title: Early-life stress-induced visceral hypersensitivity and anxiety behavior is reversed by histone deacetylase inhibition.
abstract: Stressful life events, especially in childhood, can have detrimental effects on health and are associated with a host of psychiatric and gastrointestinal disorders including irritable bowel syndrome (IBS). Early-life stress can be recapitulated in animals using the maternal separation (MS) model, exhibiting many key phenotypic outcomes including visceral hypersensitivity and anxiety-like behaviors. The molecular mechanisms of MS are unclear, but recent studies point to a role for epigenetics. Histone acetylation is a key epigenetic mark that is altered in numerous stress-related disease states. Here, we investigated the role of histone acetylation in early-life stress-induced visceral hypersensitivity. Interestingly, increased number of pain behaviors and reduced threshold of visceral sensation were associated with alterations in histone acetylation in the lumbosacral spinal cord, a key region in visceral pain processing. Moreover, we also investigated whether the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), could reverse early-life stress-induced visceral hypersensitivity and stress-induced fecal pellet output in the MS model. Significantly, SAHA reversed both of these parameters. Taken together, these data describe, for the first time, a key role of histone acetylation in the pathophysiology of early-life stress-induced visceral hypersensitivity in a well-established model of IBS. These findings will inform new research aimed at the development of novel pharmaceutical approaches targeting the epigenetic machinery for novel anti-IBS drugs.
authors.affiliation: Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork, Cork, Ireland.|Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland.
authors.forename: R D
authors.initials: RD
authors.lastname: Moloney
authors.affiliation: Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork, Cork, Ireland.|Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
authors.forename: R M
authors.initials: RM
authors.lastname: Stilling
authors.affiliation: Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork, Cork, Ireland.|Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland.
authors.forename: T G
authors.initials: TG
authors.lastname: Dinan
authors.affiliation: Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork, Cork, Ireland.|Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
authors.forename: J F
authors.initials: JF
authors.lastname: Cryan
mesh_terms: D000818:Animals; D001007:Anxiety / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D006930:Hyperalgesia / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology*; D043183:Irritable Bowel Syndrome / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D008426:Maternal Deprivation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000150:complications*; D059265:Visceral Pain / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology*; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D006655:Histone Deacetylases
keywords: SAHA; epigenetics; histone acetylation; irritable bowel syndrome; stress; visceral pain