Interkingdom Interactions in the Gut: Ecological Mechanisms, Homeostasis, and Therapeutic Modulation

ABSTRACT The gut microbiota constitutes a highly complex and dynamic ecosystem that profoundly influences host physiology, metabolism, and immunity. This review provides an integrative overview of the mechanisms through which gut microorganisms—particularly bacteria and fungi—interact with host cells and with each other to maintain intestinal homeostasis. We first summarize the key microbial factors, including surface structures, extracellular vesicles, and metabolites such as short‐chain fatty acids, bile acids, and tryptophan derivatives, which mediate host–microbe cross talk. We then discuss the pivotal role of the gut mycobiota in immune education and metabolic balance, as well as the cooperative and antagonistic interkingdom interactions shaping gut ecological stability. Thirdly, we highlight host regulatory mechanisms—including immune responses, secretory molecules, and extracellular vesicles—that modulate microbial composition. Finally, we examine emerging microbiome‐targeted interventions, including fecal microbiota transplantation, probiotics, prebiotics, phage therapy, engineered microbes, and traditional medicine‐based strategies. Understanding the molecular and ecological principles governing microbiota–host interactions will be key to developing precision microbiome therapeutics for maintaining health and combating dysbiosis‐related diseases.