Milena Bogunovic, MD, PhD, Pennsylvania State University ($100,000) for Macrophages, Homeostasis of Enteric Neurons and Post-IBD Neuropathy.

Dr. Bogunovic's Research Abstract

Gastrointestinal (GI) health is essential for overall body health. Inflammatory insults to the GI mucosa often cause profound and irreversible changes of GI homeostasis, including disrupted enteric neural regulation and subsequent alteration of GI function. Mucosal inflammation causes irreversible structural changes of the enteric nervous system (ENS), demonstrating a strong linkage between inflammation and GI innervation. Understanding of the cellular and molecular mechanisms that link mucosal inflammation with the loss/regeneration of enteric neurons are the focus of this proposal.

We characterized a phenotypically and transcriptionally distinct subset of intestinal macrophages that reside along the neural fibers of enteric neurons and are particularly enriched at the level of myenteric neural plexus of the ENS; we discovered a novel mechanism of crosstalk between these macrophages with enteric neurons. By using infectious and non-infectious murine models of transient mucosal inflammation and state of the art immunological and physiological techniques we will determine the role of mucosal inflammation, ENS-associated macrophages and the factors that they produce in regulation of homeostasis and function of enteric neurons during mucosal inflammation. The proposed studies will substantially advance our understanding of the pathophysiology of post-inflammatory enteric neuropathy known as irritable bowel syndrome (IBS) common in patients with IBD.

Ken Cadwell, PhD, New York University ($100,000) for Isolation of Novel Clostridiales Strains that Can Reverse Dysbiosis.

Dr. Cadwell's Research Abstract

Inflammatory bowel disease (IBD) is less common in parts of the world with parasitic worm infections than in the developed world. Understanding why may lead to new types of therapy. We recently found that infection by parasitic worms increases the number of beneficial anti-inflammatory Clostridiales bacteria in the intestine, and that these bacteria can outcompete harmful disease-causing bacteria. Therefore, one reason why people living in the developed world are more likely to develop IBD may be because their intestines are no longer colonized by these beneficial bacteria. To restore a healthy “gut microbiome”, we may need to recolonize patients with these beneficial bacteria as a way to treat IBD. We propose to isolate beneficial Clostridiales bacteria from indigenous people of Malaysia who are infected by parasitic worms. These bacteria are potentially more beneficial when administered to IBD patients. We will test this by examining their ability to kill harmful disease-causing bacteria and restore a healthy gut microbiome. We will also use an animal model of IBD to determine whether this approach can reverse disease. If successful, we believe that Clostridiales from indigenous Malaysians, or products that these bacteria produce, can be used to treat IBD.

John Chang, MD, University of California, San Diego ($100,000) for Edible Immunomodulatory Algae as a Therapeutic Strategy for Inflammatory Bowel Disease.

Dr. Chang's Research Abstract

Although many powerful drugs are currently available for inflammatory bowel disease, these drugs do not work in every patient and can have life-threatening side effects. Thus, new therapies that work in different ways and utilize new approaches to reduce the side effects of these therapies are urgently needed. This project tests the idea that we can deliver therapies directly to the intestine using edible green algae as a means to treat intestinal inflammation. We have called our concept “EAT IBD”, which stands for Edible Algae Therapy for the treatment of Inflammatory Bowel Disease. We will test this idea to see if it improves intestinal disease in mice and if successful, will provide evidence that this concept may be used for the treatment of human patients with IBD in the future.

Jean-Frédéric Colombel, MD, Icahn School of Medicine at Mount Sinai ($100,000) for The Role of Viral Exposures Preceding IBD Diagnosis in Disease Pathogenesis.

Dr. Colombel's Research Abstract

So far, most research on the microbiome in IBD has mostly focused on gut bacteria. However, there is increasing evidence to support that other members of the microbiome, such as viruses, may also have an important role. Herein we plan to study the role of viral exposures in IBD development. A major challenge of this type of study is to disentangle what is cause, and what is consequence of the inflammatory process. However, having access to a unique cohort of pre-clinical samples, where we were able to gather thousands of samples from patients with Crohn´s disease and ulcerative colitis, years before their diagnosis, as well as matched healthy individuals, addresses some of the challenges. Acquiring mechanistic information into preclinical disease can therefore potentially uncover key pathogenic events. In this unique cohort, we will use also a unique method, recently described, called the VirScan. This is a very sensitive and specific assay, that has the ability assess all viral exposures that happened throughout the life span of an individual. By combining this unique technique in a distinctive cohort, we hope to be able to identify whether there are specific viral exposures that may act as triggers for the development of IBD.

