Alcohol overuse disrupts liver function and alters gut microbial communities, with alcohol-related liver disease (ALD) causing half of all liver-related deaths worldwide. Bile acids (BAs) regulate liver and gut function, but their homeostasis becomes disrupted in ALD. Gut microbes transform primary BAs to secondary BAs, which are reabsorbed via enterohepatic circulation, but BA metabolism during ALD progression remains poorly understood.

Microbes are ubiquitous on Earth, forming microbiomes that sustain macroscopic life and biogeochemical cycles. Microbial dispersal, driven by natural processes and human activities, interconnects microbiomes across habitats, yet most comparative studies focus on specific ecosystems. To study planetary microbiome structure, function, and inter-habitat interactions, we systematically integrated 85,604 public metagenomes spanning diverse habitats worldwide. Using species-based unsupervised clustering and parameter modeling, we delineated 40 habitat clusters and quantified their ecological similarity. Our framework identified key drivers shaping microbiome structure, such as ocean temperature and host lifestyle. Regardless of biogeography, microbiomes were structured primarily by host-associated or environmental conditions, also reflected in genomic and functional traits inferred from 2,065,975 genomes. Generalists emerged as vehicles thriving and facilitating gene flow across ecologically disparate habitat types, illustrated by generalist-mediated horizontal transfer of an antibiotic resistance island across human gut and wastewater, further dispersing to environmental habitats, exemplifying human impact on the planetary microbiome.

Understanding the human gut microbiome requires comprehensive genomic catalogues, yet many lack geographic diversity and contain medium-quality metagenome-assembled genomes (MAGs) missing up to 50% of genomic regions, potentially distorting functional insights. Here we describe an enhanced Human Reference Gut Microbiome (HRGM2) resource, a catalogue of near-complete MAGs (≥90% completeness, ≤5% contamination) and isolate genomes. HRGM2 comprises 155,211 non-redundant near-complete genomes from 4,824 prokaryotic species across 41 countries, representing a 66% increase in genome count and a 50% boost in species diversity compared to the Unified Human Gastrointestinal Genome catalogue. It enabled improved DNA-based species profiling, resolution of strain heterogeneity and survey of the human gut resistome. The exclusive use of these genomes improved metabolic capacity assessment, enabling high-confidence, automated genome-scale metabolic models of the entire microbiota and revealing disease-associated microbial metabolic interactions. This resource will facilitate reliable functional insights into gut microbiomes.

Microbes differ greatly in their organismal structure, physiology, and environmental adaptation, yet information about these phenotypic traits is dispersed across multiple databases and is largely unavailable for taxa that remain uncultured. Here, we present metaTraits, a unified and accessible trait resource that integrates culture-derived trait information from BacDive, BV-BRC, JGI IMG, and GOLD with genome-based predictions for medium and high-quality isolate and metagenome-assembled genomes (MAGs) from proGenomes and SPIRE. metaTraits covers over 2.2 million genomes and >140 harmonized traits mapped to standardized ontologies, spanning cell morphology (e.g. shape, size, and Gram staining), physiology (e.g. motility and sporulation), metabolic and enzymatic activities, environmental preferences (e.g. temperature, salinity, and oxygen tolerance), and lifestyle categories. All records are linked to the original evidence, and species are cross-linked to NCBI and GTDB taxonomies. The interactive metaTraits website provides search and visualization tools, taxonomy-level summaries, and two workflows for annotating user-submitted genomes or community profiles. metaTraits substantially advances accessibility and interoperability of microbial trait data, enabling comprehensive trait-based analyses of microbiomes across diverse environments. metaTraits is accessible via https://metatraits.embl.de.

Immune checkpoint blockade (ICB) has become a standard anti-cancer treatment, offering durable clinical benefits. However, the limited response rate of ICB necessitates biomarkers to predict and modulate the efficacy of the therapy. The gut microbiome's influence on ICB efficacy is of particular interest due to its modifiability through various interventions. However, gut microbiome biomarkers for ICB response have been inconsistent across different studies. Here, we identify TANB77, an uncultured and distinct bacterial clade, as the most consistent responder-enriched taxon through meta-analysis of ten independent ICB recipient cohorts. Traditional taxonomy fails to distinguish TANB77 from unrelated taxa, leading to its oversight. Mice with higher gut TANB77 abundance, either naturally or through transplantation, show improved response to anti-PD-1 therapy. Additionally, mice injected with TANB77-derived pilin-like protein exhibit improved anti-PD-1 therapy response, providing in vivo evidence for the beneficial role of the pilin-like protein. These findings suggest that pilins from the TANB77 order may enhance responses to ICB therapy across diverse cohorts of cancer patients.