Diagram illustrating the proposed pathways by which dietary capsaicin (CAP) influences the glucose homeostasis and obesity, through modulatory action on intestinal microbiota. CAP decreases Lactobacillus abundance in type 2 diabetic mice (db/db), which reduces the bile salt hydrolase activity (BSHa), increases the levels of conjugated bile acids (BA) in the gut, and especially tauro-β-muricholic acid (TβMCA), an antagonist of farnesoid X receptor (FXR). A change in FXR signaling occurs and also a suppression in enterohepatic FXR-FGF15 axis (FGF15—fibroblast growth factor 15), leading to an upregulation of the cholesterol 7α-hydroxylase (CYP7A1) expression and enhancement in hepatic BA synthesis. CAP increases Roseburia and suppresses Bacteroides and Parabacteroides abundances in obese diabetic mice (ob/ob), followed by an increase in fecal butyrate level and plasma glucagon-like peptide-1 (GLP-1), and a reduction in plasma total ghrelin and proinflammatory cytokines. CAP exerts anti-obesity effects in high-fat diet (HFD)-fed mice by modulating the gut–brain (hypothalamus) axis, finally targeting brown adipose tissue (BAT), white adipose tissue (WAT), and mice food intake. CAP diminishes the abundance of Gram-negative pathogens able to secrete LPS(i) (intestinal bacterial lipopolysaccharide), such as S24_7 family members, and increases the butyrogenic bacteria abundance (e.g., Ruminococcaceae and Lachnospiraceae), and consequently the fecal butyrate, in HFD mice. CAP attenuates the increased gut permeability and bacterial translocation, and suppresses the intestinal cannabinoid receptor type 1 (CB1(i)) expression, in HFD mice. By these pathways, CAP increases gut barrier strength in these obese mice, which alongside the reduction in high levels of LPS(i) generated by altered intestinal flora, results in a reduction in high levels of plasma-circulating LPS (LPS(p)), a reduction in metabolic endotoxemia, and alleviation of the chronic low-grade inflammation (CLGI). Other symbols: ↑- up regulation, ↓- down-regulation.