From Gut to Genome: Systems‐Level Microbiome Signaling in Inter‐Organ Communication in Health and Disease

ABSTRACT Gut microbiome has emerged as a pivotal regulator of host physiology, extending its influence beyond gastrointestinal homeostasis to the coordinated regulation of multiple distant organs. This regulation is mediated through an intricate network of microbial metabolites, immune mediators, neuroactive compounds, and epigenetic modulators that collectively facilitate inter‐organ communication and systemic homeostasis. Among the key microbial‐derived molecules, short‐chain fatty acids (SCFAs), secondary bile acids, and tryptophan metabolites play fundamental roles in modulating host metabolic, immune, and neuroendocrine signaling pathways. In parallel, microbiota‐driven cytokine production and neurotransmitter synthesis contribute to bidirectional gut‐organ axes, including gut‐brain, gut‐liver, gut‐heart, and gut‐kidney axes. Disruption of these tightly regulated signaling networks leads to microbial dysbiosis, which is increasingly implicated in the pathogenesis of metabolic syndrome, neurodegenerative disorders, cardiovascular diseases, and immune‐mediated conditions. Recent advancements in multi‐omics technologies, including metagenomics, transcriptomics, metabolomics, and epigenomics, alongside systems biology and computational modeling, have enabled high‐resolution characterization of microbiome–host interactions and mechanistic insights into disease associations. This review consolidates current evidence on systems‐level microbiome signaling, highlighting molecular mediators, inter‐organ communication pathways, and disease relevance. Furthermore, it highlights emerging translational strategies such as microbiome‐based therapeutics, precision nutrition, and biomarker development. By synthesizing findings across microbiology, immunology, neuroscience, and systems biology, this work provides a comprehensive framework for understanding how gut microbial networks interface with host regulatory systems to influence health and disease trajectories.