Prematurity and the Microbiome
The GI Research Foundation has provided a $42,000 grant for 4 germ free Isolators, supplies and a technician. With these resources she expects to be able to understand the effect of antibiotics on the early development of microbial communities and the impact of these microbial alterations on brain development. She expect this work to be able to be translated to revised antibiotic protocols for preterm infants and furthermore, to enhance our understanding of antibiotic impact on the microbiome relevant to other patient populations.
Translational Core Registry
Gut Anti-Bacterial Defenses and their Failure in Inflammatory Bowel Disease
The GI Research Foundation provided an $112,278 grant to support this project and its completely new approach to uncovering the role of bacteria in inflammatory bowel disease and has the potential to reshape the field with respect to how the microbial component of inflammatory bowel disease is diagnosed and treated. Specifically, this work paves the way for treatments designed to lock bacteria into their beneficial states and promote healing in the intestine.
IBD Translational Research
Colorectal Cancer Disparities
2012 Taxman Foundation Gift in Honor of Joseph B. Kirsner
Taxman, CEO and founder of the Taxman Corp., a real estate development company in the Chicago area, announced the intended donation at the annual fundraising event for the GI Research Foundation to support the training of specialists in digestive diseases.
The gift consists of:
– $1.5 million to the Joseph B. Kirsner Endowed Fellowship to enable leading young GI physician-scientists from around the world to train with the University of Chicago Medicine’s top-ranked gastroenterologists.
– $500,000 for the establishment of the Joseph B. Kirsner Endowment for Excellence, to ensure the University of Chicago Medicine remains at the forefront of GI patient care, research and education.
– $500,000 for a faculty area at the Center for Care and Discovery to keep Joseph B. Kirsner’s memory alive for future generations of digestive diseases doctors and their patients. The area is named “The Joseph B. Kirsner GI Faculty Reception Area made possible by Nancy and Seymour Taxman.”
Summer Student Program
Subphenotyping of Inflammatory Bowel Disease patients with Primary Sclerosing Cholangitis to Prevent and Identify Molecular Markers which Predict the Onset of Neoplasia
Investing in the Future of GI Research
Dr. Leone’s most recent findings that have recently been funded by GIRF suggest that having the right kind of gut microbes early in life can aid in the proper development of our sleep/wake habits and eating behaviors. Disrupting the gut microbes early on could result in improper wiring of these circuits and could be, in part responsible for the onset of childhood obesity. The funds provided by GIRF will be used to purchase cutting-edge equipment that will advance our knowledge of how gut microbes influence the development of our day vs. night patterns and how this can predispose us to develop metabolic disorders. These studies will allow us to discover novel, microbe-centric personalized cures that can be used as treatments for diseases including obesity.
TRANSLATING RESEARCH INTO CURES (TREC)
Phases One and Two ($3 Million)
“Systems Biology”, the development of a comprehensive, integrated research database—the first of its kind—to house patient and disease information, from clinical presentation to the molecular profiles. Sophisticated computation will enable our scientists to evaluate genetic trends, responses to different therapies, and the role of stress and environment in IBD. The database will be the largest and most comprehensive collection of digestive diseases research and patient care data in the world, allowing doctors to predict the best course of treatment and prevention for patients. Immediately this will make the database accessible to investigators from other institutions, and as a shared resource, it will encourage broad-scale, cross-disciplinary research initiatives throughout the country.
The recruitment of a world-class leader in GI cancers to advance clinical trials and complement our robust laboratory research activities. This leader will bring expertise in both treatment- and prevention-focused clinical trial design to the University of Chicago, and greatly transform the Section’s ability to lead studies aimed at sparing individuals from developing GI cancers.
Phase Three ($4 Million)
Outfitting state-of-the-art GI clinical research facilities in the Center for Care and Discovery. The acute care facility will be a clinical research hub and will expand the clinical space currently dedicated to digestive diseases patients. It will hold the latest technology and imaging equipment necessary for doctors and nurses to improve diagnosis and long-term care.
