Nitric Oxide (NO) is a simple molecule consisting of one atom of nitrogen and one of oxygen, making it even simpler than water. Research into the effects of this small but important molecule began in the 1970’s when scientists started to examine why blood vessels relaxed when certain compounds were added. This led to the discovery of NO and its amazing effects in the body, with NO being named the molecule of the year in 1992. In 1998, twenty-some years after this research first began, a Nobel Prize was awarded to these researchers for their breakthrough discoveries regarding NO. Over
While researchers do not yet know why, they doknow that the rate of autism is increasing. According to the 2018 Report of the National Autism Spectrum Disorder Surveillance System, an estimated 1 in 66 children have been diagnosed with autism spectrum disorder (ASD).[i] ASD is a neurodevelopmental disorder and refers to a range of conditions characterized by challenges with social skills, repetitive behaviours, speech, and nonverbal communication, as well as by unique strengths and differences.[ii] There is not one form of autism but rather many types, caused by different combinations of genetic and environmental influences.[iii]
Currently, physicians diagnose the neurodevelopmental condition based on behavioral symptoms. ASD has neither a distinct pathogenesis nor pharmaceutical treatment. This type of chronic, multifaceted health condition is incredibly challenging for the Western, conventional medical model in which researchers usually target a single pathogen, gene, or faulty mechanism responsible. Autism can affect the whole body. For example, children with autism are nearly eight times more likely to suffer from one or more chronic gastrointestinal disorders than are other children.[iv] An accumulation of evidence also demonstrates immune dysfunction and inflammation in specific brain regions of children diagnosed with the neurodevelopmental condition.[v]
The Role of Inflammation
A collaborative group of researchers in Boston and Italy have discovered that pro- and anti-inflammatory cytokines apparently play roles in ASD. Susan Leeman of Boston University and her colleagues described cytokine influences that are unique to autism. They pinpointed a type of cytokines called interleukins, which flourish in regions of the brain associated with behavior. Interleukins (IL) are involved in a vast array of activities, including cell signaling and both triggering and tamping down inflammation. In the Proceedings of the National Academy of Sciences the researchers explain: “IL-37, an anti-inflammatory cytokine, is increased along with the pro-inflammatory cytokine IL-18 and its.”[vi] Other researchers from Harvard University and the University of Chieti in Pescara, Italy also participated in the groundbreaking investigation. According to them, because IL-37 is produced in an attempt to quell the flow of pro-inflammatory proteins, the development of IL-37 as a potential therapeutic agent could provide the first targeted medication for ASD. However, Leeman also mentioned that other inflammatory proteins are present in the brains of children with autism such as interleukin-1-beta, tumor necrosis factor, and chemokine ligand 8.
A Reductionist Approach?
Although other interleukin-based agents are used to dampen inflammation in certain diseases such as cancer, could an IL-37-derived medication address all the inflammatory processes found in autism? And will quenching inflammation translate into significant improvement in their condition? Inflammation is an immune response to an aggression so will halting this process without addressing the trigger be causing more harm than good? Moreover, it is important to keep in mind that correlation does not always translate into causation. The fact that inflammation is present in the brain of children with autism does not necessarily mean that it is the cause.
My experience as a clinician working with ASD patients for a decade has proven to me time and time again that we are dealing with a multifactorial condition involving different causative factors, intertwined in various ways through a particular chain of events which arespecific to each child. Trying to narrow autism down to a single cause might prove to be too simplistic and overlooking the fact that many effects may result from some complex combination of partial causes.
Leaky gut, Leaky Brain
In any case, there are several ways that we can address the cause of inflammation and reduce it naturally while we wait for these ‘wonder-drugs’. Given the prevalence of gastrointestinal disorders amidst this population, adopting an anti-inflammatory diet is a crucial element. The gluten-free, casein-free diet is a popular dietary intervention for children on the ASD. Clinical observations describe increased intestinal permeability in these patients and permeability to food antigens derived from the incomplete digestion of wheat (gliadorphins) and cow’s milk (casomorphins) has been reported.[vii] A group of researchers led by Maria Fiorentino and involving Dr Fasano – a specialist on gluten sensitivity and gut hyperpermeability – investigated whether an altered gut permeability and permissive blood–brain barrier (BBB) were part of the pathophysiology of ASD. They hypothesized that inappropriate antigen trafficking through an impaired intestinal barrier, followed by passage of these antigens or immune-activated complexes through a ‘leaky’ BBB could be part of the chain of events leading to these disorders. Fiorentino and her colleagues concluded that there is an altered expression of genes associated with BBB integrity coupled with increased neuroinflammation and possibly impaired gut barrier integrity in the ASD brain.[viii] Beyond eliminating gluten and possibly dairies, we have to consider improving the gut’s microbiome with probiotics and to support its integrity with glutamine supplementation.
