Faculty Bibliography

OBJECTIVES/OBJECTIVE:Individuals with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), often experience a higher prevalence of gastrointestinal (GI) symptoms but have complex medical and behavioral comorbidities that make diagnosis and treatment difficult. A multi-stakeholder conference was convened to (a) determine patient and family experiences related to GI symptoms in NDDs, (b) review the clinicians' and researchers' perspectives, and (c) determine actionable steps for future research. METHODS:The Consortium for Autism, Neurodevelopmental Disorders and Digestive Diseases (CANDID; www.candidgi.com) virtually over 2 days in 2022 and consisted of four key activities: (1) an electronic family survey to assess underlying NDDs and GI symptoms, (2) a session focused on family perspectives, (3) review current clinical care and research, and (4) discussion to identify key next steps. Survey results were obtained electronically via the REDCap platform, and descriptive statistics were generated. The sessions were recorded, and themes were identified. RESULTS:The pre-conference survey ran for ~2 months and 739 families provided responses, with 634 completing all items. 83% had a child with an NDD under age 18, and most patients were White (85%) and non-Hispanic (87%). Constipation (80%), gastrointestinal reflux disease (51%), and bloating (49%) were the most frequently reported symptoms. Families gave unstructured feedback that the measures used in the surveys were often difficult to answer for patients with NDDs or who were nonspeaking. Family and clinical/scientific sessions identified several common themes, including (1) the need for less invasive diagnostic modalities, (2) the need to validate or adapt existing diagnostic measures (e.g., the Rome IV criteria) and outcome assessments, and (3) the need for enhanced attention to parent and caregiver input in treatment plans. CONCLUSIONS:Those providing care to children with NDDs, especially those with communication and cognitive challenges, should be aware of the differing needs in this community and consider family perspectives in managing, treating, and measuring GI issues. Future research should focus on adapting or creating diagnostic and research measures for those with NDDs, developing new diagnostic methods to account for diversity in neurodevelopment and communication, and improving methods for family and caregiver engagement in the care of GI disorders.

Autism spectrum disorders (ASDs) are recognized as central neurodevelopmental disorders diagnosed by impairments in social interactions, communication and repetitive behaviours. The recognition of ASD as a central nervous system (CNS)-mediated neurobehavioural disorder has led most of the research in ASD to be focused on the CNS. However, gastrointestinal function is also likely to be affected owing to the neural mechanistic nature of ASD and the nervous system in the gastrointestinal tract (enteric nervous system). Thus, it is unsurprising that gastrointestinal disorders, particularly constipation, diarrhoea and abdominal pain, are highly comorbid in individuals with ASD. Gastrointestinal problems have also been repeatedly associated with increased severity of the core symptoms diagnostic of ASD and other centrally mediated comorbid conditions, including psychiatric issues, irritability, rigid-compulsive behaviours and aggression. Despite the high prevalence of gastrointestinal dysfunction in ASD and its associated behavioural comorbidities, the specific links between these two conditions have not been clearly delineated, and current data linking ASD to gastrointestinal dysfunction have not been extensively reviewed. This Review outlines the established and emerging clinical and preclinical evidence that emphasizes the gut as a novel mechanistic and potential therapeutic target for individuals with ASD.

INTRODUCTION/UNASSIGNED:Critical phases of neurodevelopment and gut microbiota diversification occur in early life and both processes are impacted by genetic and environmental factors. Recent studies have shown the presence of gut microbiota alterations in neurodevelopmental disorders. Here we performed a systematic review of alterations of the intestinal microbiota composition and function in pediatric and adult patients affected by autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and Rett syndrome (RETT). METHODS/UNASSIGNED:We searched selected keywords in the online databases of PubMed, Cochrane, and OVID (January 1980 to December 2021) with secondary review of references of eligible articles. Two reviewers independently performed critical appraisals on the included articles using the Critical Appraisal Skills Program for each study design. RESULTS/UNASSIGNED:sp. prevented the onset of Asperger and ADHD symptoms in adolescence. Micronutrient supplementation improved disease symptomatology in ADHD without causing significant changes in microbiota communities' composition. DISCUSSION/UNASSIGNED:Several discrepancies were found among the included studies, primarily due to sample size, variations in dietary practices, and a high prevalence of functional gastrointestinal symptoms. Further studies employing longitudinal study designs, larger sample sizes and multi-omics technologies are warranted to identify the functional contribution of the intestinal microbiota in developmental trajectories of the human brain and neurobehavior. SYSTEMATIC REVIEW REGISTRATION/UNASSIGNED:https://clinicaltrials.gov/, CRD42020158734.

Although it is most well-known for its roles in central nervous system (CNS) function, the vast majority of serotonin, or 5-hydroxytryptamine (5-HT), is produced in the gastrointestinal (GI) tract. 5-HT is synthesized mostly by enterochromaffin (EC) cells of the GI epithelium and, in small part, by neurons of the enteric nervous system (ENS). The GI tract contains an array of broadly distributed 5-HT receptors, which participate in functions such as motility, sensation, inflammation, and neurogenesis. The roles of 5-HT in these functions are reviewed, as well as its role in the pathophysiology of disorders of gut-brain interaction (DGBIs) and inflammatory bowel diseases (IBD). © 2023 American Physiological Society. Compr Physiol 13:4851-4868, 2023.

The enteric nervous system (ENS) is derived from both the vagal and sacral component of the neural crest (NC). Here, we present the derivation of sacral ENS precursors from human PSCs via timed exposure to FGF, WNT, and GDF11, which enables posterior patterning and transition from posterior trunk to sacral NC identity, respectively. Using a SOX2::H2B-tdTomato/T::H2B-GFP dual reporter hPSC line, we demonstrate that both trunk and sacral NC emerge from a double-positive neuro-mesodermal progenitor (NMP). Vagal and sacral NC precursors yield distinct neuronal subtypes and migratory behaviors in vitro and in vivo. Remarkably, xenografting of both vagal and sacral NC lineages is required to rescue a mouse model of total aganglionosis, suggesting opportunities in the treatment of severe forms of Hirschsprung's disease.