# Current Research on the Effects of Non-Digestible Carbohydrates on Metabolic Disease
## 4 NDCs and SCFAs  
During the last few decades, scientific evidence of the health benefits of NDC consumption has accumulated. In particular, the relationship between gut health and NDCs is well-demonstrated. The mechanisms by which NDCs modulate host health through the gut microbiota are summarized in Figure 1. NDCs are fermented by the gut microbiota and SCFAs; primarily, acetic acid, butyrate acid, and propionic acid associated with various physiological functions in the human body [41] are produced during fermentation. SCFAs produced from NDCs stimulate the secretion of satiety hormones, glucagon-like peptide (GLP-1) and peptide tyrosine tyrosine (PYY) [42], through the activation of G protein-coupled receptors (GPRs), GPR41 and GPR43, of the enteroendocrine L-cells in the intestine, especially in the ileum and colon [41]. Both hormones influence the hypothalamus to promote satiety. PYY acts on the arcuate nucleus in the hypothalamus, leading to the suppression of neuropeptide Y neurons to promote satiety, activate propoipalancortin neurons, reduce intestinal transit time from the mouth to the eccum, and decrease the gastric emptying rate [5; 43]. Moreover, GLP-1 stimulates the hypothalamus by binding to the GLP-1 receptor, improving insulin sensitivity, and promoting glucose tolerance by acting on pancreatic \(\beta\)-cells [6; 7]. Furthermore, SCFAs can be converted into glucose via intestinal gluconeogenesis (IGN), which activates adipocytes to produce leptin, thereby improving satiety and preventing obesity [8]. Additionally, an increase in IGN by SCFAsinhibits hepatic gluconeogenesis, resulting in increased glucose tolerance. For example, butyrate activates IGN gene expression through a cAMP-dependent mechanism, whereas propionate, an IGN substrate, stimulates IGN via a gut-brain neural circuit [44]. Along with the direct effects of SCFAs, SCFAs shift the intestinal environment by decreasing pH, preventing overgrowth of pH-sensitive pathogenic bacteria [45; 46] and protease activity associated with the production of harmful metabolites, such as ammonia, a potentially carcinogenic product of protein fermentation [47; 48]. Moreover, SCFAs are involved in the intestinal defense system against pathogens and toxic compounds [49]. The primary physical intestinal barriers that protect the gut from pathogen infection or toxic compounds are mucin secreted from goblet cells and tight junctions (TJs) between mucosal epithelial cells [9]. SCFAs improve gut barrier function by modulating the expression of mucin and TJ proteins [50]. SCFA signaling through GPRs stimulates L-cells to secrete GLP-2, leading to an increase in expression of TJ proteins, including zonula occludens-1 (ZO-1) and Claudin-3, consequently reducing LPS translocation, inhibiting endotoxemia-induced inflammation, and improving gut permeability [51]. Similarly, SCFAs increase goblet cell mucin secretion, resulting in a reduction in LPS translocation through the epithelium. SCFAs also exert immunomodulatory effects by regulating antimicrobial peptide (AMP) synthesis, Treg expansion, and myeloid cell function, leading to reduced inflammation. Consequently, the overall effect of NDC-induced SCFA production was associated with improvement in MD, including obesity, T2D, and CVD [39].  
Figure 1: Effect of non-digestible carbohydrates (NDCs) on metabolic diseases (MD) through short-chain fatty acids (SCFA) produced by gut fermentation. AMP, antimicrobial peptides; CVD, cardiovascular disease; GLP, glucagon-like peptide; IGN, intestinal gluconeogenesis; LPS, lipopolysaccharide; PYY, peptide tyrosine tyrosine; SCFAs, short-chain fatty acids; T2D, type 2 diabetes; Tregs, regulatory T-cells; Zo-1, Zonula occludens.