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Abstract or Project Description

Abstract or Project Description

Inflammatory Bowel Disease (IBD), including Crohn’s disease and ulcerative colitis, is a condition where the immune system mistakenly attacks the intestine, leading to chronic inflammation and bowel damage. One unique feature of IBD is the growth of new lymphatic vessels—tiny tubes responsible for draining fluids and immune cells to maintain balance in the body. However, in IBD, even with the formation of new lymphatic vessels, inflammation persists, suggesting that these vessels may not function properly.

Our recent findings reveal a specialized drainage system in the colon that follows specific structures called colonic folds. These folds degrade during colitis, disrupting the drainage system and contributing to inflammation. Additionally, we found that lymphatic vessels can adopt different structural states—either tightly sealed or more open—which can affect how well they transport fluids and immune cells.

We aim to understand how these lymphatic changes influence inflammation and immune responses in IBD. By studying the growth of lymphatic vessels and how their structures affect immune cell movement, we hope to uncover new ways to reduce inflammation and restore gut health. This research may lead to new treatments for people living with IBD by targeting lymphatic vessels to improve their function.

Abstract or Project Description

We currently lack cures for chronic intestinal diseases. Despite incredible advances in understanding and targeting inflammation that promotes diseases like Crohn’s and ulcerative colitis, many patients develop resistance to treatment, suggesting alternative disease drivers beyond immune cells and the inflammatory molecules they produce. While the gut has remarkable regenerative capacity due to specialized stem cells that can rapidly generate all mature epithelial cells, diseases may impact underlying structural cells called fibroblasts which typically guide epithelial cell regeneration. 

Our research vision is to identify the root causes of inflammatory diseases in the human gut. Our work suggests that fibroblasts play a central role, and our experiments to date have developed a unique and simple way to test how fibroblasts work closely with inflammatory immune cells. The specific internal cellular wiring diagrams and external cellular communication systems responsible for the identity and variety of fibroblasts that exist in the gut remain elusive. Our project aims to realize an integrative research plan that bridges careful human observation, computation and mechanistic experimental models. Our group is fundamentally interested in determining whether and how fibroblasts store and propagate disease in intestinal tissues to develop cures for IBD.

Abstract or Project Description

Males and females with IBD differ in terms of incidence of disease, symptoms and response to treatments. The underlying reasons are largely unknown. Understanding why these sex differences exist could reveal why many patients develop IBD as they enter young adulthood. Sex hormones such as testosterone surge during adolescence and then circulate at very different levels in males and females. These hormones are powerful signaling molecules that regulate diverse aspects of physiology and may play a role in IBD. Clinical studies hint that testosterone signaling is protective in IBD, but it is largely unclear which cells this hormone signals to in the gut and how this signaling might influence intestinal inflammation. We have discovered that testosterone signals to an important population of nerve cells along the gut-brain axis, called nociceptors, that communicate information about the gut to the brain and regulate local immune responses. Using mice in which we can specifically disable testosterone signaling in nociceptors without altering it in the rest of the body, we will determine how testosterone influences inflammation and tissue repair in colitis. The results will advance the understanding of how sex hormones impact disease activity in IBD, potentially explain sex-dependent outcomes and inform therapeutic strategies.

Abstract or Project Description

The epithelial cells lining the intestine control responses to gut bacteria, limiting intestinal damage in Crohn’s disease. A critical gene in this pathway is DUOX2, which is up-regulated in response to bacteria and helps maintain intestinal health. We discovered that Crohn’s disease patients who carry genetic variants in DUOX2 are more likely to progress to fibrotic disease complications requiring surgery. We tested an intestinal gene signature for refractory pediatric Crohn’s disease in a database containing 2000 small molecules, identifying 140 which might be more effective therapies. Our studies will now utilize a novel Human Intestinal Organoid, or “mini-gut” model system for refractory pediatric Crohn’s disease that we have developed informed by genetic factors like DUOX2. We have prepared stem cells from pediatric Crohn’s disease patients who did or did not have DUOX2 genetic variants, and will differentiate them into white blood cells and human intestinal organoids. This novel model system will be used to test ways to modulate pathways linked to fibrosis in patients, by screening the top small molecules which we have identified as potentially beneficial. Our studies will advance precision medicine, by developing a platform to screen new therapies in patient-derived intestinal organoids with clinically important genetic variants.

Abstract or Project Description

Several lines of evidence have implicated stress in the endoplasmic reticulum (ER stress) of intestinal cells to the pathogenesis of IBD. ER stress is a common feature in tissues from individuals with IBD, and mutations in genes in ER homeostasis are risk factors for both ulcerative colitis and Crohn’s disease. In animal models, genetic deletion of factors required for resolution of ER stress sensitizes to intestinal inflammation or results in spontaneous inflammation, whereas chemical mitigation of ER stress protects from inflammation. Overall, it is clear that unresolved ER stress can both cause and exacerbate intestinal inflammation. It remains largely unknown, however, what factors trigger ER stress, especially in the context of IBD pathogenesis in humans. Our project will evaluate roles of the human microbiome in regulation of ER stress in human cells and the contribution of such roles to the pathogenesis of IBD. Our goal is to define causal roles of the human microbiome in IBD and to lay the groundwork for the development of novel diagnostics and therapeutics.

