Exploring the role of microbial metabolites in human health guided by omics analysis

Abstract

The human microbiome possesses a vast potential for producing metabolites that can impact human health and disease. However, this potential remains largely unexplored. Understanding the intricate interactions between microbiome-derived small molecules and the host and other microbes holds significant implications for human health. With the exponential growth of human microbiome sequencing data in public databases, there is a tremendous opportunity for the discovery of bioactive small molecules. Harnessing the power of genome mining and omics data analysis will enable efficient identification and characterization of small molecules derived from the human microbiome. Chapter 1 provides an overview of the microbiomes’ role in maintaining human health through bioactive metabolites and their chemical interactions. Chapter 2 focuses on ribosomally synthesized and post-translationally modified peptides (RiPPs) in the human microbiome. Our study systematically analyzes 306,481 human microbiota-associated genomes, uncovering a broad array of yet-to-be-discovered RiPPs. These RiPPs are distributed across various body sites but show a specific enrichment in the gut and oral microbiome. Big data omics analysis reveals that numerous RiPP families are inversely related to various diseases, suggesting their potential positive effects on health. For a proof of principle study, guided by biosynthetic prediction, nine autoinducing peptides (AIPs) were chemically synthesized for in vitro and ex vivo assay. Our findings revealed that five AIPs effectively inhibit the biofilm formation of disease-associated pathogens, with one demonstrating significant anti-inflammatory capabilities. Furthermore, when ex vivo testing gut bacteria from mice with inflammatory bowel disease (IBD), we observed that two AIPs could regulate the microbial community and reduce harmful species. These findings highlight the vast potential of human microbial RiPPs in regulating microbial communities and maintaining human health, emphasizing their potential for therapeutic development. In Chapter 3, we utilized disease-related omics datasets to establish a direct connection between the biosynthesis of functional metabolites and human health. Using our unique biosynthetic enzyme-guided disease correlation approach and targeted chemoinformatic and metabolomic analyses, we investigated the relationship between Sulfonolipids (SoLs) biosynthesis and the development of IBD in humans. We further validated these correlations using a mouse model of IBD. Through cell-based assays, we explored the immunomodulatory activity of SoLs and identified their primary mechanism of action. Our findings indicate that SoLs exert their immunomodulatory effects by interacting with Toll-like receptor 4 (TLR4). Specifically, SoLs bind directly to TLR4 and displace lipopolysaccharide (LPS) at higher concentrations, suppressing TLR4 signaling pathways. This promotes an anti-inflammatory macrophage phenotype (M2 polarization) while inhibiting pro-inflammatory macrophage activation (M1 polarization). These results provide evidence for a bioinformatics-guided approach focusing on functional metabolites, shedding light on the chemical basis and molecular mechanisms underlying complex host-microbe interactions. Additionally, we propose a potential mechanism by which gut microbial SoLs contribute to protecting against IBD progression by disrupting LPS-mediated TLR4 signaling. Overall, we utilized genome mining and omics data analysis to identify potential microbial small molecules from the human microbiome and investigate their potential role(s) in human health.