Christopher Contag, PhD, Stanford University ($100,000) for Raman Microendoscopy and Functionalized SERS Nanoparticles to Detect Dysplasia and Malignancy in Patients with Ulcerative Colitis.

Dr. Contag's Research Abstract

Patients suffering from IBD, especially UC, are at an increased risk of the life-threatening colorectal cancer, and early detection is critical. The standard of care for prevention and early treatment is to inspect the colon with white-light endoscopy, however, the appearance of the tissue is often insufficient for early identification of cancer. While the intensity of inflammation and the occurrence of high-grade dysplasia are predisposing conditions for cancer, these are also difficult to evaluate by white-light endoscopy. Raman spectroscopy is a tool that can identify molecular determinants of disease, but the generally weak endogenous Raman signals have prevented effective clinical translation due to the long scan times that are required. We have designed an ultrafast Raman-based microendoscope that will enable screening at rates compatible with conventional endosocopic exams. We use these instruments to detect functionalized surface enhanced nanoparticles that are targeted to molecular markers of inflammation, dysplasia and malignancy. This would provide the endoscopist with a rapid and highly sensitive detection system that can identify hidden lesions or even discriminate between low- and high-grade dysplasia. This would have a significant impact on treatment versus surveillance and would improve overall survival and quality of life for patients suffering with IBD.

Jun Huh, PhD, University of Massachusetts ($100,000) for Maternal Inflammation: An Environmental Risk Factor for the Development of IBD?

Dr. Huh's Research Abstract

Environmental factors are thought to contribute to the development of a range of human diseases, including inflammatory bowel disease (IBD) and autism spectrum disorder (ASD). Interestingly, the incidence of IBD is higher in patients with autism, compared to those without. We propose that inflammation to which a developing embryo may be exposed in the maternal womb, could be an environmental risk factor linking autism and IBD.

We previously showed that a particular type of immune cells, Th17 cells, in mothers, promotes autism-like phenotypes in offspring, using a mouse model of inflammation-induced neurodevelopmental disorders (i.e. autism). Th17 cells, and the pathways that control them, are also implicated in IBD. We propose that prenatal, maternal inflammation, through Th17 cells both enhances autistic phenotypes and increases IBD susceptibility in offspring. Our work thus aims to elucidate the intricate connection between maternal inflammation, autism and IBD. In addition, this research will lay the foundation for future studies to identify novel therapeutics for treating maternal inflammation- induced IBD.

Nobuhiko Kamada, PhD, University of Michigan ($100,000) for Dietary Amino Acids Allow Pathobionts to Thrive in Patients with Crohn’s Disease.

Dr. Kamada's Research Abstract

Adherent-invasive Escherichia coli (AIEC), a pathogenic form of E. coli, is known to accumulate in the intestinal mucosa of patients with Crohn’s disease (CD). Although it is believed that AIEC exacerbates the disease by promoting intestinal inflammation, the precise mechanism underlying the abnormal expansion of AIEC in the intestinal mucosa remains largely unknown. We have found that AIEC prefers amino acids as a source of nutrients during inflammation and this nutritional preference is critical for its ability to gain a competitive edge over commensal non-pathogenic E. coli. Importantly, we have demonstrated that intestinal amino acids used by AIEC as nutrients are mainly derived from the diet and, therefore, the removal of certain key amino acids from the diet will prevent AIEC from thriving in the gut. In this study, we will aim [1] to clarify the role of dietary amino acid utilization by AIEC in the development of intestinal inflammation and [2] to unravel the mechanisms by which intestinal inflammation regulates the substrate preference of AIEC. A successful completion of this project is expected to result in the development of novel therapeutic strategies that will control the pathogen by restricting the availability of its preferred source of nutrients.

Hyun Jung Kim, PhD, University of Texas at Austin ($100,000) for Personalized “Crohn’s Disease-on-a-Chip” towards Precision Therapeutics.

