Children with Autism Spectrum Disorders are at increased risk of gastrointestinal symptoms

The gut is a major microbial-host interface, and a dominant immune organ. Immune function, hypothalamic-pituitary-adrenal (HPA) axis regulation, and the microbiota-gut-brain axis interact and co-evolve in the mother-infant complex adaptive system, and are each affected by stress. The infant gut microbiome in very early life has life-long effect on the settings of metabolism, immune, endocrine, and gut health. Gut dysbiosis is associated with impaired gut barrier integrity, inflammation and autoimmune disease.1, 2

Mothers of children with Autism Spectrum Disorders are twice as likely to report at least one gastrointestinal symptom in their child between 6-36 months. High-risk siblings have a greater prevalence of gastrointestinal symptoms. Young children diagnosed with ASD demonstrate significant gut dysbiosis.3 Chronic constipation is the most common gastrointestinal problem in children with ASD. Many children with ASD have functional gastrointestinal tract disorders relating to selective eating, medications, and differences in sensory processing, which are associated with increased anxiety.4 Gastrointestinal problems may worsen developmental cascades of child behavior problems and disrupted family interactions. Studies show a strong correlation between gastrointestinal dysfunction and autism severity, across all domains including speech, social and behavioral.5 Early clinical trials suggest that by targeting the gut ecosystem, both ASD and gastrointestinal tract symptoms can be impacted, suggesting potential shared mechanisms.4

Gut dysbiosis results from multiple interacting environmental factors

However, the NDC neurobiological model proposes that widespread inappropriate medicalisation of infant behavioral cues, usually as signs of gut problems, results in a failure to identify and manage the underlying environmental factors which precipitate chronic SNS-HPA hyperarousal in very early life. Inappropriate medicalisation of upregulated behavior and the failure to identify and manage underlying clinical problems have deleterious effects on gut health long-term. Instead of applying a linear and causative disease model which assumes that gut dysbiosis causes excessive infant crying, the neurobiological model of cry-fuss problems proposes that chronic SNS-HPA hyperarousal, proton pump inhibitors, and feeding problems interact in the complex adaptive system of the mother and infant, out of which gut dysbiosis emerges.6-9 The NDC model proposes that these and other environmental factors may disrupt parent-infant biobehavioral synchrony in very early life, precipitating multiple trajectories of atypical development in infants who are genetically susceptible to ASD.

Chronic inflammation and ASD

Chronic inflammation is emerging as the critical pathophysiological feature of mental disorders generally, associated with dysregulation of normal microglial synaptic pruning.2 Siniscalco hypothesizes that pro-inflammatory processes and immune alterations in very early life are etiological events for autism.10 ASD has been linked with:

• Increased pro-inflammatory cytokines in the cerebro-spinal fluid

• Acquired mitochondrial dysfunction, an early sign of neurodegeneration

• Decreased antioxidants in urine

• Higher plasma GABA levels

• Amino acid and neuropeptide disruptions

• Increased autoimmune antibodies targeting central nervous system proteins.

Chronic SNS-HPA hyperarousal releases cortisol, which alters intestinal motility, gut epithelial permeability, and induces changes in gut microbial composition. This paper argues that the pro-inflammatory state of children with ASD arises from chronic SNS-HPA hyperarousal, or stress and anxiety, with long-term multi-directional impacts upon gut health, behavior and immune trajectories.10-14

Excessive infant crying, or chronic SNS-HPA hyperarousal, is a pro-inflammatory state, impacting on gut microbiome and permeability, with long-term effects on metabolic, immune and mental health in susceptible infants.6, 15 The Affect Diathesis model theorises that behaviorally hypo-aroused infants also experience chronic SNS-HPA hyperarousal, with PNS override, which would be expected to similarly predispose to pro-inflammatory states.16 Anxiety disorder is common in adults with ASD, and symptoms of anxiety cause substantial functional impairment in ASD adults more broadly.4 The NDC model theorises that chronic anxiety and gastrointestinal problems in children and adults diagnosed with ASD are a downstream effect of chronic SNS-HPA axis dysregulation that begins in very early life.

References

1. Warner BB. The contribution of the gut microbiome to neurodevelopment and neuropsychiatric disorders. Pediatric Research. 2018:doi.org/10.1038/s41390-41018-10191-41399.
2. Cenit MC, Sanz Y, Codoner-Freanch P. Influence of gut microbiota on neuropsychiatric disorders. World Journal of Gastroenterology. 2017;23(30):5486-5498.
3. Coretti L, Paparo L, Riccio MP, Amato F, Cuomo M, Natale A. Gut microbiota features in young children with Autism Spectrum Disorders. Frontiers in Microbiology. 2018;9:3146.
4. Tye C, Runicles AK, Whitehouse AJO, Alvares GA. Characterizing the interplay between Autism Spectrum Disorder and comorbid medical conditions: an integrative review. Frontiers in Psychiatry. 2019;9:751.
5. Ding HT, Taur Y, Walkup JT. Gut microbiota and autism: key concepts and findings. Journal of Autism and Developmental Disorders. 2017;47:480-489.
6. Rhoads JM, Collins J, Fatheree NY, Hashmi SS, Taylor CMea, Luo M, et al. Infant colic represents gut inflammation and dysbiosis. Journal of Pedatrics. 2018;203:55-61.
7. Castellani C, Singer G, Kashofer K, Huber-Zeyringer A, Flucher C, Kaiser M, et al. The influence of proton pump inhibitors on the fecal microbiome of infants with gastroesophageal reflux - a prospective longitudinal interventional study. Frontiers in cellular and infection microbiology. 2017;111(7):444.
8. Douglas PS, Hill PS. A neurobiological model for cry-fuss problems in the first three to four months of life. Med Hypotheses. 2013;81:816-822.
9. Douglas PS, Hill PS. The crying baby: what approach? Curr Opin Pediatr. 2011;23:523-529.
10. Siniscalco D. Cmmentary: The impact of neuroimmune iterations in autism spectrum disorder. Frontiers in Psychiatry. 2015;6:doi:10.3389/fpsyt.2015.00145.
11. De Palma G, Collins SM, Bercik P, Verdu EF. The microbiota-gut-brain axis in gastrointestinal disorders: stressed bugs, stressed brain or both? Journal of Physiology. 2014;592:2989-2997.
12. Ding HT, Taur Y, Walkup JT. Gut microbiota and autism: key concepts and findings. Journal of Autism and Developmental Disorders. 2017;2017(47):480-489.
13. Carter CJ. Autism genes and the leukocyte transcriptome in autistic toddlers relate to pathogen interactomes, infection and the immune system. Neurochemistry International. 2019;126:36-58.
14. Gottfried C, Bambini-Junior V, Francis F, Riesgo R, Savino W. The impact of neuroimmune alterations in autism spectrum disorder. Hypothesis and Theory. 2015;6:doi:10.3389/fpsyt.2015.00121.
15. Partty A, Kalliomaki M, Salminen S, Isolauri E. Infantile colic is associated with low-grade systematic inflammation. Journal of Pediatric Gastroenterology and Nutrition. 2017;64(5):691-695.
16. Greenspan S. The Affect Diathesis Hypothesis: the role of emotions in the core deficit in autism and in the development of intelligence and social skills. Journal of Developmental and Learning Disorders 2002;5(1):1-44.