Spatial host-microbiome profiling demonstrates bacterial-associated host transcriptional alterations in pediatric ileal Crohn's disease

Abstract

BackgroundCrohn's disease (CD) is a chronic inflammatory bowel disease involving complex relationships between the gut microbiome and host immune system. However, the spatial relationships between tissue-resident bacteria and host cells in CD pathogenesis remain poorly understood. We developed a spatial host-microbiome profiling approach to simultaneously detect host transcriptomics and bacterial species at high taxonomic resolution in pediatric ileal CD tissues.ResultsIn this prospective case-control study, we analyzed 14 terminal ileal tissue samples from six pediatric patients with ileal CD and two controls. Spatial host-microbiome sequencing, combined spatial transcriptomics and in-situ polyadenylation, and bulk shotgun metagenome sequencing were performed. We developed a comprehensive bioinformatics pipeline to identify bacterial species and analyze host-microbiome interactions at cellular resolution, resulting in 13,876 analyzed cells. Our approach revealed increased bacterial abundance in CD tissues compared with controls. The extent of bacterial infiltration at diagnosis correlated with disease prognosis and severity of endoscopic findings. We identified 16 potentially beneficial and nine pathogenic microbiome members in ileal CD, including several newly discovered risk-modulating bacterial species. Cell-type-specific host gene expression analysis revealed transcriptome alterations related to bacterial defense mechanisms in the presence of various bacterial species.ConclusionsOur spatial host-microbiome profiling approach enables simultaneous species-level identification of bacteria and host transcriptomics. It reveals the intricate interactions between host cells and bacteria, providing cellular-level insights into CD pathogenesis. Our approach offers a powerful tool for investigating host-microbiome interactions in various microbiome-associated diseases to direct new strategies for microbiome-based therapeutics and prognostic markers.6UAJbQDPTw96ByYq5fxSzyVideo AbstractConclusionsOur spatial host-microbiome profiling approach enables simultaneous species-level identification of bacteria and host transcriptomics. It reveals the intricate interactions between host cells and bacteria, providing cellular-level insights into CD pathogenesis. Our approach offers a powerful tool for investigating host-microbiome interactions in various microbiome-associated diseases to direct new strategies for microbiome-based therapeutics and prognostic markers.6UAJbQDPTw96ByYq5fxSzyVideo Abstract