Pediatric neuropsychiatric syndromes associated with infection and microbiome alterations: clinical findings, possible role of the mucosal epithelium, and strategies for the development of new animal models

ABSTRACT

Introduction

Pediatric obsessive-compulsive disorder (OCD) and autism spectrum disorder (ASD) have been associated with respiratory tract infections and alterations in the intestinal microbiome, respectively. Pediatric Acute-onset Neuropsychiatric Syndromes (PANS) refers to the sudden onset of neuropsychiatric symptoms that are triggered by several infectious and non-infectious factors. Studies indicate that inflammation plays an important etiological role in PANS, as well as in ASD associated with gut dysbiosis.

Areas Covered

The present review provides an overview of clinical studies of PANS and ASD associated with gastrointestinal symptoms, as well as existing strategies for investigating these syndromes in rodent models. The authors highlight similarities between these syndromes that may provide clues to common etiological mechanisms.

Expert opinion

Although data from animal models are consistent with an important role for anti-neuronal antibodies in PANS triggered by GAS infection, we lack models for identifying pathophysiological mechanisms of PANS associated with other infectious and noninfectious triggers. The authors propose an animal modeling strategy that incorporates known vulnerability and triggering factors for PANS into the modeling process. This novel strategy should expand our understanding of the pathophysiology of PANS, as well as facilitate the development of new pharmacological treatments for PANS and related syndromes.

KEYWORDS:

• Antineuronal antibodies
• autism spectrum disorder
• autoimmunity
• microbiome
• mucosal epithelium
• obsessive-compulsive disorder
• PANDAS
• PANS
• tics disorders
• tourette’s syndrome

Article highlights

• In pediatric patients, neuropsychiatric symptoms such as obsessive-compulsive symptoms, tics, and restrictive eating can occur abruptly in association with certain infectious and non-infectious triggers; this syndrome is called Pediatric Acute-onset Neuropsychiatric Syndrome (PANS).

• Autism spectrum disorder (ASD) has been associated with gastrointestinal symptoms and alterations in the gut microbiome.

• A number of strategies have been developed for modeling neuropsychiatric symptoms associated with group A beta-hemolytic streptococcal (GAS) infection (‘strep throat’), including immunization and infection with GAS, and administration of GAS antibodies.

• Strategies that have been applied for investigations on the microbiome-gut-brain axis and its association with ASD and other neuropsychiatric symptoms include the use of germ free animals, antibiotic treatment, microbiota transfer, and probiotics.

• There are several commonalities between PANS and ASD associated with gastrointestinal symptoms indicating that immune processes that occur within the mucosal epithelium most likely have a fundamental pathogenic role in both syndromes.

• Strategies for developing new rodent models for PANS should incorporate known vulnerability and triggering factors, such as altered immune function, allergy, respiratory infection, and stress, into the modeling process.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.