Abstract or Project Description

Intestinal fungi, collectively known as the mycobiota, have emerged as significant contributors to intestinal disease severity. Our prior research demonstrated the efficacy of fecal microbiota transplantation in inducing clinical responses in UC patients associated with decreased fungal colonization over time. Further investigations in mouse models and UC patients revealed that fungi exacerbate disease severity through the production of a toxin called candidalysin. Utilizing an array of approaches, we determined a wide fungal genetic variation within the gut of UC patients. With this proposal we will explore innovative approaches for fungal targeting in UC employing dietary approaches.

Abstract or Project Description

Glucocorticoids are the mainstay treatment to quell acute flare events in the context of Inflammatory Bowel Disease. These steroids are taken systemically and have broad and long-lasting side effects. As a result, alternative, safer approaches are sought. We have recently discovered that proteins made by the gut microbiota found predominantly in healthy individuals trigger the same receptors. This suggests that these proteins may have therapeutic benefit. The proposed research aims to further our understanding of these interactions. We aim to test whether these proteins, when amended to the gut microbiome of mice with colitis, are sufficient to reduce inflammation. Our ultimate goal is to develop therapeutics for patients with IBD that perform the role of glucocorticoids and act locally on inflamed tissue in the gut. 

Abstract or Project Description

Inflammatory Bowel Disease (IBD) remains difficult to treat, partly because we do not fully understand how dying cells within the intestinal lining influence immune responses and tissue repair. Different types of cell death—apoptosis (non-inflammatory), necroptosis, pyroptosis (inflammatory)—occur in IBD, but how immune responses to them shape healing remains unclear. When intestinal epithelial cells die through apoptosis, dendritic cells (DCs) help maintain balance by producing molecules that suppress inflammation and promote regulatory T cells (Tregs), which aid repair. However, necroptosis and pyroptosis release signals that trigger inflammation. While inflammation is often thought to hinder repair, we hypothesize that these signals shape immune responses in ways that influence healing. Specifically, we propose that DCs interpret these signals and drive the formation of distinct Treg cell populations, each with unique repair roles. This idea challenges the paradigm that inflammation and repair are at odds, suggesting instead that certain inflammatory responses may help set the stage for recovery. Using innovative mouse models, we aim to uncover how DCs integrate signals from different types of cell death to direct tailored repair processes. By understanding these mechanisms, we hope to develop therapies that not only control inflammation but also promote lasting healing in IBD patients. 

Abstract or Project Description

Patients with Inflammatory Bowel Disease (IBD) have dysfunctions in gut motility (the movement of muscles in the gastrointestinal tract). Currently, most available therapeutics developed to directly target the gut fail to stabilize symptoms, suggesting that dysfunctions in gut motility could arise from pathological changes occurring outside the gut. Intriguingly, gut motility problems also occur at high frequencies in patients with neurological disorders, including neurodegenerative, neurodevelopmental and neuropsychiatric diseases, associated with dysregulated neural activity in a specific region of the brain—the cerebral cortex. We propose that dysregulated neural activity in the cortex contributes to the emergence of gut dysfunction. We will test this hypothesis by first identifying specific regions in the cortex that are anatomically connected to the gut and then determining if modulating neural activity within these regions alters gut function. Additionally, we will use established mouse models of various neurological disorders and IBD to ask whether restoring homeostatic levels of neural activity to the cortex improves gut phenotypes. Our study will provide anatomical and functional evidence to support the concept that cortical modulations regulate gut motility. Furthermore, the insight gained from the study can lead to novel therapeutics for ameliorating gut motility symptoms in IBD patients.

Abstract or Project Description

The etiology of Inflammatory Bowel Disease (IBD) is unknown. Epidemiological and experimental studies report an association between early life events and the susceptibility to develop IBD later in life. Indeed, reduced contact with gut microbiota early in life can program the immune system toward increased susceptibility to develop gut inflammation later in life, an immune memory phenomenon termed “pathological imprinting.” However, the underlying mechanisms and the nature of pathological imprinting remain unclear. The goal of this project is to understand how the dietary change in fat/fiber amounts early in childhood affects gut microbiota establishment, the intestinal mucosal homeostasis and the susceptibility to develop colitis. We will take the advantage of advanced high-throughput sequencing and mouse models harbouring controlled microbiota to uncover the cellular and molecular mechanisms underlying pathological imprinting. Since in high-income countries, the dietary predilection to western-style diets rich in fats parallels an increase in IBD incidence, the results of this project will propel future studies aimed at preventing IBD development in individuals at high risk of developing this debilitating disease.

Abstract or Project Description

Our skin and gut house multitudes of bacteria that influence our health via interactions with key immune sentinel cells that engulf these microbes and respond dynamically to their signals. Previously we have had to rely heavily on animal models to try to decode this language between our immune sentials and the bacteria they sense, because we have lacked to tools to meaningfully capture the relevant information from human tissues. To overcome this hurdle we have recently developed a novel single-cell genomic method for simulatenously capturing and sequencing DNA from both these immune sentinel cells and the bacteria they contain, therby providing us with an unprecendented view into the nature of these bacteria-immune cell interactions. By applying this novel approach to samples of healthy human skin and gut, we hope to shed new light on how helpful and harmful bacteria are sensed at these barrier tissues, how the immune system decides when (and what) to attack and the molecular and cellular cues that guide these decisions. These studies will transform our understanding of bacterial influences on our health and set the stage for future work to interrogate their role in specific human diseases such as Inflammatory Bowel Disease.