• Cutaneous microbial dysbiosis is associated with inflammatory signaling (e.g., IL-6, IL-17) and neuroimmune mediators that are relevant to affective symptoms, but direct causal evidence for brain outcomes remains limited. • Stress-related neuroendocrine signaling (HPA axis and sympathetic outflow) can impair skin barrier function and antimicrobial peptide expression, plausibly reshaping the skin microbial ecology and sustaining symptom-worsening feedback loops. • Tyrosinase-related pathways provide a hypothesis-generating biochemical bridge between peripheral pigmentation/inflammation and neuromelanin-related vulnerability, warranting targeted mechanistic validation. The skin functions as a neuro-immuno-endocrine organ with an extensive microbial interface capable of bidirectional signaling with the central nervous system. While the gut–brain axis is well established, the skin–microbiota–brain (SMB) axis remains underexplored, particularly with respect to affective symptom dimensions (depression, anxiety, stress) that commonly co-occur with chronic inflammatory dermatoses. This review synthesizes evidence across clinical, translational, and experimental studies and organizes it by strength (associational findings, mechanistic plausibility, and limited interventional signals). We outline a systems-level model in which cutaneous microbial dysbiosis is associated with brain-relevant pathways via immune, neuropeptide, and metabolic routes. Candidate mediators include cytokines (IL-6, IL-17, TNF-α), neuropeptides (e.g., substance P, CGRP), and microbial-derived metabolites (e.g., SCFA-like compounds and tryptophan catabolites). These signals are hypothesized to influence neuroimmune tone and neurovascular signaling based largely on broader systemic inflammation and stress biology; direct causal evidence specifically attributing affective outcomes to skin microbiome perturbations in humans remains limited. In parallel, top-down neuroendocrine signaling via hypothalamic–pituitary–adrenal (HPA) axis activation, cortisol-related signaling, and sympathetic outflow can alter skin barrier function, antimicrobial peptide expression, and microbial ecology, potentially contributing to symptom-maintaining loops (e.g., itch–sleep disruption–stress). Importantly, we consider counterarguments (psychosocial burden, reverse causality, treatment effects, and the localized nature of lesions) and identify research priorities required to test causality (longitudinal sampling, mechanistic biomarker panels, and preregistered interventional studies with affective endpoints and mediation analyses). By integrating dermatological, microbiological, and neuroimmunological evidence within a symptom-centered framework, the SMB axis is positioned as a biologically plausible but still evolving model that may help explain affective symptom burden in subsets of patients with inflammatory skin disease and guide mechanism-informed translational research.
Roberto Coccurello (Wed,) studied this question.