from the ocean work just as well on samples taken from the human gut. These same tools can be used to identify rare or unusual strains of bacteria that could be linked with disease.

“There is enormous complexity in microbial communities in the human body and even greater complexity in the ocean,” Sogin said. “The question becomes then, why? Where did that complexity come from? What are they doing for us? What are they doing for the oceans? So the field sites are very, very different, but the questions are fundamentally the same.”

Chang and Sogin have been working with computer scientist and microbiologist A. Murat Eren, PhD, an MBL Fellow now based at the UChicago Department of Medicine, to analyze microbiome samples and genetic data taken from patients at many points in time during their treatment. Eren developed a software platform called David T. Rubin, MD, and Sushila Dalal, MD; colorectal surgeons Neil Hyman, MD, and Ben Shogan, MD; molecular engineers Jun Huang, PhD, and Savas Tay, PhD; and geneticists Oni Basu, PhD, and Sebastian Pott, PhD. In addition, microbiologists Sean Crosson, PhD, formerly of UChicago and now at Michigan State, and Dionysios Antonopoulos, PhD, Interim Division Director of Biosciences at Argonne, are contributing their expertise.

Building tools to change understanding of disease

By applying next generation technologies to study the genetic and functional properties of individual cells and microbes from human IBD specimens, these investigators will disentangle the complexities of events that cause the disease. The human gut is made up of many different cell types. Analyzing individual cells from biopsies taken from various places in the gut, and at different times during the course of the disease, will help the team understand how these cells — and perhaps their unique genetic expression — interact with the gut microbiome.

This work will help develop a biomarker, a genetic or microbial signature that physicians can test to see if a patient is susceptible to developing pouchitis. Chang’s lab, lead by immunologist and project manager Candace Cham, PhD, is also developing gut organoids, small clusters of cells grown from biopsy samples. These miniature organs can serve as proxies for the patients’ own tissues at distinct points in time or stages of disease. The researchers can then rapidly test multiple drugs on the organoids to see how they respond, or study how they interact in combination with various microbes — a new form of personalized medicine that will help doctors decide what medications a patient should get and which ones would work best.

What we’re doing is unprecedented. We have technology and software that no one else is using because we made it ourselves.

Chang believes the discoveries made thus far extend beyond the unique circumstances of pouchitis to other forms of IBD, and even to other autoimmune diseases or food allergies.

“I think this explains why not everybody who has a gene variant that’s associated with risk for IBD actually gets IBD,” he said. “Often there’s a history in an IBD patient’s course where they have some kind of event, like a bout of gastroenteritis or exposure to antibiotics, that triggers their disease.”

The various tools and techniques being developed for this project have the potential to change our understanding of these diseases, Chang says.

“What we’re doing is unprecedented. We have technology and software that no one else is using because we made it ourselves,” he said. “If we’re right, our findings will be paradigm shifting in ways that will change concepts and best practices relevant to many complex immune disorders.”