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A common mechanism links activities of butyrate in the colon

preprint
submitted on 17.09.2017 and posted on 19.09.2017 by Mohit S. Verma, Michael J. Fink, Gabriel L Salmon, Nadine Fornelos, Takahiro E. Ohara, Stacy S. Ryu, Hera Vlamakis, Ramnik J. Xavier, Thaddeus S. Stappenbeck, George M. Whitesides
Two biological activities of butyrate in the colon (suppression of proliferation of colonic epithelial stem cells and inflammation) correlate with inhibition of histone deacetylases. Cellular and biochemical studies of molecules similar in structure to butyrate, but different in molecular details (functional groups, chain-length, deuteration, oxidation level, fluorination, or degree of unsaturation) demonstrated that these activities were sensitive to molecular structure, and were compatible with the hypothesis that butyrate acts by binding to the Zn2+ in the catalytic site of histone deacetylases. Structure-activity relationships drawn from a set of 36 compounds offer a starting point for the design of new compounds targeting the inhibition of histone deacetylases. The observation that butyrate was more potent than other short-chain fatty acids is compatible with the hypothesis that crypts evolved (at least in part), to separate stem cells at the base of crypts from butyrate produced by commensal bacteria.

Funding

This work was funded by the Wyss Institute for Biologically Inspired Engineering, the Center for Microbiome Informatics and Therapeutics (Award # 6935953), the Crohn’s & Colitis Foundation, and the Helmsley Charitable Trust. MSV was funded by a Banting Postdoctoral Fellowship (Code: 201409BAF-344359-257936) from the Government of Canada. MJF was funded by an Erwin Schrödinger Fellowship (grant no. J3771-N28) of the Austrian Science Fund (FWF). GLS was supported by the Wyss Institute for Biologically Inspired Engineering. NF, HV, and RJX are funded by the Crohn’s and Colitis Foundation (Grant #20144126).

History

Topic

  • Biochemistry
  • Cell and Molecular Biology
  • Microbiology

Email Address of Submitting Author

mfink@gmwgroup.harvard.edu

Institution

Harvard University

Country

United States of America

ORCID For Submitting Author

0000-0003-0023-8767

Declaration of Conflict of Interest

None.

Exports