Changes in diet can also have dramatic effects on the composition of gut microbiota. Commensal bacteria of the gastrointestinal tract are critical regulators of health and disease by protecting against pathogen encounter whilst also maintaining immune tolerance to certain allergens. Moreover, consumption of fibre and vegetables typical of a non-Western diet generates substantial quantities of short-chain fatty acids (SCFAs) which have potent anti-inflammatory properties. Dietary interventions such as probiotic supplementation have been investigated for their pleiotropic effects on microbiota composition and immune function. Probiotics may restore intestinal dysbiosis and improve clinical disease through elevated SCFA levels in the intestine. Although the precise mechanisms by which such dietary factors mediate these effects, SCFA metabolites such as butyrate also function as histone deacetylase inhibitors (HDACi), that can act on the epigenome through chromatin remodeling changes. The aim of this review is to provide an overview of HDAC enzymes and to discuss the biological effects of HDACi. Further, we discuss the important relationship between diet and the balance between health and disease and how novel dietary interventions such as probiotics could be alternative approach for the prevention and/or treatment of chronic inflammatory disease through modulation of the intestinal microbiome. 1. Introduction The histone deacetylase inhibitors (HDACi) suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza) and depsipeptide (Romidepsin, Istodax) have been approved by the US Food and Drug Administration (FDA) for the treatment of refractory cutaneous T-cell lymphoma, in 2006 and 2009, respectively [1, 2]. Further, at least 15 HDACi are currently undergoing clinical trials either alone or in combination with other therapeutic modalities for the treatment of various haematological and solid malignancies [3–5]. Apart from hydroxamic acids (e.g., SAHA) and cyclic peptides (e.g., depsipeptide), the short-chain fatty acids (SCFAs) represent another class of HDACi with clinical potential [6]. A notable example is valproic acid (VPA), a simple SCFA (eight-carbon) with more than 40 years clinical history in the treatment of epilepsy [7]. The mechanism of action of VPA in epilepsy is not fully understood, however, it is known to increase levels of the inhibitory neurotransmitter, γ-aminobutyric acid in the brain [8, 9]. In more recent years, VPA has also been shown to possess HDACi activity resulting in differentiation, cell death, and apoptosis in malignant cells
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