Dietary- and host-derived metabolites are used by diverse gut bacteria for anaerobic respiration

Abstract

Anaerobic respiration encompasses a major class of microbial energy metabolisms that employ reductases to respire different non-oxygen electron acceptors. Respiratory reductases play important roles in multiple geochemical cycles but their significance in other contexts remains unclear. 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 representative species from each family, we discover 22 metabolites used as respiratory electron acceptors in a species-specific manner. Identified respiratory reactions transform multiple classes of dietary- and host-derived fecal metabolites, including bioactive molecules like resveratrol and the immunometabolite itaconate. Reductase substrate-profiling identifies enzyme-substrate pairs and paints a striking picture of reductase evolution, including evidence that reductases with specificities for related cinnamate substrates but distinct mechanisms independently emerged at least four separate times. These studies define an exceptionally versatile form of respiration that directly links microbial central metabolism to the gut metabolome.

Distinct Energy-Coupling Factor Transporter Subunits Enable Flavin Acquisition and Extracytosolic Trafficking for Extracellular Electron Transfer in Listeria monocytogenes

“…As some bacteria use the same ATPase subunits to engage multiple ECF transport systems, we reasoned that the ATPases that function in the RibU ECF transporter flavin import system might also participate in FAD secretion ( 30 , 31 ). To test this hypothesis, we generated a Δ ecfA /Δ ecfA ′ strain that lacked both of the previously characterized RibU ATPases ( 19 ). Consistent with EcfA/EcfA′ being essential for FAD export, the Δ ecfA /Δ ecfA ′ strain was deficient in EET activity and PplA flavinylation and resembled Δ fmnA and Δ eetB strains in its response to ribDEAHT expression and exogenous FAD application ( Fig.…”

“…We further found that FmnB is essential for the flavinylation of the extracytosolic fumarate reductase FrdA, a flavin reductase encoded outside the EET gene cluster that uses fumarate as an electron acceptor ( 18 ). Strikingly, numerous extracytosolic flavin reductases that are related to fumarate reductase but use different electron acceptors (such as the small molecule urocanate) are found in diverse bacteria ( 4 , 18 , 19 ). Proteins flavinylated by FmnB in L. monocytogenes and related bacteria thus play critical roles in electron transfer to a variety of different extracytosolic electron acceptors.…”

A bile metabolite atlas reveals infection-triggered interorgan mediators of intestinal homeostasis and defense

“…4i), supporting the idea that reduced abundance of GCDH and SUGCT may explain elevations of glutarate in bile of infected animals (Fig.1i, j). Host pathways for the derivation of 2-methylsuccinate are not clear, but this dicarboxylate may in part be derived from the microbiota 32 .…”

“…Recently dicarboxylates, including itaconate have been found to be capable of supporting the respiration of gut microbiota 32 . In Eggerthella lenta , respiration of itaconate yields 2-methylsuccinate 32 , but little is known about the function of this dicarboxylate, which was elevated in the bile of infected animals (Fig. 1i, j).…”

“…Host pathways for the derivation of 2-methylsuccinate are not clear, but this dicarboxylate may in part be derived from the microbiota 32 .…”