Capsaicin, allicin, and 6-gingerol: Modulation of gut microbiota and impact on metabolic, immune, and neurobiological health in mice.

Most consumers exhibit a preference for spicy substances; however, the metabolic complexities and health impacts associated with these substances-capsaicin (from chili), allicin (from garlic), and 6-gingerol (from ginger)-remain largely unexplored. This study evaluated the effect of dietary capsaicin, allicin, 6-gingerol association among gut microbiota, immune, and neurobiological responses in healthy male ICR mice by using enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), hematoxylin-eosin staining (HE), Western Blot analysis, and 16S rDNA sequencing. The findings revealed that capsaicin, allicin, and 6-gingerol alter the gut microbiota (increasing Firmicutes, Desulfobacterota, and decreasing Bacteroidota) which correlated with elevated serum total cholesterol (0.1 to 1.1-fold), triglyceride (0.17 to 1.9-fold), reduced peptide YY (0.02 to 0.37-fold) and glucagon-like peptide-1 (0.1 to 0.15-fold), enhanced colon sIgA (0.013 to 0.13-fold) and colon tight junction proteins E-cadherin(0.2 to 0.5-fold). Furthermore, capsaicin, allicin, and 6-gingerol reduced hippocampal granule cell number, decreased superoxide dismutase (SOD) activity, and altered blood-brain barrier tight junction proteins (OCLN downregulation, CLDN5 upregulation). In conclusion, Firmicutes positively correlated with serum lipids (TC, TG, LDL-C) and immune indices (IL-21, IgM)(P > 0.05), while Bacteroidota positively correlated with PYY, IL-6(colon), JAK1, P-JAK1, JAK2, P-JAK2, STAT3, TJP1, and SOD(P > 0.05); at the genus level, Rikenella was significantly negatively correlated with TC and intestinal tight junction proteins (Occludin, E-cadherin,and OCLN)(P < 0.05), and significantly positively correlated with PYY(P < 0.05). This research provides correlational evidence for the context-dependent effects of these spicy compounds on healthy mice, with gut microbiota potentially acting as a mediator. However, causal relationships and broader applicability require further validation.