numerous effects on energy homeostasis and related diseases (diabetes and obesity), inflammation, and immune function (e.g., it has pronounced antimicrobial and anticarcinogenic effects) in humans. these effects occur through its metabolism by mitochondria to generate atp during fatty acid metabolism or through one or more of its histone-modifying enzyme targets (i.e., the class i histone deacetylases) and g-protein coupled receptor targets (i.e., ffar2, ffar3, and hca2). in the mammalian gut butyrate is essential to host immune homeostasis. although the role and importance of butyrate in the gut is not fully understood, many researchers argue that a depletion of butyrate-producing bacteria in patients with several vasculitic conditions is essential to the pathogenesis of these disorders. a depletion of butyrate in the gut is typically caused by an absence or depletion of butyrate-producing-bacteria (bpb). this depletion in bpb leads to microbial dysbiosis. this is characterized by an overall low biodiversity and a depletion of key butyrate-producing members. butyrate is an essential microbial metabolite with a vital role as a modulator of proper immune function in the host. it has been shown that children lacking in bpb are more susceptible to allergic disease and type 1 diabetes. butyrate is also reduced in a diet low in fiber which can induce inflammation and have other adverse affects insofar as these short-chain fatty acids activate ppar-γ. butyrate exerts a key role for the maintenance of immune homeostasis both locally (in the gut) and systemically (via circulating butyrate). it has been shown to promote the differentiation of regulatory t cells. in particular, circulating butyrate prompts the generation of extrathymic regulatory t cells. the low-levels of butyrate in human subjects could favor reduced regulatory t cell-mediated control, thus promoting a powerful immuno-pathological t-cell response. on the other hand, gut butyrate has been reported to inhibit local pro-inflammatory cytokines. the absence or depletion of these bpb in the gut could therefore be a possible aide in the overly-active inflammatory response. butyrate in the gut also protects the integrity of the intestinal epithelial barrier. decreased butyrate levels therefore lead to a damaged or dysfunctional intestinal epithelial barrier. in a 2013 research study conducted by furusawa et al., microbe-derived butyrate was found to be essential in inducing the differentiation of colonic regulatory t cells in mice. this is of great importance and possibly relevant to the pathogenesis and vasculitis associated with many inflammatory diseases because regulatory t cells have a central role in the suppression of inflammatory and allergic responses. in several research studies, it has been demonstrated that butyrate induced the differentiation of regulatory t cells in vitro and in vivo. the anti-inflammatory capacity of butyrate has been extensively analyzed and supported by many studies. it has been found that microorganism-produced butyrate expedites the production of regulatory t cells, although the specific mechanism by which it does so unclear. more recently, it has been shown that butyrate plays an essential and direct role in modulating gene expression of cytotoxic t-cells. butyrate also has an anti-inflammatory effect on neutrophils, reducing their migration to wounds. this effect is mediated via the receptor hca1 in the gut microbiomes found in the class mammalia, omnivores and herbivores have butyrate-producing bacterial communities dominated by the butyryl-coa:acetate coa-transferase pathway, whereas carnivores have butyrate-producing bacterial communities dominated by the butyrate kinase pathway. immunomodulation and inflammation butyrate's effects on the immune system are mediated through the inhibition of class i histone deacetylases and activation of its g-protein coupled receptor targets: hca2 (gpr109a), ffar2 (gpr43), and ffar3 (gpr41). among the short-chain fatty acids, butyrate is the most potent promoter of intestinal regulatory t cells in vitro and the only one among the group that is an hca2 ligand. it has been shown to be a critical mediator of the colonic inflammatory response. it possesses both preventive and therapeutic potential to counteract inflammation-mediated ulcerative colitis and colorectal cancer. butyrate has established antimicrobial properties in humans that are mediated through the antimicrobial peptide ll-37, which it induces via hdac inhibition on histone h3. in vitro, butyrate increases gene expression of foxp3 (the transcription regulator for tregs) and promotes colonic regulatory t cells (tregs) through the inhibition of class i histone deacetylases; through these actions, it increases the expression of interleukin 10, an anti-inflammatory cytokine. butyrate also suppresses colonic inflammation by inhibiting the ifn-γ–stat1 signaling pathways, which is mediated partially through