Lifestyle-mediated shifts in the gut microbiome and host genetics modulate gene expression in intestinal organoids
- 1University of Chicago
Abstract
Industrialization-associated shifts in the gut microbiome have been linked to disease, but the mechanisms by which microbial communities influence host gene regulation remain poorly understood. We developed a live microbiome-colonic organoid (colonoid) co-culture system to investigate genotype-dependent host responses to gut microbial community variation. Colonoid 2D monolayers from healthy donors were co-cultured with live gut microbial communities from individuals living urban or rural lifestyles, followed by RNA-sequencing. Urban and rural microbiomes elicited largely shared transcriptional responses, however they induced distinct host genetic effects on gene expression. We identified 511 host genes with microbiome-dependent allele-specific expression (ASE) which were involved in epithelial architecture, cell-matrix interactions and structural integrity. Notably, 149 host genes had distinct allelic effects between Urban and Rural microbiomes (urban-rural condition specific ASE or cASE), revealing genotype-dependent host responses to lifestyle-associated microbiomes. Urban-rural cASE was associated with microbial community composition, predominantly involving Prevotella and Bacteroides species. Targeted Prevotella copri spike-in recapitulated Prevotella-associated allelic effects at specific loci, including one in the IBD-associated autophagy gene, ATG4B. Together, these findings establish an experimental framework to investigate genotype-by-microbiome interactions, and demonstrate that lifestyle-mediated shifts in the microbiome modify host cis-regulatory genetic effects on gene expression.
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BibTeX
@misc{nirmalan2026lifestylemediated,
title = {{Lifestyle-mediated shifts in the gut microbiome and host genetics modulate gene expression in intestinal organoids}},
author = {S. Nirmalan and S. Arif and G. Garlicki and A. Alazizi and K. Hutchins and M. Poyet and M. Groussin and P. Carbonetto and R. Pique-Regi and R. Blekhman and F. Luca},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.07.765058},
url = {https://www.biorxiv.org/content/10.64898/2026.11.07.765058v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Lifestyle-mediated shifts in the gut microbiome and host genetics modulate gene expression in intestinal organoids
AU - S. Nirmalan
AU - S. Arif
AU - G. Garlicki
AU - A. Alazizi
AU - K. Hutchins
AU - M. Poyet
AU - M. Groussin
AU - P. Carbonetto
AU - R. Pique-Regi
AU - R. Blekhman
AU - F. Luca
PY - 2026
DA - 2026/11/07
PB - bioRxiv
DO - 10.64898/2026.11.07.765058
UR - https://www.biorxiv.org/content/10.64898/2026.11.07.765058v1
AB - Industrialization-associated shifts in the gut microbiome have been linked to disease, but the mechanisms by which microbial communities influence host gene regulation remain poorly understood. We developed a live microbiome-colonic organoid (colonoid) co-culture system to investigate genotype-dependent host responses to gut microbial community variation. Colonoid 2D monolayers from healthy donors were co-cultured with live gut microbial communities from individuals living urban or rural lifestyles, followed by RNA-sequencing. Urban and rural microbiomes elicited largely shared transcriptional responses, however they induced distinct host genetic effects on gene expression. We identified 511 host genes with microbiome-dependent allele-specific expression (ASE) which were involved in epithelial architecture, cell-matrix interactions and structural integrity. Notably, 149 host genes had distinct allelic effects between Urban and Rural microbiomes (urban-rural condition specific ASE or cASE), revealing genotype-dependent host responses to lifestyle-associated microbiomes. Urban-rural cASE was associated with microbial community composition, predominantly involving Prevotella and Bacteroides species. Targeted Prevotella copri spike-in recapitulated Prevotella-associated allelic effects at specific loci, including one in the IBD-associated autophagy gene, ATG4B. Together, these findings establish an experimental framework to investigate genotype-by-microbiome interactions, and demonstrate that lifestyle-mediated shifts in the microbiome modify host cis-regulatory genetic effects on gene expression.
ER -