Dr. Kim's Research Abstract

The goal of the proposed research is to develop a laboratory model of Crohn’s disease (CD), “Crohn’s Disease-on-a-Chip”. We mimic the microstructure and physiological function of human intestine by integrating tools developed in a microchip computer technology, tissue engineering, and clinical microbiology. We have a platform technology to maintain viable human intestinal cells in a thumb-size microchip with dynamic flow and bowel movement from days to weeks. The bottom line of our innovation is to take human samples including gut cells, immune cells, and gut bacteria isolated from CD patients as well as non-CD healthy individuals, then place them in the CD-on-a-Chip to recapitulate disease progression of CD. This approach allows us to build CD patient’s avatars (i.e. multiple CD chips) that can simulate CD symptoms of a single CD patient. We will recruit at least 10 CD patients. Thus, we expect to have ten different CD patients’ avatars to test possible therapeutics. We will test fecal microbiota transplantation (FMT), where we add gut bacteria isolated from healthy donors into CD patient’s chips to validate if this approach can contribute to the rescue of CD. As a trendsetter, the CD-on-a-Chip may provide a translational platform to discover personalized precision therapeutics.

Eric Martens, PhD, University of Michigan ($100,000) for Dietary Fiber Deprivation as a Mediator of Mucosal Barrier Dysfunction and IBD Trigger.

Dr. Martens' Research Abstract

Many genetic factors have been associated with increased IBD susceptibility. However, these only explain a fraction of the disease risk that an individual with such a predisposition experiences. Environmental factors have been proposed to work in combination with host genetics to cause IBD. Diet and the normally beneficial community of bacteria that live in the human intestine are candidate “environmental” factors. The industrialized world, in which IBD is more prevalent, has experienced reduced consumption of dietary fiber–a term used to represent a group of complex carbohydrates abundant in vegetables and grains. Humans cannot directly digest fiber, so it transits to the distal intestine and is digested by gut bacteria. We have shown that a lack of dietary fiber causes gut bacteria to turn to a different source of carbohydrates to survive: protective intestinal mucus, which normally forms a barrier that keeps bacteria at a “safe distance” from host tissue. We propose that chronic or transient reductions in fiber trigger gut bacteria to erode the mucus layer, bringing them into proximity with the host and causing disease flares. Support for our model will allow us to explore dietary therapies to prevent IBD occurrence by reinforcing the integrity of the mucus layer.

Corinne Maurice, PhD, McGill University ($100,000) for Interrogating Immune-bacteriophage Dynamics to Mitigate Intestinal Inflammation.

Dr. Maurice's Research Abstract

The human gut is home to trillions of bacteria affecting our health. Even more abundant are viruses that specifically infect these bacteria. These viruses are called bacteriophages and have the ability to control the number and function of the bacteria that live within us. Individuals with inflammatory bowel disease (IBD), such as Crohn’s disease or ulcerative colitis, have an imbalance in their gut bacteria that causes the activation of the underlying immune system, chronic inflammation, and tissue injury. We predict that changing the bacteriophages in the gut of patients with IBD could provide a new therapeutic approach to limit inflammation and disease progression. However, the specific type of bacteriophages that live in the gut and their influence on this important ecosystem are not known. Using mice in which the normal gut microbes have been replaced with bacteria and bacteriophages from healthy individuals or from patients with IBD, we will determine how each of these microbial components contribute to immune dysfunction and susceptibility to animals models of human colitis. Results generated from our work will identify how viruses can be harnessed to ameliorate intestinal inflammation and disease.

Inga Peter, PhD, Icahn School of Medicine at Mount Sinai ($100,000) for Bacterial Transmission in Utero and Newborn Mucosal Immunity in IBD.

Dr. Peter's Research Abstract

Inflammatory bowel disease (IBD) affects women during their reproductive years and 25% become pregnant after an initial diagnosis of IBD. New data suggest that babies are born not-sterile, and bacteria, also known as microbiome, are passed from the pregnant mother to the fetus in the womb. The make-up of these initial bacteria significantly contributes to the development of newborn’s immune system and may affect the risk of diseases later in life. While it is well established that patients with IBD have an altered microbiome, no data exist on the types of bacteria passed from pregnant women with IBD to their babies or on the role these bacteria play in the development of baby’s immune system. Therefore, we propose to transplant the stool of newborn babies born to women with and without IBD to germ-free mice, known to have underdeveloped immune system, and characterize the changes in their immune system before and after the transplantation. We will also track particular bacteria that were successfully engrafted into germ-free mice and determine their effect on the maturation of immune responses. This research could inform future clinical trials of microbial manipulation during pregnancy as a possible strategy to prevent IBD risk transmission.