Isolation of potentially novel species expands the genomic and functional diversity of Lachnospiraceae

The Lachnospiraceae family holds promise as a source of next-generation probiotics, yet a comprehensive delineation of its diversity is lacking, hampering the identification of suitable strains for future applications. To address this knowledge gap, we conducted an in-depth genomic and functional analysis of 1868 high-quality genomes, combining data from public databases with our new isolates. This data set represented 387 colonization-selective species-level clusters, of which eight genera represented multilineage clusters. Pan-genome analysis, single-nucleotide polymorphism (SNP) identification, and probiotic functional predictions revealed that species taxonomy, habitats, and geography together shape the functional diversity of Lachnospiraceae. Moreover, analyses of associations with atherosclerotic cardiovascular disease (ACVD) and inflammatory bowel disease (IBD) indicated that several strains of potentially novel Lachnospiraceae species possess the capacity to reduce the abundance of opportunistic pathogens, thereby imparting potential health benefits. Our findings shed light on the untapped potential of novel species enabling knowledge-based selection of strains for the development of next-generation probiotics holding promise for improving human health and disease management. We present a comprehensive exploration of Lachnospiraceae, leveraging an extensive cultured-based genome collection. Phylogenetic analysis reveals previously underestimated taxonomic diversity. A thorough gene set analysis, comprising a 1.5 M gene catalog, sheds light on the functional richness of Lachnospiraceae. Notably, exploration of short-chain fatty acid synthesis pathways highlights their synthetic potential, with strains displaying distinct capacities for butyrate and propionate production. Disease association analysis establishes correlations between Lachnospiraceae strains and atherosclerotic cardiovascular disease and inflammatory bowel disease, offering valuable insights into their potential roles in human health and disease. image Comprehensive genome analysis reveals underestimated species diversity and distinct functions of Lachnospiraceae. Cataloging 1.5 M genes highlights Lachnospiraceae's significant role in the human gut microbiota, with potential novel species contributing. Lachnospiraceae demonstrates a vast potential for synthesizing short-chain fatty acid (SCFA), producing secondary metabolites, and forming spores, which is promising for future studies and applications. The abundance of Lachnospiraceae correlates inversely with diseases like atherosclerotic cardiovascular disease (ACVD) and inflammatory bowel disease (IBD), indicating a potential protective role.