## 4 Discussion
### Antioxidant and Anti-Inflammatory Pathways Targeted by Phytochemicals for the Treatment of IBD  
Phytochemicals and plant extracts target activated inflammatory and OS pathways in patients suffering from IBD (Figure 6). These substances seem to reverse or counter-balance the activated damaging pathways in various ways and are presented separately for each compound. Figure 6: Various inflammatory and oxidative stress pathways activated in patients with IBD. Phytochemicals and plant extracts target these pathways. CB1-2: cannabinoid receptor 1-2, COX-2: cyclooxygenase-2, GPX: glutathione peroxidase, IFN-\(\gamma\): interferon gamma, IL: interleukin, NF-kB: nuclear factor kappa B, ROS: reactive oxygen species, SCFAs: short-chain fatty acids, SOD: superoxide dismutase, STAT: signal transducer and activator of the transcription factor, TGF-b: transforming growth factor b, Th1-17: T helper 1-17 cells, TNF-a: tumor necrosis factor a.  
Plantago ovata seeds are used as a form of dietary fiber, also known as _Ispaghula_ seeds [25]. These are fermented and degraded by the anaerobic bacteria along the intestine to yield large amounts of short-chain fatty acids (SCFA), mostly butyrate and acetate. Diminished b-oxidation of luminal butyrate deprives the colonic microbiota of its preferred fuel and also results in energy deficiency of colonic epithelial cells. This has also been implicated in the pathogenesis of UC, as shown in rat studies [102]. Butyrate also inhibits the production of some cytokines and lowers the transcription of the nuclear factor kappa B (NF-kB) factor while improving the health of the gut microbiota [103]. Cancer protective effects of butyrate have also been described in a rat model [104]. These effects have also been researched in butyric acid supplements that can modulate the gut microbiota but were deemed mostly ineffective on IBD patients as shown in several studies [105; 106; 107]. Since butyric acid is not strictly a phytochemical, although it is a product of fermentable plant fiber, we excluded these studies [107]. Plant essential oil supplementation to lower prostaglandin E2 and thromboxane A concentrations in the gut has been investigated [27]. Increased concentrations of these inflammatory eicosanoids in biopsies of active UC patients have been documented. The arachidonic acid inflammatory pathway resulting in the production of prostaglandandins, thromboxane and leukotrienes has been associated with UC [108]. Thus, gamma-linolenic acid found in evening primrose essential oil that lowers arachidonic acid release was selected to target this pathway [109]. The regulation of pathways of lipid metabolism or oxidative stress in immunmediated diseases by microRNAs is a field of research receiving a lot of attention. In IBD, microRNAs are implicated in intestinal barrier function regulation as well as inflammatory pathways such as the NF-kB, the signal transducer and activator of the transcription (STAT)/IL-6 and Th17 signaling pathway. Phytochemicals have been shown to modulate microRNA expression [110; 111]. Mastiha is a plant extract with anti-inflammatory and lipid lowering properties [112]. The results after using it as a supplement in IBD patients indicate that it appears to regulate circulating levels of microRNA-155, a critical player in the differentiation of Th17 cells and other pro-inflammatory cells responding to TNF-a and interferons [19]. Berberine has anti-inflammatory effects as described in animal studies, along with antioxidant and anti-cancer properties [113; 114]. Another interesting property, also found in other bioactive phytochemicals of interest in IBD, is that it maintains high concentration inside the lumen of the gut with low systemic absorption. In contrast, another study showed that berberine did not alter gut tissue inflammation biomarkers COX-2 and NF-kB or cell proliferation marker Ki-67. As expected, plasma cytokine levels like TNF-a, IL-6 and IL-8 were also not altered by berberine administration [45].