The profound health impacts of distinct long-term work environments, such as indoor sedentary versus outdoor physical labor, remain poorly understood at the microbial and metabolic levels. Here, using an integrated metagenomic and metabolomic approach, we systematically compared the oral and gut ecosystems of indoor sedentary workers (university teachers) and outdoor physical laborers (construction and transportation workers). Our analysis revealed stark, niche-specific differences: outdoor laborers exhibited higher salivary microbial diversity, reflecting greater environmental contact, whereas indoor workers displayed higher gut microbial diversity but a marked reduction in microbial resistance genes, aligning with lower pollutant exposure. Crucially, causal mediation analysis of the “environment-microbiome-metabolite” axis uncovered fundamentally different regulatory logics in oral versus gut niches. The oral ecosystem operates on a “push-and-pull” model of co-existing positive and negative mediation; notably, the indoor sedentary lifestyle elevates the key metabolic risk marker, uric acid, by suppressing purine-competing Prevotella species. In stark contrast, the gut ecosystem displays a deterministic architecture of uniform suppression, where diverse microbial shifts driven by the indoor workstyle converge in a “many-to-one” fashion to robustly inhibit a small set of metabolites, with a single exogenous steroid derivative acting as the primary target. These distinct signatures are highly predictive, with salivary metabolome data distinguishing the two groups with up to 98.04% accuracy. Collectively, this study establishes that multi-omics profiles serve as a sensitive “biological archive” of an individual’s work environment, offering novel biomarkers for health monitoring and forensic inference, and identifying tangible microbe-metabolite targets for precision interventions tailored to lifestyle-specific risks.