Metabolic cross-feeding of a dietary antioxidant enhances anaerobic energy metabolism by human gut bacteria

The degradation of complex carbohydrates and other macromolecules by human gut bacteria generates metabolites that are used by neighboring microbes for anaerobic respiration. However, it is largely unknown whether cross-feeding of other dietary compounds can drive energy-yielding redox reactions in the gut. We show that gut bacteria from different phyla cross-feed a common dietary antioxidant to produce energy under anaerobic conditions. Clostridium symbiosum encodes ergothionases that transform ergothioneine, a mushroom-derived antioxidant, into the electron acceptor thiourocanic acid (TUA). TUA is reduced by Bacteroides xylanisolvens, increasing bacterial ATP synthesis and growth. Furthermore, TUA is selectively produced and consumed by certain human fecal microbial communities. Consistent with emerging links between intestinal ergothioneine homeostasis and colorectal cancer, ergothionase is significantly enriched in fecal metagenomes from colorectal cancer patients. Together, these results illustrate how commensalistic cross-feeding of an antioxidant nutrient enhances microbial energy metabolism, which may contribute to interpersonal differences in disease risk.