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The relationship between the gut microbiome and exercise provides a unique opportunity to maximize the therapeutic capacity of the gut microbiome. Here, we summarize the potential of leveraging the gut microbiome to confer the health benefits of exercise through a novel class of microbial metabolites termed microbial-derived exerkines (MDEs). We identify multiple candidate and established MDEs described in the literature (e.g., pipecolic acid, succinate, short-chain fatty acids, indole-3-propionic acid, and 3-hydroxyphenylacetic acid) and explore their implications in conditions such as inflammatory bowel disease, aging, skeletal muscle atrophy, cancer, diabetes, cardiovascular disease, and Alzheimer\u2019s disease. 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