Translating priority effects and niche engineering into rational microbiome therapeutics across the gut-lung axis

The homeostasis of the human microbiome relies on "colonization resistance" governed by complex ecological rules. However, severe perturbations such as broad-spectrum antibiotics can dismantle this defense, shifting the microbial community into a "dysbiotic trap" driven by pathogen niche construction-an alternative stable state that is notoriously difficult to spontaneously reverse. This ecological mechanism explains the frequent failure of empirical therapies like fecal microbiota transplantation (FMT) and blind probiotic supplementation. Crucially, local ecological collapse triggers systemic cascades via the "gut-lung axis." The depletion of core gut metabolites, such as short-chain fatty acids, impairs the metabolic reprogramming and antimicrobial capacity of distal alveolar macrophages. This cascade drastically increases host susceptibility to respiratory infections. To break this clinical deadlock, microbiome medicine must transition from "empirical transplantation" to "rational microbiome engineering." This review systematically outlines the core pillars of this translational framework: achieving "precision niche clearing" via targeted bacteriophages; capturing optimal intervention windows to harness "priority effects"; and ultimately engrafting "synthetic microbial consortia" (SMCs) rationally designed upon metabolic cross-feeding principles. This strategy offers a promising avenue to durably shatter the dysbiotic deadlock and restore host immune homeostasis across the gut and systemic levels.