histone deacetylase inhibition. while transient ifn-γ signaling is generally associated with normal host immune response, chronic ifn-γ signaling is often associated with chronic inflammation. it has been shown that butyrate inhibits activity of hdac1 that is bound to the fas gene promoter in t cells, resulting in hyperacetylation of the fas promoter and up-regulation of fas receptor on the t-cell surface. similar to other hca2 agonists studied, butyrate also produces marked anti-inflammatory effects in a variety of tissues, including the brain, gastrointestinal tract, skin, and vascular tissue. butyrate binding at ffar3 induces neuropeptide y release and promotes the functional homeostasis of colonic mucosa and the enteric immune system. cancer butyrate has been shown to be a critical mediator of the colonic inflammatory response. it is responsible for about 70% of energy from the colonocytes, being a critical scfa in colon homeostasis. butyrate possesses both preventive and therapeutic potential to counteract inflammation-mediated ulcerative colitis (uc) and colorectal cancer. it produces different effects in healthy and cancerous cells: this is known as the "butyrate paradox". in particular, butyrate inhibits colonic tumor cells and stimulates proliferation of healthy colonic epithelial cells. the explanation why butyrate is an energy source for normal colonocytes and induces apoptosis in colon cancer cells, is the warburg effect in cancer cells, which leads to butyrate not being properly metabolized. this phenomenon leads to the accumulation of butyrate in the nucleus, acting as a histone deacetylase (hdac) inhibitor. one mechanism underlying butyrate function in suppression of colonic inflammation is inhibition of the ifn-γ/stat1 signalling pathways. it has been shown that butyrate inhibits activity of hdac1 that is bound to the fas gene promoter in t cells, resulting in hyperacetylation of the fas promoter and upregulation of fas receptor on the t cell surface. it is thus suggested that butyrate enhances apoptosis of t cells in the colonic tissue and thereby eliminates the source of inflammation (ifn-γ production). butyrate inhibits angiogenesis by inactivating sp1 transcription factor activity and downregulating vascular endothelial growth factor gene expression. in summary, the production of volatile fatty acids such as butyrate from fermentable fibers may contribute to the role of dietary fiber in colon cancer. short-chain fatty acids, which include butyric acid, are produced by beneficial colonic bacteria (probiotics) that feed on, or ferment prebiotics, which are plant products that contain dietary fiber. these short-chain fatty acids benefit the colonocytes by increasing energy production, and may protect against colon cancer by inhibiting cell proliferation. conversely, some researchers have sought to eliminate butyrate and consider it a potential cancer driver. studies in mice indicate it drives transformation of msh2-deficient colon epithelial cells. potential treatments from butyrate restoration owing to the importance of butyrate as an inflammatory regulator and immune system contributor, butyrate depletions could be a key factor influencing the pathogenesis of many vasculitic conditions. it is thus essential to maintain healthy levels of butyrate in the gut. fecal microbiota transplants (to restore bpb and symbiosis in the gut) could be effective by replenishing butyrate levels. in this treatment, a healthy individual donates their stool to be transplanted into an individual with dysbiosis. a less-invasive treatment option is the administration of butyrate—as oral supplements or enemas—which has been shown to be very effective in terminating symptoms of inflammation with minimal-to-no side-effects. in a study where patients with ulcerative colitis were treated with butyrate enemas, inflammation decreased significantly, and bleeding ceased completely after butyrate provision. addiction butyric acid is an hdac inhibitor that is selective for class i hdacs in humans. hdacs are histone-modifying enzymes that can cause histone deacetylation and repression of gene expression. hdacs are important regulators of synaptic formation, synaptic plasticity, and long-term memory formation. class i hdacs are known to be involved in mediating the development of an addiction. butyric acid and other hdac inhibitors have been used in preclinical research to assess the transcriptional, neural, and behavioral effects of hdac inhibition in animals addicted to drugs. butyrate salts and esters the butyrate or butanoate ion, c3h7coo−, is the conjugate base of butyric acid. it is the form found in biological systems at physiological ph. a butyric (or butanoic) compound is a carboxylate salt or ester of butyric acid. salts sodium butyrate esters butyl butyrate butyryl-coa cellulose acetate butyrate (aircraft dope) estradiol benzoate butyrate ethyl butyrate methyl butyrate pentyl butyrate tributyrin