## 8 Probiotics and Butyrate
The antitumoral activity of butyrate is well known, although its mechanisms of action have not been fully elucidated yet. In the oncologic field the literature identifies the butyrate as an epigenetic modulator, especially as an inducer of the HDAC inhibition [125]. It is indeed supposed to be a potential agent for both cancer therapy and prevention [126]. The main effect produced by butyrate through the epigenetic modulation is the anti-inflammatory one exerted through several mechanisms: The suppression of the proinflammatory cytokines such as IL-1\(\beta\), TNF-\(\alpha\), and IL-6 [127], and the reduction of the pro-inflammatory NF-kB [128]. Besides its anti-inflammatory effect, butyrate has a direct effect on the tumoral development, by inhibiting the growth of colonic cancer cell lines [129]. Several lines of evidence show that the epigenetic modulation exerted by butyrate has a proliferative effect on noncancerous cells, whereas it inhibits the tumoral cell proliferation. [PERSON] et al. assessed this duality in correlation with the cellular energy metabolism and the regulation of gene expression [130]. According to this study, the butyrate exerts its epigenetic mechanism in a cell-specific and dose-dependent manner. In normal colonocytes the butyrate is metabolized and transformed to acetyl-CoA, representing a fundamental oxidative energy source. In turn, the acetyl-CoA directly leads to the stimulation of HAT activity and consequently to the cell proliferation. On the contrary, in tumor cells the Warburg effect shifts the metabolic processes from oxidative to glycolytic, thus the butyrate is scarcely metabolized and it is accumulated in the nucleus, leading to an increase of HDAC inhibition. Although both mechanisms increase histone acetylation, different target genes are upregulated, and as a result, in malignant colonocytes butyrate inhibits cell proliferation and increases apoptosis [130]. Recently, the butyrate-induced chromatine remodeling has been corroborated by [PERSON] et al., with the discovery of a further epigenetic role of SCFA in the demethylation processes [131]. In colorectal cancer cell lines it was demonstrated that butyrate up-regulates the isocitrate dehydrogenase 1 (IDH1), and that the consequent increase of \(\alpha\)-ketoglutate induces the DNA demethylation, up-regulating the promoter region of DNA mismatch repair genes (MMR) and inhibiting the colorectal carcinogenesis [131]. Based on these observations, it is clear that the butyrate is an epigenetic modulator with an antitumoral effect exerted through several mechanisms. As for the differentiating properties of butyrate, it has been demonstrated that the butyrate potentiates the effects exerted by vitamin D, resulting in the increase of cell differentiation [132]. Indeed, the butyrate-induced cell differentiation in colon cancer cells is supposed to be mediated by VDR [133] through the TGF\(\beta\)/SMAD3 pathway [134]. As demonstrated in recent studies, TGF\(\beta\) controls the remodeling of VDR cistrome [135], induces VDR expression, and the receptor exerts a negative feedback regulation of TGF\(\beta\) activities [136]. All together these observations lead to the conclusion that butyrate increases the activity of the TGF\(\beta\) pathway, which upregulates VDR expression and activity by epigenetic mechanisms, creating an autoregulatory loop; the boosted VDR activity explains the differentiating properties of butyrate. The accumulation of butyrate can lead to adverse effects. For example a clinical trial showed that in patients with advanced colorectal carcinoma the administration of high doses of butyrate resulted in a high toxicity and liver insufficiency [137]. For this reason, the more physiological production of butyrate by the intestinal tissue is recommended, which can be incremented by probiotic administration. Probiotics can be orally administered, and they show no adverse effects both in patients and healthy adults. [PERSON] et al.