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Interactions between the gut microbiome and host gene regulation in cystic fibrosis

Gargi Dayama, Sambhawa Priya, David E. Niccum, Alexander Khoruts, Ran Blekhman
doi: https://doi.org/10.1101/596312
Gargi Dayama
1Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN
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Sambhawa Priya
1Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN
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David E. Niccum
2Department of Medicine, University of Minnesota, Minneapolis, MN
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Alexander Khoruts
2Department of Medicine, University of Minnesota, Minneapolis, MN
3Center for Immunology; BioTechnology Institute
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  • For correspondence: khoru001@umn.edu blekhman@umn.edu
Ran Blekhman
1Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN
4Department of Ecology, Evolution, and Behavior, University of Minnesota, Minneapolis, MN
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  • For correspondence: khoru001@umn.edu blekhman@umn.edu
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Abstract

Cystic Fibrosis (CF) is the most common autosomal recessive genetic disease in Caucasians. It is caused by mutations in the CFTR gene, leading to poor hydration of mucus and impairment of the respiratory, digestive, and reproductive organ functions. Advancements in medical care have lead to markedly increased longevity of patients with CF, but new complications have emerged, such as early onset of colorectal cancer (CRC). Although the pathogenesis of CRC in CF remains unclear, altered host-microbe interactions might play a critical role. Here, we characterize the changes in the gut microbiome and host gene expression in colonic mucosa of CF patients relative to healthy controls. We find that CF patients show decreased microbial diversity, decreased abundance of taxa such as Butyricimonas, Sutterella, and Ruminococcaceae, and increased abundance of other taxa, such as Actinobacteria and Firmicutes. We find that 1543 genes, including CFTR, show differential expression in the colon of CF patients compared to healthy controls. Interestingly, we find that these genes are enriched with functions related to gastrointestinal and colorectal cancer, such as metastasis of CRC, tumor suppression, cellular dysfunction, p53 and mTOR signaling pathways. Lastly, we modeled associations between relative abundances of specific bacterial taxa in the gut mucosa and host gene expression, and identified CRC-related genes, including LCN2 and DUOX2, for which gene expression is correlated with the abundance of CRC-associated bacteria, such as Ruminococcaceae and Veillonella. Our results provide new insight into the role of host-microbe interactions in the etiology of CRC in CF.

  • Abbreviations

    CF
    cystic fibrosis;
    CRC
    colorectal cancer;
    GI
    gastrointestinal;
    FDR
    false discovery rate;
    OTU
    operational taxonomic unit;
    PICRUSt
    Phylogenetic Investigation of Communities by Reconstruction of Unobserved States;
    KEGG
    Kyoto Encyclopedia of Genes and Genomes.
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    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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    Posted April 02, 2019.
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    Interactions between the gut microbiome and host gene regulation in cystic fibrosis
    Gargi Dayama, Sambhawa Priya, David E. Niccum, Alexander Khoruts, Ran Blekhman
    bioRxiv 596312; doi: https://doi.org/10.1101/596312
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    Interactions between the gut microbiome and host gene regulation in cystic fibrosis
    Gargi Dayama, Sambhawa Priya, David E. Niccum, Alexander Khoruts, Ran Blekhman
    bioRxiv 596312; doi: https://doi.org/10.1101/596312

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