The article by Michelle G. Rooks and Wendy S. Garrett discusses the intricate relationship between the gut microbiota, metabolites, and host immunity. The authors highlight the importance of microbial communities in maintaining immune homeostasis and their influence on susceptibility to immune-mediated diseases. They review technological and computational approaches for studying the microbiome, including high-throughput DNA sequencing and metagenomic and metatranscriptomic sequencing. These methods have revealed the functional potential and real-time activity of microbiomes, providing insights into the interactions between microbial metabolism and host development. The article also emphasizes the role of specific microbial metabolites, such as short-chain fatty acids (SCFAs), in modulating immune responses and disease risk. SCFAs, produced by the fermentation of dietary components in the colon, have diverse regulatory functions, including inhibiting histone deacetylases (HDACs) and acting as ligands for G protein-coupled receptors (GPCRs). These effects contribute to immune homeostasis and can be therapeutic in inflammatory and autoimmune diseases. Additionally, the authors discuss the importance of microbial components, such as polysaccharide A (PSA), formyl peptides, and host-bacteria derived metabolites like high-bioavailability products (HBP), in driving innate immune responses. These components can activate pattern recognition receptors (PRRs) and initiate conserved signaling cascades, leading to the production of antimicrobial peptides, cytokines, and chemokines. The article concludes by emphasizing the complex crosstalk between the microbiota and the immune system, influenced by environmental cues. It underscores the need for further research to understand how microbial metabolites and components influence immune cell subsets and their functions, and highlights the potential of these findings in developing diagnostics and therapeutics for various diseases.The article by Michelle G. Rooks and Wendy S. Garrett discusses the intricate relationship between the gut microbiota, metabolites, and host immunity. The authors highlight the importance of microbial communities in maintaining immune homeostasis and their influence on susceptibility to immune-mediated diseases. They review technological and computational approaches for studying the microbiome, including high-throughput DNA sequencing and metagenomic and metatranscriptomic sequencing. These methods have revealed the functional potential and real-time activity of microbiomes, providing insights into the interactions between microbial metabolism and host development. The article also emphasizes the role of specific microbial metabolites, such as short-chain fatty acids (SCFAs), in modulating immune responses and disease risk. SCFAs, produced by the fermentation of dietary components in the colon, have diverse regulatory functions, including inhibiting histone deacetylases (HDACs) and acting as ligands for G protein-coupled receptors (GPCRs). These effects contribute to immune homeostasis and can be therapeutic in inflammatory and autoimmune diseases. Additionally, the authors discuss the importance of microbial components, such as polysaccharide A (PSA), formyl peptides, and host-bacteria derived metabolites like high-bioavailability products (HBP), in driving innate immune responses. These components can activate pattern recognition receptors (PRRs) and initiate conserved signaling cascades, leading to the production of antimicrobial peptides, cytokines, and chemokines. The article concludes by emphasizing the complex crosstalk between the microbiota and the immune system, influenced by environmental cues. It underscores the need for further research to understand how microbial metabolites and components influence immune cell subsets and their functions, and highlights the potential of these findings in developing diagnostics and therapeutics for various diseases.