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Autism spectrum disorder (ASD) is a heterogeneous neuro-developmental disorder characterized by the core symptoms of impaired social interaction and communication abilities in addition to the presence of restricted and repetitive patterns of behaviors and interests. In addition, psychological symptoms (including anxiety and stress reactivity) and gastrointestinal symptoms, in particular exaggerated food selectivity, altered bowel habits (mainly constipation) and abdominal pain and discomfort are common comorbidities in ASD. Changes in the gut of animal models of ASD and in the gut microbiome of patients have led to the conceptualization of ASD as a brain gut disorder.

“The most recent reports in the US have put the prevalence of ASD at 1 in every 44 individuals.”

Even though genetic factors are likely to increase the risk of ASD, the worldwide prevalence of ASD has increased progressively and dramatically over the last three decades, suggesting an important role of the exposome (e.g. various environmental factors) including the dramatic change in maternal diet and metabolic health and exposure to environmental toxins that have evolved over the past 75 years. The most recent reports in the US have put the prevalence of ASD at 1 in every 44 individuals. The impact on the lives of affected children and their caregivers is enormous and the annual cost of caring for individuals with ASD in the US is projected to reach $461 billion by 2025. Despite being a major public health concern, a breakthrough in the pathophysiological understanding and in effective treatment strategies for the core symptoms remain elusive.

“…children with ASD have distinct gut microbiota profiles compared with neurotypical children.”

There is considerable scientific evidence that points to a possible role of the gut microbiome in the etiology of some ASD symptoms. Numerous studies have found that children with ASD have distinct gut microbial profiles compared with neurotypical children. However, the consistency and quality of these studies is limited (including no or little control for dietary patterns) and the largely epidemiological and cross sectional findings have not allowed to determine whether the observed alterations in gut microbial prevalence play a causative role in the pathophysiology of ASD. Alternatively, they may simply related to the often highly restricted dietary preferences or the influence of severe psychosocial stress and emotions common in affected children on the gut microbiome. Recent clinical studies from investigators at the University of Arizona have provided evidence that direct modulation of the gut microbiome by repeated fecal microbial transplants (FMTs), can reverse gut microbial alterations and some behavioral symptoms in children with ASD, and that some of these improvements are maintained over time. In a preliminary open-label trial (the Tapestry Autism Study), a small-molecule drug that reduces the absorption of a microbial metabolite has recently shown some improvement in anxiety and irritability in children with ASD, but whether this intervention improves some of the core ASD symptoms (i.e., social interaction, communication, and repetitive behaviors) is unknown.

To test the hypothesis that certain gut microbial species may have a therapeutic benefit in patients with ASD, an Italian research group at the Child Neurology and Psychiatry Unit, Department of Neurosciences, Policlinico Tor Vergata Foundation Hospital, in Rome performed a double-blind, randomized, placebo controlled, parallel-design pilot trial in 43 children with a diagnosis of ASD. The study aimed to investigate the possible clinical benefits of a 6 months treatment with the commensal bacterial species Limosilactobacillus (L.) reuteri (formerly known as Lactobacillus reuteri). The results were recently published in the prestigious journal Cell Host and Microbe by Luigi Mazzone and colleagues.

Preclinical studies had already shown that L. reuteri selectively reversed social deficits in several mouse models of ASD. The Italian researchers had discovered that L. reuteri selectively reversed the social deficits in a maternal high-fat-diet mouse model for neurodevelopmental disorders. Subsequent studies aimed at dissecting the mechanism(s) by which L. reuteri modulates social behavior revealed that the microorganism reverses the social deficits in ASD models through vagal nerve signaling to the brain, and promotes social reward by targeting the oxytocin dopaminergic reward network a critical pathway involved in social behaviors.

“…consumption of two different strains of L. reuteri, compared with placebo was safe and significantly improved social functioning and reduced social deficits…”

In their recent clinical trial, the research team found that the consumption of two different strains of L. reuteri, compared with placebo was safe and significantly improved social functioning and reduced social deficits as assessed by different validated questionnaires. However, the ingested microbes did not improve overall autism severity, restricted and repetitive behaviors, and co-occurring psychiatric, gastrointestinal and behavioral problems, nor did it significantly modulate the microbiome or the immune response. L. reuteri which is a normal constituent of the human gut microbiome has been certified as ‘‘generally recognized as safe’’ (GRAS) for use in humans by the United States Food and Drug Administration (FDA) and has already been safely administered to newborns within the first 3 months of life in a clinical trial for ASD-unrelated disorders. Based on their results, the authors concluded that consumption of L. reuteri microbial strains has the potential for improving social deficits associated with ASD in children.

“…gastrointestinal comorbidities and certain behavior aspects may be a more realistic target…”

Are the new research finding a breakthrough in the treatment of ASD? Even though current preclinical and clinical evidence suggest that L. reuteri administration is a simple and safe intervention to address one small segment of the ASD core symptoms, we still have a long way to go to reach the elusive goal of fully understanding ASD pathophysiology, and to develop effective therapies for this devastating disease. In my personal assessment of the challenge, I don’t believe that therapies targeted at the gut microbiome in children and adults with ASD will significantly alter the core symptoms, even though gastrointestinal comorbidities and certain behavior aspects may be a more realistic target. In my opinion, more research will have to focus on maternal factors. Specifically, the maternal microbiome, and maternal metabolic health and immune activation are major factors in ASD pathophysiology. As evidenced by the most commonly used mouse models for ASD (e.g. the maternal immune activation or the maternal high fat diet model), the detrimental influence of low grade systemic immune activation in the pregnant mother can have a major effect on fetal brain development resulting in irreversible structural and functional alterations on the newborn’s brain which manifest in ASD related behaviors in the first few years of life. Until convincing data from well controlled clinical trials emerge, microbiome targeted treatment interventions at this late developmental stage (e.g. infancy) are unlikely to have a major therapeutic effect on the core symptoms.