*3.4.1.2 Phytochemicals*

*Canine Genetics, Health and Medicine*

and apoptosis [102] (**Figure 3**).

small molecules with biological functions [105].

and increased acetylation results in higher expression of FOXP3 [99, 101]. As a consequence of HDAC inhibition, butyrate triggers the factor activator protein 1 (AP-1) signaling pathway in the epithelial cell lines that controls cell proliferation

SCFAs modulate several cancer hallmarks, such as cell proliferation, apoptosis and level of expression of certain genes (via inhibition of HDACs), mechanisms that lead to high anticancer activity (**Figure 3**). This protection can affect both stroma and cancer cells, since they have free fatty acid receptors. It was demonstrated that microbial fermentation of high-fiber diet increased concentrations of butyrate in blood and tumor and significantly decreased tumor growth in mouse with lymphoma, suggesting that dietary fiber protects against human lymphoma cancer [104]. A metabolomics-proteomics approach in colorectal cancer provided a mechanistic link between the M2 isoform of a pyruvate kinase (a direct binding target of butyrate) and metabolic remodeling and the antitumorigenic function of butyrate, highlighting an applicable approach to uncovering protein targets for

Studies in veterinary medicine are very scarce. There is one comparative study reporting higher concentrations of β-hydroxybutyrate in blood from dogs with lymphoma than in healthy dogs, but further investigations are essential to understand the significance of this increase [106]. Another research demonstrated that fecal dysbiosis in dogs with acute diarrhea was associated with altered systemic metabolic states, in which concentrations of fecal propionic acid were significantly decreased compared to healthy dogs [107]. In addition, dogs with inflammatory colorectal polyps (ICRP) showed lower amounts of propionic acid and lower proportions of Bifidobacterium compared to feces of control dogs suggesting that the association

*Modulation of immune signaling through microbial metabolites SCFAs and BA. The metabolic effects directly stimulate the cells of the immune system or are relayed by the intestinal epithelium (adapted from Levy et al.,* 

**122**

**Figure 3.**

*2019 [103].*

Phytochemicals are bioactive non-nutrient chemical compounds found in fruits, vegetables, grains, and other plant foods, which have biological effects associated with reduced risk of diseases, including cancer [109]. They can be categorized into polyphenols, organosulfur compounds, carotenoids, alkaloids, and nitrogen compounds, but the polyphenols are the most studied ones [109].

Their anti-cancer role includes antioxidant effects, modulation of xenobiotic detoxification pathways and cell proliferation, apoptosis and inflammation [110]. They neutralize reactive oxygen species (ROS) that can damage DNA and predispose to carcinogenesis [97]. A study in human breast cancer cell lines, showed that aqueous extract of the *Pouteria sapota* leaf is rich in phytochemicals with antioxidant properties and significant anti-cancer effects [111]. There is still need for more research and clinical trials in humans and dogs that identify and illustrate the action of phytochemicals.
