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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)
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.
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.
Reprogrammed intestinal microbiota in TMF−/− mice
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