The intestinal lining is protected by a mucous barrier composed predominantly of complex carbohydrates. Gut microbes employ diverse glycoside hydrolases (GHs) to liberate mucosal sugars as a nutrient source to facilitate host colonization. Intensive catabolism of mucosal glycans, however, may contribute to barrier erosion, pathogen encroachment, and inflammation. Sialic acid is an acidic sugar featured at terminal positions of host glycans. Characterized sialidases from the microbiome belong to the GH33 family, according to CAZy (Carbohydrate-Active enZYmes Database). In 2018 a functional metagenomics screen using thermal spring DNA uncovered the founding member of the GH156 sialidase family, the presence of which has yet to be reported in the context of the human microbiome. A subset of GH156 sequences from the CAZy database containing key sialidase residues was used to build a hidden Markov model. HMMsearch against public databases revealed ~10x more putative GH156 sialidases than currently cataloged by CAZy. Represented phyla include Bacteroidota, Verrucomicrobiota, and Firmicutes_A from human microbiomes, all of which play notable roles in carbohydrate fermentation. Analyses of metagenomic data sets revealed that GH156s are frequently encoded in metagenomes, with a greater variety and abundance of GH156 genes observed in traditional hunter-gatherer or agriculturalist societies than in industrialized societies, particularly relative to individuals with inflammatory bowel disease (IBD). Nineteen GH156s were recombinantly expressed and assayed for sialidase activity. The five GH156 sialidases identified here share limited sequence identity to each other or the founding GH156 family member and are representative of a large subset of the family. [ABSTRACT FROM AUTHOR]