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Abstract or Project Description

Crohn’s colitis that does not respond to medical therapy is treated surgically with removal of the colon and rectum and creation of a permanent end ileostomy. This can be devastating for some patients and is fraught with potential surgical morbidity, and even disease recurrence in the small intestine in a third of patients. Mesenchymal stem cells target pathways of inflammation important for Crohn’s disease and are being increasingly utilized for the treatment of perianal fistulizing Crohn’s disease. We are herein delivering mesenchymal stem cells with endoscopic injection into the colon wall at the time of colonoscopy to treat inflammation of the colon and rectum related to Crohn’s disease that is not responding to medical therapy in order to avoid surgical intervention.

Abstract or Project Description

There is still no medical cure for inflammatory bowel diseases (IBD) and the clinical management is challenging. In particular, differentiating between Crohn’s disease (CD) and ulcerative colitis (UC) and predicting the clinical course or the response to therapy is difficult.
In this study, we aim to characterize tissue samples from IBD and control patients with a new diagnostic approach using infrared (IR) light and providing a molecular fingerprint of the disease. It is our goal to identify specific diagnostic fingerprints for CD and UC, for the prediction of the clinical course and the treatment response in patients. Finally, we will use a laser-based technique to obtain areas with specific molecular fingerprints from the tissues. Such material will be analyzed for all expressed genes with so called next-generation sequencing to determine the molecular changes associated with disease-specific fingerprints. Thereby, we hope to identify new diagnostic tools and targets for future therapy.

Abstract or Project Description

IBD is a complex disorder that results from a dysregulated immune response in the gut. Current and emerging therapy for IBD treatment is mainly focused on regulation of the immune response. Exosomes are nanovesicle packing different molecules that transfer their cargo to recipient cells. Mammalian milk contains high concentrations of exosomes (MDE) carrying immune-related molecules. Our preliminary results demonstrate that MDE have a beneficial effect on experimental induced colitis. Based on these results we hypothesize, that MDE exert an anti-inflammatory immunomodulated effect on intestinal tissue. We plan to use specialized tools obtained or generated by our research groups to confirm this hypothesis and to assess how MDE might contribute to IBD treatment. In the long term we aim to study the effect of MDE on IBD patients. The use of MDE is a new promising therapeutic strategy using natural factors and safety compared to conventional immune suppression used for IBD.

Abstract or Project Description

Humans evolved with, and continue to harbor, trillions of microorganisms living inside or on our bodies. As a result, these microbes play fundamental roles in our health. The last 20 years of research has focused almost exclusively on our resident bacteria. New technologies have enabled identification of viruses within the intestine, i.e. “the virome”. Moreover, recent studies indicate that the gut virome is significantly altered in patients with IBD, and that viruses can have a protective function in mice. However, the contribution of the virome to a healthy gut and how changes in virus composition impacts gut inflammation is almost completely unknown. Here, we propose to identify components of the human intestinal virome that shape our immune system in the context of health and IBD. This work will identify protective roles for the intestinal virome – a contrast to the misconception that all viruses are harmful.

Abstract or Project Description

Precise manipulation of diet and gut microbiota is a novel and non-invasive therapy for IBD which is of great interest to patients. Enteral nutrition provides a clear example of a dietary intervention improving clinical outcomes such as mucosal healing. However, previous studies in IBD have altered several different dietary components at once making it challenging to identify specific dietary factors with quantifiable, causal roles in IBD. Identifying these dietary ingredients that influence disease will allow us to compose a broader range of precise and clinically effective diets for IBD with better patient tolerance and adherence than enteral nutrition. In animal models, we screened over 30 defined diets to identify that protein and fiber in combination influence gut leakiness and inflammation. We will profile the effect of these diets on the mucosal immune system and leaky gut in healthy individuals and patients with moderate ulcerative colitis

Abstract or Project Description

NOD2 (nucleotide-binding oligomerization domain-containing protein 2) is one of the most prominent risk factors in Crohn’s disease (CD), but the chemical mechanisms by which NOD2 mutations gives rise to CD is unclear. NOD2 is a proposed sensor of bacterial cell wall fragments that when mutated results in intestinal inflammation. However, the specific commensal bacteria that activate NOD2 and mechanism(s) by which NOD2 detects cell wall fragments at the molecular level is unknown. To elucidate how NOD2 senses gut bacteria and their cell wall fragments, we will evaluate specific commensal bacteria in mouse models of CD NOD2 mutants and determine the structure of cell wall fragments in complex with NOD2. Our collaborative studies provide a unique multi-disciplinary and synergistic approach to address the molecular mechanisms of NOD2 CD mutations. Understanding these fundamental mechanisms of NOD2 should afford new opportunities to design novel therapeutics targeted at NOD2 mutations in CD.

Abstract or Project Description

Abstract or Project Description

Although there are many drugs available for the treatment of IBD, most patients do not respond long-term to any one drug. One possible reason is that the condition we call “IBD” likely represents many distinct diseases, rather than simply just ulcerative colitis and Crohn’s disease, and each subtype may require a different treatment. Here we will address this problem by using a suite of state-of-the-art laboratory techniques that will allow us to study the genetic instructions (RNA) of thousands of individual cells sampled from the intestines of patients with IBD. Using bioinformatic methods, we will use this information to classify IBD into different diseases, which may help us to determine how best to treat each subtype. We also hope to discover new molecules that are involved in causing IBD, an important first step to developing new treatments for IBD

Abstract or Project Description

The gut microbiota is believed to play a critical role in inflammation in Crohn’s disease (CD). Adherent–invasive Escherichia coli (AIEC) often colonize the intestinal mucosa of CD patients. AIEC colonization may promote intestinal inflammation in CD patients. We have found that AIEC prefers to use the amino acid L-serine for growth in the inflamed gut. As dietary proteins are a major source of L-serine in the gut lumen, withholding L-serine from the diet prevents the growth of AIEC in the gut of mice. These facts suggest that a diet deprived of L-serine may alleviate CD symptoms by modulating the gut microbiota, in particular, the colonization by AIEC. In this project, we will validate the effect of dietary L-serine modification on the microbiome and disease outcomes by using a human microbiota–associated mouse model and studying CD patients

Abstract or Project Description

Lymphatic vessels are specialized vessels that transport immune cells and fat out of the gut to maintain health. Surgeons treating Crohn’s disease decades ago argued that impaired lymphatic flow may be a key problem in the disease. However, only recently have tools emerged to study lymphatic vessels in detail. We have data that lymph transport is impaired even in early Crohn’s disease. However, treatments targeting the cytokine TNF reverse the impaired transport. As investigators specializing in different lymphatic research areas, we will synergistically utilize human subjects’ studies with research in mice and rats to map in detail how terminal ileal inflammation alters lymph flow. We will also address whether a gut hormone called GIP that is overproduced in the setting of TNF neutralizing therapy accounts for how therapy against TNF restores lymph flow. If so, mimetics of the hormone may have utility in subjects unable to use therapeutics against TNF.