*1.2. Short Chain Fatty Acid Production and Their Importance*

Key end products of microbial fermentation in the large intestine are short chain fatty acids. They are saturated carboxylic acids containing less than six carbons in their chain structure. The main sources of SCFAs are dietary macromolecules, especially fiber-rich plant-derived polysaccharides that are indigestible to humans due to the lack of enzymes required for breaking the glycosidic bonds. Thus, they are available to microbes in the intestinal lumen, which ferment them and make them available to the host. SCFAs are

transported into the colonic epithelial cells by solute transporters or by simple diffusion across the membranes [23]. 95% of the total SCFAs in the human gut are acetate, propionate, and butyrate, and their levels are largely dependent on the diet and the amount of fiber, which affect the microbiota composition. The main species involved in the production of acetate are *Akkermansia muciniphila, Bacteroidetes* spp., and *Prevetolla* spp. Propionate is mostly produced by *Bacteroidetes* and *Firmicutes*, with the latter also producing butyrate. SCFAs are an important energy source for colonocytes and hepatocytes, but they also enter the systemic circulation and act as signaling molecules to exert a variety of regulatory functions. The presence of SCFAs is closely linked to gut integrity, not only through increased expression of tight junction (TJ) proteins but also through modulation of the host immune system. They act as ligands for G-protein-coupled receptors (GPR), their main targets being GPR43 and GPR41, also called free fatty acid receptor-2 (FFAR2) and free fatty acid receptor-3 (FFAR3), respectively. It has also been reported that butyrate can interact with GPR109/HCA2 (hydroxycarboxylic acid receptor 2). These receptors are involved in the glucose metabolism, lipid regulation, and gut homeostasis, as well as being expressed on immune cells, where they can influence the inflammation. Indeed, acetate has been implicated in resolving enteritis through GPR43 signaling [24]. Propionate, butyrate, and valerate can influence gene transcription by inhibiting histone deacetylase (HDAC) and thus making chromatin more accessible to transcription factors. Butyrate has been shown to be a potent suppressor of CD4+ T cell activation, acting through GPR43 and HDAC inhibition to decrease proliferation and production of proinflammatory cytokines (IFN-γ, IL-17) [25,26]. Studies show that butyrate-mediated inhibition of class II HDAC in the gut CD4+ T cells epigenetically induces the transcription of genes responsible for regulatory T cell (Treg) function [27]. There are many examples of the anti-inflammatory roles of SCFAs, but some studies report a dual effect, inducing both Treg and cytotoxic effector T cells, which points out the need for further studies [23].

Importantly, SCFAs can also cross the blood-brain barrier and affect the brain, which renders them as a potential target in neuroinflammatory diseases [20]. Supplementation of sodium butyrate has been tested on the R6/2 mouse model of HD, yielding positive results. When compared to untreated controls, the supplemented group showed improved motor performance, increased brain weight, and decreased striatal neuronal atrophy. However, sodium butyrate supplementation had no effect on the formation of mutant huntingtin (mHTT) aggregates or weight loss [28]. The study conducted on the YAC128 mouse HD model has also shown a beneficial effect of sodium butyrate supplementation, as the treated group displayed improved learning and motor skills, as well as improved cortical energy levels and increased histone 3 acetylation, suggesting that butyrate acting as an HDAC inhibitor can improve mitochondrial and transcriptional dysfunctions present in HD [29].
