| The Role of Fecal Microbiota Transplantation in the Treatment of Autism Spectrum Disorder


10.4


The Role of Fecal Microbiota Transplantation in the Treatment of Autism Spectrum Disorder


Thomas J. Borody, MD, PhD, DSc and Anoja W. Gunaratne, BAMS (Hon), MSc, PhD


Autism spectrum disorder (ASD) encompasses a heterogeneous group of child neurodevelopment conditions characterized by disorders in social interaction, verbal and nonverbal communication, sensory processing, and repetitive behaviors.1 In a 2014 report by the Centers for Disease Control and Prevention (CDC), the prevalence of ASD among 8-year-old children was found to have increased by 15% over the prior 2 years, resulting in 1 in 59 children having ASD.2 In up to 50% of children with ASD, development occurs typically until approximately 2 years of age, at which time regression and loss of previously acquired communication and social skills occurs.3,4 Treatment options are limited and include behavioral therapy, speech-language and/or social therapy, psychiatric medications for a specific cohort, and dietary and nutritional approaches.5 However, no treatments currently exist that target the underlying etiology or core symptoms of ASD.


Link Between the Gut Microbiome and Autism Spectrum Disorder


Although the etiopathogenesis of ASD remains unknown, increasing evidence suggests that the gut microbiome plays a pivotal role in the development and perpetuation of ASD symptoms. Prenatal and early-life antibiotic exposure are associated with an increased risk of ASD development.6,7 Recent evidence suggests that children with ASD have abnormal gut microbiome composition (dysbiosis), including increased levels of Clostridia, Lactobacillus, Collinsella, Corynebacterium, and Dorea and decreased Bacteroidetes, Alistipes, Bilophila, Dialister, Parabacteroides, and Veillonella species.8 Finegold et al9,10 demonstrated the presence of abnormal Clostridia and Desulfovibrio bacteria in the stool of children with ASD compared with controls. They postulated that neurotoxins manufactured by these pathogens are capable, either via circulation or by neuronal streaming, of crossing the blood-brain barrier to cause ASD-like symptoms. It has been demonstrated that children with ASD experience significantly higher rates of GI symptoms compared with healthy controls, including higher rates of diarrhea, constipation, and abdominal pain.11 Further, the severity of GI symptoms has been shown to positively correlate with disease severity, strengthening the link between a gut-brain connection in ASD.11 This section will review the current literature assessing the use of microbiome interventions, including FMT, in patients with ASD.


Manipulation of the Gut Microbiome in Autism Spectrum Disorder


Early studies using antibiotics have resulted in significant, albeit temporary, improvements in ASD symptoms. Vancomycin, one of the first studied antibiotics, is a nonabsorbable agent with broad activity against the dominant phyla of obligate anaerobes (Bacteroidetes and Firmicutes) in the intestine.12 In a pilot clinical trial that assessed the use of oral vancomycin for 8 weeks in children with ASD, dramatic reversal of ASD symptoms and improvement in gut symptoms were observed in 8 of 10 patients.13 However, the benefits were lost a few weeks after stopping treatment, pointing to the need for continuing intervention.12 In another study, 6 months of antibiotics (amoxicillin and/or azithromycin) helped to reduce ASD symptoms and improve behavior.14


Clinical studies examining the use of prebiotics and probiotics in ASD treatment have shown mixed effects on ASD symptoms.1521 Multiple studies have shown improvements in GI symptoms, irritability scores, concentration, carrying out orders, and behavior after either prebiotics or probiotic supplementation in children with ASD.1520 One placebo-controlled study (N = 39) showed lower levels of Clostridioides in stools after probiotics (Lactobacillus plantarum) supplementation; however, no major differences in behavior or GI symptoms were observed.22


More recently, FMT has been used as a treatment for ASD, with promising results (Table 10.4-1).2326 A number of methods have been used to administer FMT to adults and children, including raw, homogenized, and filtered fresh FMT material and lyophilized FMT material (encapsulated or as powder) to facilitate delivery to the entire GI tract.27,28 In an open-label study conducted in 18 children with ASD, FMT for up to 8 weeks led to a 82% reduction in GI symptoms and significant improvements in core ASD symptoms by 22% (language, social interaction, and behavior measured by the validated Childhood Autism Rating Scale) compared with baseline, which corresponded with increased microbial diversity.24 At 2-year follow-up of these children, most GI symptom improvements were maintained, and ASD-related symptoms further improved at the 2-year review, with 44% of participants below the ASD diagnostic cut-off scores (Figure 10.4-1).25 After FMT, Bacteroidetes and Firmicutes increased and Clostridioides was inhibited in the GI tract.24,25 No significant safety concerns were observed, and the treatment was well-tolerated. A limitation of this promising study is that it was uncontrolled with a patient-reported outcome and there was an absence of dose-finding preliminary work to identify the starting dose regimen. Additionally, it is unclear whether pretreatment antibiotics and bowel lavage are required for clinical efficacy. Notably, it took 5 to 6 weeks of daily FMT for GI symptoms to appropriately respond, supporting the role of maintenance therapy. Following this proof-of-principle study, dose and dose-regimen studies are needed, and once the ideal dose regimen is identified, placebo-controlled trials are warranted.


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May 23, 2021 | Posted by in GASTROENTEROLOGY | Comments Off on | The Role of Fecal Microbiota Transplantation in the Treatment of Autism Spectrum Disorder

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