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Research Article

Reprogrammed and transmissible intestinal microbiota confer diminished susceptibility to induced colitis in TMF−/− mice

Shai Bel, Yoav Elkis, Hila Elifantz, Omry Koren, Rotem Ben-Hamo, Tal Lerer-Goldshtein, Roni Rahimi, Shomron Ben Horin, Abraham Nyska, Sally Shpungin, and Uri Nir
  1. aThe Mina and Everard Goodman Faculty of Life Sciences and
  2. eQuaresa Institute for Cancer Research, Bar-Ilan University, Ramat-Gan 5290002, Israel;
  3. bFaculty of Medicine, Bar-Ilan University, Safed 1311502, Israel;
  4. cDepartment of Gastroenterology, Sheba Medical Center, Tel-Hashomer 52621, Israel; and
  5. dSackler School of Medicine, Tel-Aviv University, Tel Aviv 36576, Israel

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PNAS first published March 17, 2014; https://doi.org/10.1073/pnas.1319114111
Shai Bel
aThe Mina and Everard Goodman Faculty of Life Sciences and
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Yoav Elkis
aThe Mina and Everard Goodman Faculty of Life Sciences and
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Hila Elifantz
aThe Mina and Everard Goodman Faculty of Life Sciences and
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Omry Koren
bFaculty of Medicine, Bar-Ilan University, Safed 1311502, Israel;
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Rotem Ben-Hamo
aThe Mina and Everard Goodman Faculty of Life Sciences and
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Tal Lerer-Goldshtein
aThe Mina and Everard Goodman Faculty of Life Sciences and
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Roni Rahimi
aThe Mina and Everard Goodman Faculty of Life Sciences and
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Shomron Ben Horin
cDepartment of Gastroenterology, Sheba Medical Center, Tel-Hashomer 52621, Israel; and
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Abraham Nyska
dSackler School of Medicine, Tel-Aviv University, Tel Aviv 36576, Israel
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Sally Shpungin
aThe Mina and Everard Goodman Faculty of Life Sciences and
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Uri Nir
aThe Mina and Everard Goodman Faculty of Life Sciences and
eQuaresa Institute for Cancer Research, Bar-Ilan University, Ramat-Gan 5290002, Israel;
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  • For correspondence: uri.nir@biu.ac.il
  1. Edited by Richard A. Flavell, Yale School of Medicine, Howard Hughes Medical Institute, New Haven, CT, and approved February 14, 2014 (received for review October 9, 2013)

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Significance

Our data demonstrate that a knockout of a single gene (tmf1) leads to the beneficial reprogramming of the gut resident microbiota. This reprogramming results in a diminished susceptibility of the genetically modified animals to induced colitis. Notably, the reprogrammed bacterial profile is transmissible, thereby conferring altered microbiome and reduced susceptibility to induced colitis in wild-type mice, when cohoused. Our findings open previously unreported avenues for unraveling regulatory factors that affect the gut homeostasis and mammalian sensitivity to the onset of inflammatory bowel diseases.

Abstract

Tata Element Modulatory Factor (TMF/ARA160) is a multifunctional Golgi-associated protein, which accumulates in colonic enterocytes and goblet cells. Mice lacking TMF/ARA160 (TMF−/−) produce thick and uniform colonic mucus that resists adherent bacterial colonization and diminishes susceptibility of these mice to induced acute colitis, through a mechanism that is not fully understood. Here, we show that mucus secretion by goblet cells is altered in the colon of TMF−/− mice, resulting in the formation of a highly oligomerized colonic gel-forming mucin, MUC2. Microbiome analysis revealed a shift in the microbiota of TMF−/− mice leading to predominance of the Firmicutes phylum and a significantly higher abundance of probiotic beneficial bacterial species. Notably, this trait was transmissible, and when cohoused with wild-type animals, TMF−/− mice influenced the microbiota and diminished the susceptibility of wild-type mice to chemically induced dextran sulfate sodium colitis. Thus, altered mucus secretion in TMF−/− mouse colons is accompanied by a reprogrammed intestinal microbiota, leading to a transmissible reduced sensitivity to induced colitis.

  • co-housing
  • inflammatory bowel disease
  • mucus granule

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: uri.nir{at}biu.ac.il.
  • Author contributions: S.B., S.S., and U.N. designed research; S.B., Y.E., T.L.-G., R.R., A.N., and S.S. performed research; S.B.H. contributed new reagents/analytic tools; S.B., H.E., O.K., R.B.-H., and U.N. analyzed data; and S.B., O.K., and U.N. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1319114111/-/DCSupplemental.

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Reprogrammed intestinal microbiota in TMF−/− mice
Shai Bel, Yoav Elkis, Hila Elifantz, Omry Koren, Rotem Ben-Hamo, Tal Lerer-Goldshtein, Roni Rahimi, Shomron Ben Horin, Abraham Nyska, Sally Shpungin, Uri Nir
Proceedings of the National Academy of Sciences Mar 2014, 201319114; DOI: 10.1073/pnas.1319114111

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Reprogrammed intestinal microbiota in TMF−/− mice
Shai Bel, Yoav Elkis, Hila Elifantz, Omry Koren, Rotem Ben-Hamo, Tal Lerer-Goldshtein, Roni Rahimi, Shomron Ben Horin, Abraham Nyska, Sally Shpungin, Uri Nir
Proceedings of the National Academy of Sciences Mar 2014, 201319114; DOI: 10.1073/pnas.1319114111
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