Identification of the Bacterial Biosynthetic Gene Clusters of the Oral Microbiome Illuminates the Unexplored Social Language of Bacteria during Health and Disease

Abstract

Small molecules are the primary communication media of the microbial world. Recent bioinformatic studies, exploring the biosynthetic gene clusters (BGCs) which produce many small molecules, have highlighted the incredible biochemical potential of the signaling molecules encoded by the human microbiome. Thus far, most research efforts have focused on understanding the social language of the gut microbiome, leaving crucial signaling molecules produced by oral bacteria and their connection to health versus disease in need of investigation. In this study, a total of 4,915 BGCs were identified across 461 genomes representing a broad taxonomic diversity of oral bacteria. Sequence similarity networking provided a putative product class for more than 100 unclassified novel BGCs. The newly identified BGCs were cross-referenced against 254 metagenomes and metatranscriptomes derived from individuals either with good oral health or with dental caries or periodontitis. This analysis revealed 2,473 BGCs, which were differentially represented across the oral microbiomes associated with health versus disease. Coabundance network analysis identified numerous inverse correlations between BGCs and specific oral taxa. These correlations were present in healthy individuals but greatly reduced in individuals with dental caries, which may suggest a defect in colonization resistance. Finally, corroborating mass spectrometry identified several compounds with homology to products of the predicted BGC classes. Together, these findings greatly expand the number of known biosynthetic pathways present in the oral microbiome and provide an atlas for experimental characterization of these abundant, yet poorly understood, molecules and socio-chemical relationships, which impact the development of caries and periodontitis, two of the world’s most common chronic diseases. IMPORTANCE The healthy oral microbiome is symbiotic with the human host, importantly providing colonization resistance against potential pathogens. Dental caries and periodontitis are two of the world’s most common and costly chronic infectious diseases and are caused by a localized dysbiosis of the oral microbiome. Bacterially produced small molecules, often encoded by BGCs, are the primary communication media of bacterial communities and play a crucial, yet largely unknown, role in the transition from health to dysbiosis. This study provides a comprehensive mapping of the BGC repertoire of the human oral microbiome and identifies major differences in health compared to disease. Furthermore, BGC representation and expression is linked to the abundance of particular oral bacterial taxa in health versus dental caries and periodontitis. Overall, this study provides a significant insight into the chemical communication network of the healthy oral microbiome and how it devolves in the case of two prominent diseases.

Deep metagenomics examines the oral microbiome during dental caries, revealing novel taxa and co-occurrences with host molecules

“…The gingival health condition of each subject was assessed using the Gingival Index (GI) (79). GI data was published previously (80). Additionally, parent/guardian of each participant completed a survey regarding oral health regimen. Radiographic Assessment.…”

CariogenicStreptococcus mutansproduces strain-specific antibiotics that impair commensal colonization

“…Although two antibiotics have been discovered from the commensal bacteria of human, including lactocillin(13) and lugdunin(35), RTCs, to our knowledge, are the first group of low molecular weight antibacterial molecules identified from a human opportunistic pathogen. While this study merely scrapes the “tip of the iceberg” of the recently identified oral biosynthetic potential(13, 36), these findings clearly exemplify that deeper exploration of leads provided by genome mining studies will help elucidate the complex ecological underpinnings of the human microbiome and its relationship to disease.…”

A Systematic Analysis of Mosquito-Microbiome Biosynthetic Gene Clusters Reveals Antimalarial Siderophores that Reduce Mosquito Reproduction Capacity

“…As a relevant disease vector, Aedes -associated bacteria were also included in our data set. Due to the limited amount of genome sequencing data on mosquito-associated bacteria, especially when compared to human microbiomes, our sample size is smaller than analogous studies (Aleti et al, 2019; Donia et al, 2014; Helfrich et al, 2018), however this enabled an in-depth bioinformatic analysis. Despite this size, our data set well-represents the unique gut microbiome of mosquitoes.…”

“…Bioinformatic tools that predict BGCs is one route to reveal the biosynthetic potential of a microbial community. This approach has been utilized to survey the human gut (Donia et al, 2014) and oral microbiomes (Aleti et al, 2019) as well as plant microbiomes (Helfrich et al, 2018), however it has yet to be applied to insect microbiomes.…”