Lifestyle-mediated shifts in the gut microbiome and host genetics modulate gene expression in intestinal organoids

In healthy-donor colonoid organoid co-cultures, lifestyle-associated urban versus rural gut microbiomes drive allele-specific expression in 511 host genes, including 149 with urban–rural condition-specific effects.

• Why it matters: Industrialization-linked microbiome changes are linked to disease, yet how microbial community variation shapes host gene regulation in a genotype-dependent way is unclear.
• What they did: Live gut microbial communities from urban or rural individuals were co-cultured with 2D colonoid monolayers from healthy donors, followed by RNA-sequencing to map microbiome-dependent allele-specific expression and condition-specific ASE.
• The result: Urban–rural condition-specific cASE tracks with microbial community composition, implicating Prevotella and Bacteroides, and targeted Prevotella copri spike-ins recapitulate Prevotella-associated allelic effects at loci including ATG4B.

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