The Gnotobiotic Research Animal Facility (GRAF)
How can we figure out what the microbiome does and how it relates to health? To test the importance of a thriving microbial community, researchers study mice that have been raised in the complete absence of microbes, known as germ-free mice. Germ-free mice can then be inoculated with specific microbes, transforming them into gnotobiotic mice. Gnotobiotic consists of the Greek words gnostos, meaning known and bios, meaning for life. The GRAF has allowed University of Chicago researchers to stay on the cutting edge of microbiome research and determine whether or not the microbiome, or individual microbes within it, play causal roles in disease development and progression. As a result, we are approaching a new era of discovery that will lead to microbiome-based interventions and diagnostics that will become the future tools of precision medicine—and ultimately lead to improved clinical outcomes and the prevention and cure of many diseases.
Why UofC needed the GRAF
Before the University of Chicago researchers had the GRAF, they either had to outsource work to commercial facilities (thus limiting the scope of research), collaborate with institutions that had an existing gnotobiotic facility in place, or use antibiotics to manipulate the microbiome. Each alternative had its own drawbacks. For instance, since there are very few gnotobiotic facilities in the U.S., demand for their resources is high, making external collaborations difficult, time-consuming, and costly. The use of broad-spectrum antibiotics simply reduces the number of microbes in the gut and may actually select for specific members of the gut microbial community that have a negative impact on health. Bringing gnotobiotic capabilities in-house has permitted U of C researchers to do germ-free and gnotobiotic studies with greater speed and efficiency, and has allowed more users to delve into the field of the microbiome.
GRAF use increasing over the years:
The users of the GRAF have steadily increased since its inception in 2007. Initially, the GRAF housed 2 germ-free isolators. The GRAF has undergone five expansions to accommodate more users and currently houses 64 germ-free isolators. The demand for this facility continues to rise and the University of Chicago is considering an additional expansion to accommodate more users.
GRAF assisting in receiving NIH Grants
The results from work performed in the GRAF have been used to procure NIH grants. Across all users the grant dollars associated with use of the GRAF during the active granting period assessed in July 2015 totaled $5,449,821 with pending NIH grants totaling $3,921,619.
Diseases researched utilizing the GRAF:
Many researchers from the Section of Gastroenterology use the GRAF to study GI diseases that are known to involve gut microbes, including inflammatory bowel diseases, necrotizing enterocolitis, colon cancer, celiac disease, and food allergies. Several researchers outside of Gastroenterology also use the GRAF to study extra-intestinal diseases such as obesity, diabetes, infectious disease, and asthma. Thus, while originally set up to help our digestive disease investigators, the GRAF has ultimately had a broad impact on many areas of medical research at the University of Chicago.
Highlights of discoveries made using the GRAF:
– Pro-inflammatory microbes and IBD: Eugene B. Chang’s group discovered that Western diets high in saturated fat alter the microbial community structure, leading to the proliferation of a specific bacterium linked with cellular toxicity and inflammation. Using the GRAF, his group defined a potential mechanism connecting high-fat diets, gut microbes, and the development of IBD in genetically susceptible populations.
– Circadian biology and the microbiome: In a separate study, Dr. Chang’s group also discovered that gut microbes exhibit 24-hour cycles in the abundance of microbes that are present, as well as in the production of various compounds and signals by the microbiome. These microbial day-night patterns help us sense what, when, and how much we eat, which sets the daily rhythm of our metabolism. Germ-free mice lacking these microbial signals have altered eating patterns, activity cycles, and metabolism. In mice raised with gut microbes, eating a diet high in saturated fat disrupts the microbial community and their day-night patterns. In humans, this disruption impacts our metabolism and can lead to development of obesity.
– Microbes and type 1 diabetes: Alexander Chervonsky has shown that gut microbes play a role in the initiation phase of organ-specific autoimmunity. His lab established that genetically susceptible germ-free mice develop type 1 diabetes (T1D) at the same rate as mice raised with a full set of gut microbes. However, mice lacking a signaling adaptor involved in immunity were only susceptible to diabetes when microbe-free. Finding normal intestinal bacteria that signal through different signaling adaptors could, and for such receptors may be able to prevent T1D. The finding, however, makes an important prediction that T1D development can be prevented by manipulation of intestinal microbes or vaccination with microbial products.
