Regulatory Immune Mechanisms and Gastrointestinal Comorbidity in ASD
Abstract
Gastrointestinal (GI) problems are a major issue in over half of all individuals with autism spectrum disorders (ASD). Untreated GI problems are now thought to impact many behavioral symptoms associated with ASD, including aggression, sudden irritability, unexplained crying, anxiety, sleep disorders, social withdrawal, self-injury, and hyperactivity. Children with ASD and GI comorbidity tend to score far worse on behavior assessments, suggesting that these chronic GI symptoms intensify core ASD deficits. Undoubtedly, GI problems in ASD impact the child’s and family’s quality of life. Yet, very few children with ASD and GI comorbidity are treated for their GI symptoms. Our proposal will address the area of interest for the FY2017 Idea Development Award, “mechanisms underlying conditions co-occurring with ASD, e.g., gastrointestinal issues.” There is a large gap in our knowledge regarding why children with ASD are 6-8 times more likely to have GI issues. Our previous work has highlighted that increased immune activation occurs in the GI tract. More immune cells are activated, and more of these cells travel into the gut lining, leading to inflammation. In many children with ASD and GI issues, we also saw evidence of an autoimmune reaction to the gut lining. This inflammation may alter gut function. A specialized type of immune cell, the regulatory T cells (Tregs) is known to reduce inflammation and control immune responses. In the GI tract, these cells will help calm inflammation that could occur in response to bacteria or food in the gut. Our proposed work will look at these cells specifically and answer the questions: Do these cells work properly? What do they produce? How many are there? Can they be formed correctly? If they appear, are they stable? Do they respond to signals from the body to be better regulators or switch to a cell type that is harmful? By answering these fundamental questions, we hope to learn a great deal about the biology of these cells in young children with ASD and GI comorbid features. We believe that there will be overlap between the faulty function of Tregs, severity of GI symptoms, and behavioral symptoms. When analyzing our data, we will pay special attention to the type of GI symptoms present in the child and their behaviors and whether there are “clusters” or patterns that can be attributed more (or less) to faulty Tregs. The outcomes of this research will provide new knowledge of how the immune system is linked to GI problems in ASD. One aspect of this project is to look at the epigenetics of Tregs. Epigenetics literally means “on top of” the genetic code and refers to modifications to DNA or chromosomes that alter gene expression. Epigenetics are at the interface of genetic and environmental risk factors involved in complex human conditions, including ASD. In this case, environmental factors may mean altered microbiota, dietary intake, or altered metabolites from bacteria or the diet. We plan to take stool samples for future experiments to look at these factors too. Recent advances in technology enable us the first glimpses of patterns of epigenetic modifications. Here, we will apply these techniques in an innovative way to focus on Tregs. How epigenetic modifications alter Tregs function and whether this change is stable will be determined in children with ASD and GI co-morbidity. One of our long-term goals is to increase knowledge on the control of cellular immune mechanisms in ASD and how they relate to behavioral outcomes and co-occurring features such as GI symptoms. This proposal is innovative in the hypotheses to be addressed, the study population, the approach for finding epigenetic and immune biological signatures, and the cutting-edge methodology to be used. We expect to identify a panel of ~8-10 epigenetic and cellular indicators of deficient Tregs function in ASD children with GI comorbidity. Once developed, we expect these markers to be a qui
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810681
Entities
People
- Paul Ashwood
Organizations
- United States Army
- University of California, Davis