Exploring the influence of gut microbiota metabolites on vitiligo through the gut-skin axis

Abstract

Vitiligo is an autoimmune skin disease with a complex pathogenesis closely linked to immune imbalance and oxidative stress. Currently, comprehensive curative treatments and effective relapse prevention strategies are lacking. Recently, the "gut-skin axis" hypothesis has offered new insights into the pathological mechanisms of vitiligo. Studies indicate that gut microbiota and their metabolic products significantly affect disease progression by regulating immune homeostasis and inflammatory responses in the host. This review systematically examines the effects of short-chain fatty acids, secondary bile acids, and tryptophan metabolites on the human immune system and the inflammatory milieu, and their direct impact on melanocytes. Furthermore, considering the reduced diversity of gut microbiota in individuals with vitiligo, this article also evaluates methods including probiotic intervention, the Mediterranean diet, and fecal microbiota transplantation, which may emerge as potential therapeutic strategies for vitiligo by restoring microbiota balance. Future multidimensional therapeutic strategies that target gut microbiota metabolites show promise for pioneering innovative approaches in vitiligo management.

Keywords: gut microbiota; secondary bile acids; short-chain fatty acids; tryptophan; vitiligo.

Figure 1

The primary pathological process of vitiligo (Created in https://BioRender.com). Phase 1: Melanocyte stress response: Stressed melanocytes manifest pathophysiological alterations characterized by endoplasmic reticulum (ER) stress, elevated ROS, and DNA damage. These cellular distress signals are recognized by cutaneous innate immune sentinels—DCs, NKs cells, ILC1s, and FBs—which subsequently undergo activation through pattern recognition receptor signaling. Phase 2: Innate immune activation: This immunogenic cascade triggers the JAK–STAT signaling axis, inducing keratinocytes to overexpress chemokines CXCL9 and CXCL10. These IFN-γ-inducible chemokines mediate CD8 + T cell recruitment to the dermo-epidermal junction via CXCR3 receptor ligation. Phase 3: Adaptive Immune Execution: Cytotoxic Mechanisms: Infiltrating CD8 + T lymphocytes release IFN-γ and cytolytic mediators (perforin, granzyme B), directly inducing melanocyte apoptosis. IFN-γ amplifies MHC class I expression on residual melanocytes, enhancing autoimmune targeting. Macrophage-Mediated Inflammation: Tissue-resident macrophages phagocytize apoptotic melanocytes, subsequently secreting pro-inflammatory cytokines (TNF-α, IL-6, IL-1β). These cytokines perpetuate local inflammation, disrupt melanocyte stem cell niches, and inhibit pigment regeneration. Pathogenic Feedback Loop: Sustained cytokine release (particularly IFN-γ and TNF-α) reactivates keratinocyte JAK–STAT signaling, establishing a self-reinforcing inflammatory circuit that drives progressive depigmentation.

Figure 2

The impact of SCFAs on the immune system and inflammation in vitiligo (Created in https://BioRender.com). Dietary fiber-derived SCFAs (e.g., acetate, propionate, butyrate), generated through gut microbial fermentation, modulate cutaneous immune homeostasis via the gut-skin axis. At physiological concentrations, SCFAs enhance Tregs proliferation and potentiate their immunosuppressive capacity to restrain CD8 + T cell cytotoxicity and Th17-mediated inflammation. Mechanistically, SCFA-primed Tregs upregulate anti-inflammatory IL-10 secretion, which suppresses pro-inflammatory cytokines including IFN-γ and IL-17. Concurrently, SCFAs inhibit DCs maturation and downregulate the production of T cell-recruiting chemokines CXCL9 and CXCL10. Furthermore, SCFAs promote M2 macrophage polarization with concomitant IL-10 release, thereby facilitating tissue repair while suppressing inflammatory cascades. In contrast, supraphysiological SCFA levels exhibit paradoxical immunostimulatory effects: Th1/Th17 Polarization: Augment differentiation of Th1 and Th17 cells, elevating IFN-γ and IL-17 production. Keratinocyte Activation: Stimulate keratinocytes to release pro-inflammatory chemokines (CXCL9/CXCL10). CD8 + T Cell Recruitment: Enhance cutaneous infiltration of cytotoxic CD8 + T lymphocytes. Tissue-resident memory T cell maintenance: Sustain survival of autoreactive Trm cells in lesional skin.

Figure 3

The impact of SBAs and BCAAs on the immune system and inflammation in vitiligo (Created in https://BioRender.com). SBAs, synthesized through microbial metabolism of hepatically derived primary bile acids, exhibit predominant anti-inflammatory properties through multifaceted immunomodulatory mechanisms. Key regulatory pathways include: T Cell Homeostasis: SBAs enhance Tregs differentiation via the gut-immune axis, while suppressing the polarization of pro-inflammatory Th17 and Th1 lineages. This Tregs/Th17 imbalance attenuates IFN-γ-mediated immune responses and downregulates TNF-α expression. Cytotoxic Cell Suppression: SBAs signaling inhibits the cytotoxic activity of CD8 + T lymphocytes and natural killer (NK) cells, thereby reducing melanocyte targeting. Innate Immune Regulation: Dendritic cells: Suppress pro-inflammatory cytokine secretion. Macrophages: Downregulate IL-1β, IL-6, and TNF-α production through a TGR5-dependent mechanism. Synergistically ameliorates inflammatory microenvironments in cutaneous tissues. BCAAs demonstrate complementary immunoregulatory effects, potentially augmenting Treg populations through analogous gut-immune crosstalk.

Figure 4

The impact of Trp on the immune system and inflammation in vitiligo (Created in https://BioRender.com). Tryptophan, derived from protein-rich diets, undergoes gut microbiota-mediated metabolism primarily through three pathways: the KYN axis, 5-HT pathway, and indole derivative biosynthesis. In vitiligo pathogenesis, dysregulation of these metabolic cascades manifests as:1. KYN Pathway Hyperactivation: Pathological Accumulation: Elevated KYN and its derivatives; Immunopathological Mechanisms: AhR Signaling: KYN activates AhR signaling in keratinocytes, triggering CXCL10 overexpression that recruits cytotoxic CD8 + T cells to melanocyte-rich areas; IFN-γ Feedback Loop: KYN-stimulated NKs release IFN-γ, which further amplifies KYN biosynthesis and melanocyte destruction via IDO1 upregulation; Anti-Inflammatory Suppression: KYNA accumulation inhibits IL-10 production, exacerbating pro-inflammatory polarization. 2. 5-HT pathway disruption. Enzymatic Inhibition: IFN-γ downregulates TPH isoforms TPH1/TPH2, reducing cutaneous 5-HT bioavailability. Melanogenic Dysregulation: Depleted 5-HT disrupts its dual modulation of melanogenesis through 5-HT1A/1B and 5-HT7 receptor signaling. 3. indole metabolite depletion. immunological consequences: Reduced microbiota-derived indoles (e.g., indole-3-aldehyde, indoleacetic acid) impair their native anti-inflammatory functions; Promotes CD8 + T cell hyperactivation and M1 macrophage polarization; Suppresses Treg differentiation via PPAR-γ/STAT3 signaling axis dysregulation.