Language
English
Publication Date
9-29-2026
Journal
mSphere
DOI
10.1128/msphere.00758-25
PMID
42578676
PMCID
PMC13621869
PubMedCentral® Posted Date
8-11-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Enteroaggregative Escherichia coli (EAEC) is a leading cause of diarrhea worldwide. Interestingly, EAEC disease outcomes vary dramatically among infected individuals, ranging from asymptomatic colonization to acute and chronic diarrhea. While previous research has focused on EAEC virulence factors, emerging evidence suggests that host genetic and cellular background may be equally important in determining disease susceptibility. To understand host-driven disease heterogeneity, we performed single-cell RNA sequencing on human colon organoids (HCOs) derived from three healthy adult donors following EAEC 042 infection. Surprisingly, despite comparable EAEC adherence across donors, we observed striking donor-specific responses to infection at multiple levels. A total of seven distinct colonic epithelial cell clusters were identified, with striking donor-specific baseline compositions. Following infection, the HCO donors exhibited three distinct response phenotypes evident in both cell type remodeling and gene regulation: hyperresponsive, intermediate, and non-responsive. We further observed extensive donor-specific cell-cell communication networks at baseline and after EAEC infection. This study suggests that the heterogeneity in host epithelial response to EAEC infection extends to the single-cell level. While the colonic regions from which the HCOs were derived represent a potential confounding factor, the magnitude of organoid-to-organoid variation exceeded previously reported regional differences, suggesting intrinsic host factors as a crucial part of response heterogeneity. These findings establish a paradigm for understanding infectious disease susceptibility through the human organoid model system.
IMPORTANCE
Understanding why similar pathogen exposures produce vastly different clinical outcomes is critical for combating infectious diseases. By conducting single-cell RNA sequencing on human colon organoids derived from three different donors, we show that each donor possesses unique intrinsic cellular compositions and distinct transcriptomic responses to enteroaggregative Escherichia coli (EAEC) infection. These findings challenge the traditional pathogen-focused paradigm and highlight the critical role of host factors in infectious disease outcomes. This study also validates human organoids as a powerful platform for studying host heterogeneity, which may help predict disease susceptibility and optimize treatment for diverse patient populations in the future.
Keywords
Humans, Organoids, Colon, Escherichia coli, Escherichia coli Infections, Single-Cell Analysis, Host-Pathogen Interactions, Epithelial Cells, Adult, Single-Cell Gene Expression Analysis, Escherichia coli, host-pathogen interactions, infection response, human intestinal organoids, epithelial cells, innate immunity, host susceptibility, bioinformatics, host heterogeneity, single-cell RNA sequencing, enteric infection, bacterial infection
Published Open-Access
yes
Recommended Citation
Qiu, Ling; Patel, Tajhal D; Jones, Hannah E; et al., "Individual Host Variation in Single-Cell Responses to Enteroaggregative Escherichia coli Infection Modeled With Human Colon Organoids" (2026). Faculty, Staff and Students Publications. 7996.
https://digitalcommons.library.tmc.edu/baylor_docs/7996