Barrier-Immune Gating Failure in Gut-Brain Neuroinflammation: A Working Hypothesis and Conceptual Framework

In the past two decades, advances in microbiomics and neuroimmunology have reframed the concept of "central immune privilege." Rather than simply proving a gut-brain connection, the translational challenge now lies in identifying how gut-derived signals are transmitted, filtered, amplified, or buffered across different neural, immune, metabolic, vascular, and barrier-related routes. Based on a structured narrative synthesis of experimental, translational, and clinical literature, this review presents barrier-immune-coupled gating failure as a working hypothesis and conceptual framework, rather than as a unifying explanation for all gut-brain interactions. Within this framework, three analytically separable but interacting dimensions are emphasized: (1) entry gating, referring to the threshold at which peripheral signals influence CNS boundary states; (2) boundary translation, in which signals are filtered or reshaped at interfaces such as the blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB), and meningeal immune zones; and (3) clearance gating, involving CSF drainage, meningeal lymphatics, glymphatic exchange, and protein or inflammatory-signal clearance. We highlight how gut-derived signals-filtered by the intestinal mucosa and gut-associated lymphoid tissue (GALT)-interact with immune set points and structural barriers. These interactions are modulated by factors such as short-chain fatty acids (SCFAs) and metabolite load, influencing whether signals are buffered or amplified. Recent findings show that skull bone marrow can directly supply immune cells to the meninges via transcortical vascular channels (TCVs), forming a responsive border niche susceptible to intestinal inflammation. At the cellular level, the review focuses on boundary-associated macrophages (BAMs) and disease-associated microglia (DAM) states, which bridge peripheral disruptions and central neuroinflammation. In selected contexts, reduced boundary buffering or impaired clearance may increase the likelihood that interface inflammation extends toward the parenchyma, particularly in proteinopathies with persistent inflammatory or protein burden. Finally, we propose a biomarker matrix for mechanistic stratification, which may help prioritize hypothesis-guided evaluation of barrier repair, drainage enhancement, immune set-point modulation, and cell-state reprogramming, while acknowledging that current human intervention evidence remains modest, inconsistent, or context-specific. By defining its scope and testable predictions, this framework may help move selected gut-brain studies from broad association toward more stratified and mechanism-oriented investigation.