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 neurodevelopmental disorders such as autism, Fragile X syndrome, and Rett syndrome, as well as chromosomal disorders such as Down syndrome. 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, and failure to thrive. GI symptoms are reported in between 23-70% of individuals with autism, a rate ~ 8 times higher than in the general population, with similar rates in individuals with other less common forms of intellectual and developmental disabilities (IDD) (Holingue et al., Autism Res 2018:11:24-36). Unfortunately, mechanisms to accurately diagnose GI conditions in this population are limited, and tailored treatments to address them are almost nonexistent, particularly since clinical trials for IDD populations are rare.

Symptom management is often only partially effective with currently available treatments, and people with neurodevelopmental disabilities may not perceive pain and discomfort in a typical way or they might have impaired communication about the gastrointestinal symptoms they experience, making diagnosis a challenge for some. Their inability to articulate these symptoms may result in irritability, behavioral outbursts, and worsening of symptoms. Many families report that GI issues significantly negatively impact quality of life for these individuals and their family members, and that these symptoms can be a major cause of family distress. Thus, effective treatments for GI issues may address some of the observed behavioral issues in this population.

There is increasing evidence pointing to a correlation between the gut and the brain, and it stands to reason that disorders that affect the function of the brain would impact the function of the “brain” in the gut—the enteric nervous system. There has also been recent interest in the function of the gut microbiome in human health and disease, particularly the role of gut microbes in this gut-brain connection. Current research findings suggest that gut microbes affect neuronal circuits involved in motor control and anxiety behavior through signaling mechanisms. Recent research has also begun to focus on potential immunological and inflammatory factors affecting gastrointestinal function and complications related to feeding tubes. Moreover, the microbiome may play a role in pathogenesis, disease modification, and potentially, as a therapeutic target. The underlying role of enteric nervous system development and function in these disorders has not been fully characterized.

The National Institute of Diabetes and Digestive and Kidney Diseases is issuing this Notice to highlight interest in receiving grant applications focused in the following area(s) to support basic, translational, and/or clinical research on the causes, diagnosis, prevention, or treatment of gastrointestinal dysfunction in people with neurodevelopmental disorders. Interdisciplinary science in this area plays a pivotal role and projects are encouraged to include close collaboration between scientists with expertise in neurodevelopmental disorders and scientists with expertise in neurogastroenterology.  Areas of programmatic interest include, but are not limited to:

• Identifying the etiology of these conditions, including mechanisms involving the enteric nervous systems; brain/gut interactions; gut motility and function; neuroendocrine function; immunological or neuroimmunological factors; or other genetic or environmental susceptibility factors (such as socioeconomically disadvantaged populations)
• Understanding disease mechanisms (in the GI system) as they are influenced by the underlying neurodevelopmental disorder, including the correlation of GI symptoms with observed behavioral problems and/or other co-morbidities
• Developing model systems (e.g. animal, model organisms, cell or organ culture) to study GI pathogenesis and serve as screening platforms for more reliable diagnosis, prevention, or therapy development
• Understanding the role of nutrition, dietary interventions, or nutrient metabolism in these GI disorders
• Accurately diagnosing these GI conditions, including imaging- or electrophysiology-based techniques as well as non-invasive measures
• Understanding the role of the microbiome in these GI disorders
• Developing biomarkers (diagnostic, prognostic, predictive and pharmacodynamic/response) for use in clinical studies for these GI conditions or developing pharmacodynamic biomarkers for use in preclinical therapy development for the same GI conditions.
• Identifying therapeutic targets in the GI tract and developing treatments, including potential novel therapies or drug/biologic repurposing for these GI conditions

This notice applies to due dates on or after October 5, 2021 and subsequent receipt dates through July 16, 2024. 

NOT-DK-21-024