Microbiome and metabolites impact enteric and central nervous systems in ALS

Amyotrophic lateral sclerosis (ALS) has been linked to gastrointestinal symptoms and alterations in the gut microbiota. The enteric nervous system (ENS) coordinates intestinal function and sits at the host-microbe interface. The mechanisms by which luminal changes relay to the central nervous system (CNS), where motor neurons reside, have yet to be completely defined. In this narrative review, we first present evidence from ALS patient cohorts and preclinical models alongside mechanistic studies of infection, dysbiosis, and related neurodegenerative diseases to discuss how the microbiota and its metabolites may affect the ENS and CNS in ALS. Next, we propose a plausible mechanism of ALS pathogenesis through the gut-microbiome-brain axis. We further offer a summary of clinical trials that have studied the impacts of the microbiota on human ALS. Finally, we discuss future directions for studies of microbiota-ENS-CNS interactions in ALS. Better understanding of the dynamic interactions among the microbiota, microbial metabolites, neuroactive metabolites, and inflammation through the ENS/CNS in ALS will provide innovative insights into ALS prevention and treatment.