Natural Inflammation Modulators
Different natural substances such as omega-3 fatty acids[ix], curcuma (Curcuma longa)[x], boswellia (Boswellia serrata)[xi] and palmitoylethanolamide (PEA)[xii] are all well-documented, evidence-based natural means to modulate inflammation in the body. Among them, PEA might be of particular interest.
PEA is a long chain fatty acid naturally produced by the body under stressful conditions but also found in foods such as egg yolk, soy, and sunflower oils. This molecule is now receiving attention because of its crucial role in the endocannabinoid system (ECS) but it has been researched for its unique and varied health benefits for 80 years. Among these benefits, PEA has been shown to inhibit inflammatory responses and to prevent glutamatergic toxicity.[xiii] Since glutamate excitotoxicity has also been proposed to participate in the propagation of autism, a group of researchers probed the efficacy of co-treatment with risperidone and PEA over 10 weeks in children with autism. The randomized, parallel group, double-blind placebo-controlled trial was the first of its kind. In the study, 70 children (aged 4-12 years) with autism and moderate to severe symptoms of irritability were randomly assigned to two treatment regimens: risperidone plus PEA or risperidone plus placebo. The findings published in the Journal of Psychiatric Research (2018) suggest that PEA may augment therapeutic effects of risperidone on autism-related irritability and hyperactivity.[xiv]
Although many promising avenues are being investigated in the hope of curing autism and managing its symptoms, we must bear in mind that when addressing a multifactorial condition, we may have to come up with an arsenal of solutions. Beyond pharmacological options, safe, effective, evidenced-based natural tools should also be part of our therapeutic options.
[i] Autism Prevalence among Children and Youth in Canada. 2018 Report of the National Autism Spectrum Disorder (ASD) Surveillance System. https://www.canada.ca/en/public-health/services/publications/diseases-conditions/infographic-autism-spectrum-disorder-children-youth-canada-2018.html
[v] Ricks, Delthia. Medical Xpress. Inflammation and autism—an important piece of the puzzle. OCTOBER 22, 2019. https://medicalxpress.com/news/2019-10-inflammation-autisman-important-piece-puzzle.html
[vi] Irene Tsilioni et al. IL-37 is increased in brains of children with autism spectrum disorder and inhibits human microglia stimulated by neurotensin, Proceedings of the National Academy of Sciences (2019). DOI.org/10.1073/pnas.1906817116.
[vii] Fiorentino, M., Sapone, A., Senger, S. et al. Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders. Molecular Autism 7, 49 (2016). https://doi.org/10.1186/s13229-016-0110-z https://link.springer.com/article/10.1186/s13229-016-0110-z#citeas
[viii] Fiorentino, M., Sapone, A., Senger, S. et al. Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders. Molecular Autism 7, 49 (2016). https://doi.org/10.1186/s13229-016-0110-z https://link.springer.com/article/10.1186/s13229-016-0110-z#citeas
[x] Hewlings SJ, Kalman DS. Curcumin: A Review of Its’ Effects on Human Health. Foods. 2017;6(10):92. Published 2017 Oct 22. doi:10.3390/foods6100092 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664031/
[xi] Siddiqui MZ. Boswellia serrata, a potential antiinflammatory agent: an overview. Indian J Pharm Sci. 2011;73(3):255-261. doi:10.4103/0250-474X.93507 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309643/
[xii] Khalaj M, Saghazadeh A, Shirazi E, et al. Palmitoylethanolamide as adjunctive therapy for autism: Efficacy and safety results from a randomized controlled trial. J Psychiatr Res. 2018;103:104-111. doi:10.1016/j.jpsychires.2018.04.022 https://pubmed.ncbi.nlm.nih.gov/29807317/
[xiii] Khalaj M, Saghazadeh A, Shirazi E, et al. Palmitoylethanolamide as adjunctive therapy for autism: Efficacy and safety results from a randomized controlled trial. J Psychiatr Res. 2018;103:104-111. doi:10.1016/j.jpsychires.2018.04.022 https://pubmed.ncbi.nlm.nih.gov/29807317/
[xiv] Khalaj M, Saghazadeh A, Shirazi E, et al. Palmitoylethanolamide as adjunctive therapy for autism: Efficacy and safety results from a randomized controlled trial. J Psychiatr Res. 2018;103:104-111. doi:10.1016/j.jpsychires.2018.04.022 https://pubmed.ncbi.nlm.nih.gov/29807317/