{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "University of Chicago"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "name": "S. Nirmalan"
    },
    {
      "name": "S. Arif"
    },
    {
      "name": "G. Garlicki"
    },
    {
      "name": "A. Alazizi"
    },
    {
      "name": "K. Hutchins"
    },
    {
      "name": "M. Poyet"
    },
    {
      "name": "M. Groussin"
    },
    {
      "name": "P. Carbonetto"
    },
    {
      "name": "R. Pique-Regi"
    },
    {
      "name": "R. Blekhman"
    },
    {
      "affs": [
        0
      ],
      "name": "F. Luca"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/b8hkc7s83wbbv.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.11.07.765058",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.11.07.765058v1.full",
  "id": "b8hkc7s83wbbv",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.11.07.765058v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "genomics"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.11.07.765058v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-07",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/b8hkc7s83wbbv.ris",
  "sources": [
    {
      "first_seen": "2026-11-10T12:21:39Z",
      "native_id": "10.64898/2026.11.07.765058",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.11.07.765058v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:genomics",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "Lifestyle-mediated shifts in the gut microbiome and host genetics modulate gene expression in intestinal organoids",
  "title_text": "Lifestyle-mediated shifts in the gut microbiome and host genetics modulate gene expression in intestinal organoids",
  "type": "preprint",
  "updated_at": "2026-11-10T12:21:39Z",
  "url": "https://research.draconitic.com/paper/b8hkc7s83wbbv",
  "venue": "bioRxiv",
  "versions": []
}