Multi-biome analysis identifies distinct gut microbial signatures and their crosstalk in ulcerative colitis and Crohn’s disease

The integrative multi-kingdom interaction of the gut microbiome in ulcerative colitis (UC) and Crohn's disease (CD) remains underinvestigated. Here, we perform shotgun metagenomic sequencing of feces from patients with UC and CD, and healthy controls in the Japanese 4D cohort, profiling bacterial taxa, gene functions, and antibacterial genes, bacteriophages, and fungi. External metagenomic datasets from the US, Spain, the Netherlands, and China were analyzed to validate our multi-biome findings. We found that Enterococcus faecium and Bifidobacterium spp. were enriched in both diseases. Enriched Escherichia coli was characteristic of CD and was linked to numerous antibiotic resistance genes involved in efflux pumps and adherent-invasive Escherichia coli virulence factors. Virome changes correlated with shifts in the bacteriome, including increased abundances of phages encoding pathogenic genes. Saccharomyces paradoxus and Saccharomyces cerevisiae were enriched in UC and CD, respectively. Saccharomyces cerevisiae and Escherichia coli had negative associations with short-chain fatty acid (SCFA)-producing bacteria in CD. Multi-biome signatures and their interactions in UC and CD showed high similarities between Japan and other countries. Since bacteria, phages, and fungi formed multiple hubs of intra- or trans-kingdom networks with SCFA producers and pathobionts in UC and CD, an approach targeting the interaction network may hold therapeutic promise.