2023 Collaborative Seed grants

Modulation of microbiota and gut-liver access inflammation by signals driven by Syk kinase-a therapeutic target in IBD and PSC

There are zero therapies for patients with primary sclerosing cholangitis (PSC). This liver disease damages the bile ducts, the tubes that carry bile. Bile is an essential life fluid that helps digest food. If bile ducts are damaged, it can cause all sorts of problems. In PSC, the problem results in end-stage liver failure and death. Medical treatments are desperately needed. 

To identify new therapies, we need to understand more about the disease. For many diseases, animals that develop diseases like what happens in humans—called “animal models of disease”—are an essential tool to understand what happens in humans and to identify therapies. In fact, before any therapy is used in humans, it must first be determined to be both safe and effective in animals models of the disease. Unfortunately, this has been impossible to do for PSC since there were no animal models that have bile duct damage like what happens in humans with PSC. Without animal models of PSC, medical breakthroughs are fenced in by a huge barrier.  

Eosinophilic esophagitis (EoE) is a chronic allergic disease of the esophagus and is one of the most common causes of trouble swallowing in the United States. It affects nearly 1 in 1000 individuals and occurs in all ages, sexes, races, yet the disease pathways that contribute to and maintain EoE inflammation are not well known. This knowledge gap and the lack of easy access testing for patients makes treatment and monitoring of EoE very challenging. EoE is thought to be a food allergy; therefore, one of the main treatments is eating a special diet, where specific foods are strictly eliminated. It is assumed that the removal of specific foods is the only reason that patients’ EoE allergy improves. However, it is known that diets – especially strict and consistent ones – change the gut microbiome and change the way the microbes function. Increasingly, gut microbes are found as important factors in the treatment and monitoring of diseases, especially those of the gastrointestinal tract. Yet, these diet-induced microbiome effects have not been explored in EoE. There is a tremendous unmet need to understand how the microbiome is affected by diet and in turn influences EoE disease, particularly since diet is a first-line therapy. We are specifically interested how EoE elimination diets affect microbial-made factors (microbial metabolites) such as short chain fatty acids because these molecules have been found to be anti-inflammatory in other gastrointestinal and allergic diseases. Gut microbes generate short chain fatty acids in the intestine by breaking down and metabolizing dietary fiber, and these metabolites are then absorbed by patients and can travel throughout the body. Microbial metabolites such as short chain fatty acids can affect immune function and therefore pose as a potential new treatment or non-invasive marker for EoE. Some of our research has shown that short chain fatty acids block eosinophil allergic inflammation triggered by the molecule interleukin-33. This suggests that dietary short chain fatty acids could have anti-inflammatory effects in EoE. To close this knowledge gap, Drs. Uchida, Stephens, and Reisdorph will determine microbial metabolite responses to a dairy and wheat free diet in EoE patients and study how short chain fatty acids block interleukin-33 inflammation in eosinophils. These investigations pave the way for an entirely new potential therapy for EoE and will help better understand how diet induced microbial metabolites impact allergic diseases.

Inflammatory diseases, as well as stress-related psychiatric disorders including anxiety disorders, mood disorders, and trauma- and stressor-related disorders such as posttraumatic stress disorder (PTSD), in which inflammation is a risk factor, are increasing in modern industrialized societies. The Hygiene hypothesis, or “Old Friends” hypothesis states that these increasing rates of inflammatory conditions are due to reduced exposure to diverse microorganisms with which humans co-evolved. This argues that one approach to reducing the risk of inflammatory conditions would be to enhance exposures to these “Old Friends”. One category of “Old Friends” is the commensal organisms found in the human gut microbiome. Indeed, individuals living traditional hunter-gatherer lifestyles have higher diversity of the gut microbiome than individuals living in modern industrialized societies, such as the United States, suggesting that persons living in modern industrialized societies may benefit from increased diversity of the gut microbiome. Indeed, as discussed at the North American branch of the International Life Sciences Institute (ILSI) North America’s conference, “Can a Healthy Gut Microbiome Be Defined through Quantifiable Characteristics?” held December 17, 2018, in Washington, DC, the consensus statement reported that “…diversity is likely more important than the presence of specific taxa.” A number of recent studies indicate that persons who report consumption of higher numbers of plants, or who report a higher frequency of consumption of fruits and vegetables, have higher diversity of the gut microbiome. Despite evidence that self-reported increases in consumption of a diversity of plants increases the diversity of the gut microbiome, no randomized controlled trials have been conducted to determine the effectiveness of consumption of a high diversity of plants on diversity of the gut microbiome, biological signatures of inflammation and mental health outcomes. Here we propose to evaluate daily consumption of a drink consisting of an extremely high diversity of plants (i.e., a “veggie shot”) for four weeks on the diversity of the gut microbiome, biological signatures of inflammation, quality of life, sleep quality, and PTSD symptoms among persons with a diagnosis of PTSD who are preselected for elevated baseline biomarkers of inflammation (i.e., >1.0 mg/L C-reactive protein, CRP). If successful, this interdisciplinary and multidisciplinary study may lead to an inexpensive, accessible, portable, and effective intervention for treatment of PTSD, and potentially other conditions in which inflammation is a risk factor. Furthermore, it would provide an evidence-based model that could be more broadly replicated to address gut and mental health challenges in various contexts. 

We broke down this barrier by generating the animal model desperately needed for PSC research. This animal model has bile duct damage that looks like PSC damage, and also has changes in the gut similar to PSC in humans. We tested a potential drug therapy in this animal model of PSC, and results were promising. In this proposal we will use our novel animal model of PSC together with drug therapy to understand how bile duct damage, or the recovery from damage upon drug therapy, is linked to bacteria in the bile, liver, or gut. These bacteria may be causing PSC to happen and if we understand the microbes, and how they change in response to therapy, we will have a solid foundation with which to make breakthrough discoveries and develop therapies that save lives.

Dynamics of diet-induced microbial metabolites in eosinophilic esophagitis

Diet and microbiome interactions: application in posttraumatic stress disorder (D-MAPS)