Gastrointestinal Biomarkers in Preclinical Models of Angelman Syndrome

The role of the microbiota-gut-brain (MGB) axis in maintaining overall health and well-being is now well established. Host-microbe interactions are paramount for maintaining normal physiology, including the brain and behavior. Nevertheless, mechanisms by which gastrointestinal (GI) microbes communicate with the brain adversely impact a wide variety of behaviors are poorly understood. Since colonization by the gut microbiota begins at birth, and maturation of the GI tract and brain development continue during neonatal life, identifying pathways of establishment of communication between these organs is critical to maintaining health across the lifespan. Disruptions to the MGB axis due to the gut microbiota, mucosal barrier defects, and/or changes in behavior, occur in multiple diseases, including GI diseases (i.e., inflammatory bowel disease) and behavioral disorders (i.e., neurodevelopmental disorders (NDD), intellectual disabilities (ID), and autism spectrum disorders (ASD), epilepsies). 

Gastrointestinal (GI) complications in children and adults with neurodevelopmental disorders have drawn attention to gaps in understanding their causes and treatment. GI dysfunction is particularly common in individuals with NDDs such as ASD, Phelan-McDermid and Rett syndromes.  GI disorders in these conditions can include gut malformations present at birth (such as pyloric stenosis or Hirschsprung disease) but also functional issues such as feeding problems, gastro-esophageal reflux disease (GERD), cyclic vomiting, delayed gastric emptying, diarrhea, bloating, celiac disease, irritable bowel symptoms, and constipation leading to encopresis, incontinence, and stool impaction. These GI issues may be associated with severe nutritional deficiencies, weight loss, failure to thrive and lack of seizure control. Unfortunately, mechanisms to accurately diagnose GI conditions in specific rare genetic NDDs are limited, and tailored treatments to address them are nonexistent, since clinical trials for IDD populations are rare, to date.