– Microbiome and infectious disease: Chervonsky’s lab also showed that during a systemic response to an infection, our bodies try to salvage and protect good bacteria by providing a food source that only the microbes can use. This food source is a sugar called L-fucose that is produced in the small intestine. During infection with pathogens, fucose is shed into the intestinal lumen and used as food by the good microbes. The microbes in turn make products called short chain fatty acids that are beneficial for us.
– Food allergy and gut microbes: Cathryn Nagler has found that a specific group of gut microbes called Clostridia can protect against the development of food allergies in a mouse model of peanut allergy. By giving germ-free mice Clostridia, her group was able to show that the Clostridia protected the germ-free mice from developing peanut allergy, whereas a separate group of microbes, Bacteroides, did not elicit protection. It is possible that some Clostridia species could be used as probiotics to treat food allergies in the future. Because Clostridia typically get wiped out by antibiotics, this study also demonstrates a possible link between widespread antibiotic use and the rise of food allergy.
– Gut immunity and the microbiome: Albert Bendelac’s laboratory recently showed that an intestinal immune factor called secretory IgA (sIgA) targets and coats microbes that live in the small intestine and not those that live in the colon. Patients with IBD are known to produce less sIgA than healthy people, but it is not clear how this impacts disease outcome. Understanding which microbes are targeted by sIgA within the small intestine could help us to better understand how it is regulated and may allow us to use sIgA therapeutically in diseases including inflammatory bowel diseases, obesity, diabetes, and celiac disease.
Research that has improved existing treatments or lead to new treatments for Digestive Diseases:
Research performed at the University of Chicago using the GRAF has shown that dietary fiber promotes a healthy gut microbiome that we think promotes states of health and metabolic control. Western diets and antibiotic treatment alter the microbial community and can affect metabolic homeostasis as well as promote immune disorders, including inflammatory bowel diseases, T1D, and food allergy development.
Work performed in the Section of Gastroenterology has shown that natural products (e.g. ginseng) consumed regularly are likely to be far more effective in promoting healthy gut microbes than just taking them sporadically.
The Microbiome campaign began in 2002 to raise $1 million to develop a state-of-the-art microbiome research program at the University of Chicago. These funds were used to build the mouse gnotobiotic research animal facility (GRAF), develop the GeneSYS program (derivation of Genetics, Next Generation, and Systems Biology and is the underpinning of the tanslational research program in) and the Integrated Translational Research Core of the DDRCC, and establish the platforms for ‘omic’ technologies (high throughput DNA sequencing, metabolomics, proteomics).
Today, thanks to the GI Research Foundation’s support, the University of Chicago is a leader in the field of microbiome studies. The infrastructure funded by GIRF to develop this research program led to the creation of a collaborative network of world-class microbiome investigators at the University of Chicago, Argonne National Laboratory, and Marine Biological Laboratory. Together, these scientists are discovering exciting new links between our microbiomes and our health that will change our approach to treating numerous diseases.
IBD Genetics and the Boyer Laboratories Discovery of the First Crohn’s Disease Gene, the NOD2
Finding this crucial genetic clue gave researchers the first real insight into the complex causes of Crohn’s disease. The NOD2 gene is predominantly active in a special type of immune cell that acts like a sentry, detecting and engulfing invaders. NOD2 allows these cells to respond to certain types of bacteria by sensing LPS molecules that decorate the outer surface of many normal bacteria in our intestine, as well as several human pathogens. The NOD2 variant identified in CD patients at University of Chicago Medicine rendered cells incapable of appropriately responding to LPS. This breakthrough discovery eventually caused the researchers at the Section of Gastroenterology/Nutrition at the University of Chicago Medicine realize the importance of gut microbes in IBD, which has shaped much of the exciting research going on there today.
Based on the NOD2 discovery, the NIH launched a major IBD genetics consortium that was led by multiple centers throughout the US, including the University of Chicago. The program still exists today and, thanks in large part to its efforts, there are now nearly 200 gene variants linked to IBD. The abundance of IBD-associated genes reflects that what we think of as IBD (CD and UC) in the clinic is more likely to be a range of diseases. An appreciation for what make each patient’s IBD unique may ultimately help doctors usher in a new, personalized era of IBD treatments based on a person’s unique genetic factors and other elements that contribute to these conditions. Thus, the NOD2 discovery was enormous not only for the University of Chicago Medicine but for patients too.
