Transcriptomics

Dataset Information

36

Microbiota facilitates dietary heme-induced epithelial hyperproliferation and hyperplasia by breaking the mucus barrier


ABSTRACT: Colorectal cancer risk is associated with diets high in red meat. Heme, the pigment of red meat, induces cytotoxicity of colonic contents and elicits epithelial damage and compensatory hyperproliferation, leading to hyperplasia. Here we explore the possible causal role of the gut microbiota in heme-induced hyperproliferation. To this end, mice were fed a purified control or heme diet (0.5 μmol/g heme) with or without broad-spectrum antibiotics for 14 d. Heme-induced hyperproliferation was shown to depend on the presence of the gut microbiota, because hyperproliferation was completely eliminated by antibiotics, although heme-induced luminal cytotoxicity was sustained in these mice. Colon mucosa transcriptomics revealed that antibiotics block heme-induced differential expression of oncogenes, tumor suppressors, and cell turnover genes, implying that antibiotic treatment prevented the heme-dependent cytotoxic micelles to reach the epithelium. Our results indicate that this occurs because antibiotics reinforce the mucus barrier by eliminating sulfide-producing bacteria and mucin-degrading bacteria (e.g., Akkermansia). Sulfide potently reduces disulfide bonds and can drive mucin denaturation and microbial access to the mucus layer. This reduction results in formation of trisulfides that can be detected in vitro and in vivo. Therefore, trisulfides can serve as a novel marker of colonic mucolysis and thus as a proxy for mucus barrier reduction. In feces, antibiotics drastically decreased trisulfides but increased mucin polymers that can be lysed by sulfide. We conclude that the gut microbiota is required for heme-induced epithelial hyperproliferation and hyperplasia because of the capacity to reduce mucus barrier function. Mice were fed a Westernized high fat control diet, or the same diet supplemented with 0.5 µmol heme/g diet. One group of control and one group of heme mice received a mixture of broad spectrum Antibiotics (Abx) (ampicilin, neomycin and metronidazole) in their drinking water. After 14 days of intervention, mice were killed and gene expression was profiled in colon.

ORGANISM(S): Mus musculus  

SUBMITTER: Roelof van der Meer  Guido J Hooiveld   Michiel Kleerebezem   Clara Belzer   Noortje IJssennagger   Michael Müller   Jan Dekker   Guido Hooiveld    

PROVIDER: E-GEOD-40670 | ArrayExpress | 2015-08-19

SECONDARY ACCESSION(S): GSE40670PRJNA174568

REPOSITORIES: GEO, ArrayExpress

altmetric image

Publications

Gut microbiota facilitates dietary heme-induced epithelial hyperproliferation by opening the mucus barrier in colon.

Ijssennagger Noortje N   Belzer Clara C   Hooiveld Guido J GJ   Dekker Jan J   van Mil Saskia W C SW   Müller Michael M   Kleerebezem Michiel M   van der Meer Roelof R  

Proceedings of the National Academy of Sciences of the United States of America 20150727 32


Colorectal cancer risk is associated with diets high in red meat. Heme, the pigment of red meat, induces cytotoxicity of colonic contents and elicits epithelial damage and compensatory hyperproliferation, leading to hyperplasia. Here we explore the possible causal role of the gut microbiota in heme-induced hyperproliferation. To this end, mice were fed a purified control or heme diet (0.5 μmol/g heme) with or without broad-spectrum antibiotics for 14 d. Heme-induced hyperproliferation was shown  ...[more]

Similar Datasets

| GSE79067 | GEO
| GSE97504 | GEO
2014-06-02 | E-GEOD-40672 | ArrayExpress
2017-12-22 | PXD006129 | Pride
| PRJNA174568 | ENA
2013-07-29 | E-GEOD-34253 | ArrayExpress
2014-06-02 | E-GEOD-37006 | ArrayExpress
2018-01-02 | PXD007229 | Pride
| GSE76087 | GEO
2011-10-02 | GSE27847 | GEO