Short-chain fatty acids alter tight junction permeability in intestinal monolayer cells via lipoxygenase activation.
OBJECTIVE
Involvement of lipoxygenase (LOX) and cyclo-oxygenase (COX) on cellular differentiation or apoptosis induced by butyrate has been reported recently, but the effect on tight junction (TJ) permeability has not been reported. One major activity of butyrate and, to a lesser extent, propionate is to modulate gene transcription via histone acetylation by their histone deacetylase inhibitor activity. In this study, we evaluated the activation of LOX and COX in TJ permeability changes by short-chain fatty acids, butyrate, propionate, and acetate in intestinal monolayer cells and their possible mechanism by histone acetylation.


METHODS
The effects of LOX and COX inhibitors on TJ permeability and the expression of LOX or COX mRNA induced by short-chain fatty acids were investigated in Caco-2 cells using Transwell chambers. The effects of hydroxyeicosatetraenoic acid (a product of LOX) on TJ permeability were also evaluated. The effects of short-chain fatty acids were compared with those of trichostatin A (histone deacetylase inhibitor).


RESULTS
A LOX inhibitor clearly inhibited the effect of butyrate on TJ permeability, whereas COX inhibitors did not. The LOX and COX inhibitors partly inhibited the effects of propionate but not of acetate. Butyrate increased LOX mRNA expression, and hydroxyeicosatetraenoic acid and trichostatin A mimicked its effect.


CONCLUSIONS
These results suggest that short-chain fatty acids, especially butyrate, induce TJ permeability changes through LOX activation through histone acetylation.
Division of Surgical Metabolism, Faculty of Health Sciences, Kobe University School of Medicine, Kobe, Japan.
Atsushi
A
Ohata
Makoto
M
Usami
Makoto
M
Miyoshi
D000107:Acetylation; D002087:Butyrates / Q000378:metabolism / Q000494:pharmacology; D018938:Caco-2 Cells; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D005232:Fatty Acids, Volatile / Q000378:metabolism* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008084:Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D010539:Permeability; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D002087:Butyrates; D016861:Cyclooxygenase Inhibitors; D005232:Fatty Acids, Volatile; D006657:Histones; D016859:Lipoxygenase Inhibitors; D012333:RNA, Messenger; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases