A bidirectional nanAKE locus enables sialic acid catabolism in gut microbiome member Hungatella hathewayi

Sialic acids are abundant components of host- and diet-derived glycans in the human gut and serve as important nutrients that shape microbial fitness and interspecies competition. Excess free sialic acids are also linked to inflammation and pathogen susceptibility. While well-studied gut bacteria such as E. coli and Bacteroides spp. catabolize sialic acids via the NanAKE or NanLE-RokA pathways, the metabolic capacity of many microbiome members remains undefined. To identify sialic acid catabolizing bacteria, we cultured fecal samples from healthy human donors. The gut anaerobe Hungatella hathewayi was selected under sialic acid-supplemented conditions. H. hathewayi is a poorly characterized gram-positive Lachnospiraceae associated with long-lived individuals and purine metabolism. Here we establish that H. hathewayi grows robustly on sialic acids as a sole carbon source using a pathway homologous to the canonical NanAKE system of E. coli, despite the species phylogenetic distance. We functionally validated these orthologs through growth assays and heterologous complementation in E. coli knockout strains. Comparative analyses further showed that key catalytic residues in H. hathewayi NanA are conserved despite overall sequence divergence from E. coli. Additionally, we find that colocalized sialic acid transporters and regulatory proteins are not orthologous to E. coli proteins and instead are related to proteins from other gut anaerobes. Together, these findings expand our understanding of sialic acid utilization within the human gut microbiome. We identify H. hathewayi as an overlooked but capable sialic acid degrader that can contribute to modulation of gut sialic acid levels and related inflammation. ImportanceSialic acids play an important role in mammalian and microbial signalling. Excess free sialic acids increase susceptibility to gut pathogens and induce inflammation. Gut bacteria can both generate and consume free sialic acids, and these pathways are conserved across diverse bacteria. E. coli and B. fragilis consume sialic acids as a carbon source, decreasing free sialic acid levels. We identify H. hathewayi as another bacteria capable of sialic acid consumption and define the enzymes responsible. H. hathewayi is a prevalent member of the human gut microbiome, but it is not genetically tractable, limiting enzymatic characterization. H. hathewayi is enriched in the gut microbiomes of long-lived individuals and expected to be an important contributor to purine degradation to limit gout risk. Defining sialic acid catabolism in non-model species is essential to understanding the evolution and conservation of this pathway as well as how nutrient competition shapes gut microbiome composition.