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Effects of the In Vivo Supply of Butyrate on Histone Acetylation of Cecum in Piglets

C. Lawrence Kien, MD, PhD^*,, Cheryl P. Peltier, BSc, Soma Mandal, PhD, James R. Davie, PhD and Ruth Blauwiekel, DVM, PhD

From the Departments of ^* Pediatrics and Medicine, College of Medicine, and Office of Animal Care Management, University of Vermont, Burlington, Vermont; and the Manitoba Institute of Cell Biology, Winnipeg, Manitoba, Canada

Correspondence: C. Lawrence Kien, MD, PhD, E203 Given Building, 89 Beaumont Ave, University of Vermont College of Medicine, Burlington, VT 05405-0068. Electronic mail may be sent to cl.kien{at}uvm.edu.

Background: In vitro, butyrate inhibits histone deacetylase and down-regulates expression of cyclin D1. We hypothesized that an increased entry rate of butyrate into the cecal lumen would have similar effects in vivo. Methods: We used frozen cecal tissue and data from previous studies, one showing that lactulose supplementation caused an increased rate of cecal synthesis of butyrate and decreased cecal cell proliferation and density of clostridia and the other showing that cecal cell proliferation was increased by an exogenous cecal butyrate infusion at a comparable rate. The ratio of acetylated to total histones (AH ratio) and cyclin D1 mRNA expression were measured in cecal tissue. Results: Lactulose supplementation caused a 189% increase in the AH ratio (p = .004), which inversely correlated with cecal cell proliferation (r = –0.782; p = .008). With cecal butyrate infusion, we observed a significant decrease in histone acetylation (p = .02), which also inversely correlated with cecal cell proliferation (r = –0.797; p = .002). Cyclin D1 expression was increased 6.5-fold by lactulose feeding (p = .02) but decreased 50% with cecal butyrate infusion (p = .004). Conclusions: The effects on histone acetylation of increased "endogenous" butyrate production produced by lactulose feeding, but not exogenous cecal infusion of butyrate, mirror those in vitro. Thus, bacterial production and exogenous infusion of butyrate have opposite effects on histone acetylation and cyclin D1 expression, suggesting that the composition of bacterial flora may play a role in butyrate's in vivo effects on the cell cycle.

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