The use of prebiotics and probiotics to improve symptoms associated with autism spectrum disorder (ASD) has varied from study to study, indicating the complex and heterogeneous nature of the disorder and the behaviors and gastrointestinal symptoms associated with ASD. There is a wide variety in the severity of symptoms and developmental impediments across the population. Gut microbiome studies have also shown unique but varied microbial signatures in ASD. While there have been successes in pre-clinical and clinical trials with prebiotic and probiotic components, the limited population sizes have promising yet inconclusive results. This study addresses this issue by 1) enrolling an ASD cohort of 296 children and adults and comparing their deep DNA metagenomic sequencing of gut microbiomes to that of an age-matched neurotypical cohort and 2) individually formulating a precision synbiotic (probiotic and prebiotic) tailored towards each individual's needs and conducting pre/post evaluations of ASD and GI symptoms and longitudinal whole genome microbiome sequencing. At baseline, there was significantly lower microbiome diversity in the ASD group relative to controls. Microbes, pathways, and gene families significantly differed between the two populations. The ASD microbiome had higher abundances of pathogens, such as Shigella, Klebsiella, Mycobacterium, and Clostridium, but lower abundances of beneficial microbes, including Faecalibacterium. With a 3-month synbiotic supplementation, the microbiome diversity of the 170 ASD participants completing the study increased and became closer to the neurotypical controls. Significant shifts in microbial and pathway abundances were also measured at the second ASD timepoint. In addition to changes in the gut microbiome, there was a significant reduction in gastrointestinal discomfort. There were also improvements in some ASD-related symptoms; however, we cannot exclude that these were potentially due to the open-label nature of the study. Changes in the gut microbiome composition and functional capacity, along with a reduction in gastrointestinal symptoms and potential changes in behavior, highlight the importance of metagenomics, longitudinal studies, and the potential for therapeutic microbial supplementation in ASD.