Joseph B. Kirsner Professorship
CELL TECH II-Expansion of Research Labs and Supporting Intestinal Lipids Research
What is the importance of lipids how do they relate to digestive diseases? Lipids are the molecules that make up fats and oils in the foods we eat. Efficient lipid digestion and absorption by the gut is essential for good health, but disruptions of these processes can lead to many digestive diseases, fatty liver disease, and atherosclerosis and heart disease. The RNA editing factor researchers found turns out to have ubiquitous function (beyond just lipid processing), and is involved in modifying RNA in ways that drastically affects cellular function.
Cell Tech II, like Cell Tech, was a stepping-stone to advance the research programs of the GI section. Several investigators funded through this campaign established a collaborative program in nutritional sciences and cancer biology that led to major grants from the National Cancer Institute of the NIH and the American Heart Association. In addition, the findings of these studies led to landmark publications in high impact scientific journals. Their discoveries led to a number of patents that formed the basis of novel drug development by several pharmaceutical companies in the areas of colon cancer and lipid disorders associated with heart disease and atherosclerosis.
Cell Tech Campaign-Molecular and Cell Biology Support
The Cell Tech investment paid handsome dividends to University of Chicago researchers in the form of numerous major grants from NIH and CCFA being awarded to faculty and trainees alike for research projects. Furthermore, the initiative led to the University of Chicago receiving a National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant for creation of the Digestive Disease Research Core Center (DDRCC). Having DDRCC status is a hallmark of a top tier gastrointestinal research program. Through the DDRCC, University of Chicago faculty have received $16,500,000 over the past 22 years in support of their research into digestive disorders.
The DDRCC is committed to building a better understanding of gastrointestinal diseases by fostering collaborative research among basic and clinical investigators, facilitating the use of new technologies in the study of digestive diseases, providing education and training for physicians and scientists, and attracting talented investigators to the field of digestive disease research. DDRCC investigators carry out basic, clinical, and translational research on disorders including IBD, celiac disease, and food allergy, looking at these conditions through the lenses of microbiology, immunology, genetics, and pathophysiology.
Important research discoveries made as a result of Cell Tech I funding include:
– Discovery of cellular protection factors (heat shock proteins) in the gut that resist inflammation-mediated injury and are capable of promoting wound healing.
– Elucidation of key cellular pathways involved in the development of colorectal cancer.
– Identification of intestinal RNA editing factors involved in the processing and absorption of lipids
– Identification of a key signaling molecule (IL15) involved in the regulation of the gut immune system
The Emma Getz Inflammatory Bowel Disease Research Center
Creation of the Inflammatory Bowel Disease (IBD) Registry
The IBD registry has been instrumental in many important studies at the University of Chicago, including studies on risk to family members, the genetics of IBD (and contributed directly to the discovery of the first gene for Crohn’s disease- these were our families!), cancer risk in IBD (including identifying patients for an important study of cancer prevention and confirming the link between cancer risk and inflammation), one of the largest studies exploring the patterns of IBD in African Americans, and identification of a new pattern of IBD in elderly people.
The IBD registry at the University of Chicago, and by extension directly, GIRF, has led the world in linking electronic medical records in real time to a registry, and we are now partnered with the University of Chicago Center for Research Informatics, and have our own staff member working directly with this Center to assist us with our work in the Digestive Diseases Center. The IBD registry now has over 4,500 patients, and is one of the largest (if not the largest) such databases in the world.
IBD Registration Today: Expansion to all Digestive Diseases
Because of the great success of the GIRF-supported IBD registry, it a priority of the Digestive Diseases Center to expand this registry to all digestive diseases. Through additional support from the GI Research Foundation, but also industry grants and partnerships, the same infrastructure is now in place to collect information from patients with liver diseases, GI malignancies, esophageal diseases, nutrition and small bowel disorders including celiac disease, pancreatic diseases and soon, surgical patients as well.
The GI Research Foundation planted the seeds and nurtured an incredible resource for the University of Chicago Medicine’s GI Section and now, for the entire Digestive Diseases Center. Without the vision and generosity of GIRF, these discoveries and this progress would not have been possible!