Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. The majority of ALS cases are sporadic with only about 20% of familial forms. Even in families with genetic predisposition, there is significant phenotypic variability, suggesting that ALS onset may be triggered by a combination of genetic factors, environmental factors (e.g., military service, deployments, exposures) (Beard and Kamel, 2015), lifestyle changes (e.g., cigarette smoke and dietary), and gut microbiome alteration. From our 2017 research paper demonstrating the beneficial role of the microbial metabolite butyrate (Zhang et al., 2017) to the newly approved Food and Drug Administration drug Relyvrio on September 29, 2022, the novel concepts and role of the gut microbiome and microbial metabolites in ALS pathogenesis have been slowly recognized by the neurology research field. Relyvrio is a combination of two drugs, sodium phenylbutyrate, and taurursodiol, that has been shown to reduce the rate of decline on a clinical assessment of daily functioning and is associated with longer overall survival (Paganoni et al., 2020). However, the role of sodium phenylbutyrate on intestinal function and microbiome in ALS progression was not included in the study, and research on metabolites correlated with the gut microbiome in ALS progression and treatment is still limited. A better understanding of the dynamic interactions among microbial metabolites, neuroactive metabolites, and inflammation in ALS will provide innovative insights into ALS prevention and treatment.