Exceptionally versatile respiratory metabolisms drive metabolite production by diverse gut bacteria

Within anaerobic ecosystems microbial respiration encompasses a major class of energy metabolisms that employ distinct reductases to respire diverse electron acceptors. Here we identify three taxonomically distinct families of gut bacteria that encode exceptionally large arsenals of tens-to-hundreds of respiratory-like reductases per genome. By screening species from each family, we discover 22 metabolites used as respiratory electron acceptors in a species-specific manner. Identified reactions transform multiple classes of dietary- and host-derived metabolites, including bioactive molecules resveratrol and itaconate. Products of identified respiratory metabolisms highlight poorly characterized gut metabolites, such as the product of itaconate respiration 2-methylsuccinate. Reductase substrate-profiling defines enzyme-substrate pairs and reveals a complex picture of reductase evolution, providing evidence that reductases with specificities for related cinnamate substrates independently emerged at least four times. These studies thus define an exceptionally versatile form of anaerobic respiration that directly links microbial energy metabolism to the gut metabolome.