The human microbiome exhibits significant variability among individuals and within body sites. Microbial interactions, including co-occurrence and co-exclusion, are crucial for this variation. Using data from the Human Microbiome Project (HMP), researchers constructed a global network of 3,005 significant microbial interactions among 197 clades across 18 body sites. This network revealed niche-specific relationships, with most associations occurring within body sites. For example, the oropharynx had three distinct habitats, while the vagina showed little region-specific interaction. Some interactions, like the co-exclusion of Porphyromonaceae and Streptococcus in subgingival plaque, were supported by biochemical dependencies. Other interactions, such as those between Bacilli and Fusobacteria, involved exclusion of taxa from other clades. The network also showed that dominant commensal taxa, like Prevotellaceae and Bacteroides in the gut, often compete, while potential pathogens, like Treponema and Prevotella in dental plaque, co-occur in complementary niches. The study used an ensemble method combining similarity measures and generalized boosted linear models (GBLMs) to detect these interactions, accounting for compositional data. The network highlighted the importance of phylogenetic and functional similarities in microbial interactions, with closely related microbes often co-occurring in similar niches. The study also identified key hubs, such as Firmicutes, that coordinate many relationships. The results suggest that microbial communities are structured by niche-specific interactions, with some interactions driven by competition, while others reflect functional complementarity. The findings provide insights into the ecological organization of the human microbiome and highlight the importance of understanding microbial interactions for future studies of health and disease.The human microbiome exhibits significant variability among individuals and within body sites. Microbial interactions, including co-occurrence and co-exclusion, are crucial for this variation. Using data from the Human Microbiome Project (HMP), researchers constructed a global network of 3,005 significant microbial interactions among 197 clades across 18 body sites. This network revealed niche-specific relationships, with most associations occurring within body sites. For example, the oropharynx had three distinct habitats, while the vagina showed little region-specific interaction. Some interactions, like the co-exclusion of Porphyromonaceae and Streptococcus in subgingival plaque, were supported by biochemical dependencies. Other interactions, such as those between Bacilli and Fusobacteria, involved exclusion of taxa from other clades. The network also showed that dominant commensal taxa, like Prevotellaceae and Bacteroides in the gut, often compete, while potential pathogens, like Treponema and Prevotella in dental plaque, co-occur in complementary niches. The study used an ensemble method combining similarity measures and generalized boosted linear models (GBLMs) to detect these interactions, accounting for compositional data. The network highlighted the importance of phylogenetic and functional similarities in microbial interactions, with closely related microbes often co-occurring in similar niches. The study also identified key hubs, such as Firmicutes, that coordinate many relationships. The results suggest that microbial communities are structured by niche-specific interactions, with some interactions driven by competition, while others reflect functional complementarity. The findings provide insights into the ecological organization of the human microbiome and highlight the importance of understanding microbial interactions for future studies of health and disease.