Physical bacteria-neuron proximity and early cellular responses: a conceptual perspective

Recent experimental observations obtained in reduced in vitro systems have reported direct proximity between bacteria and neuronal cells associated with intracellular Ca²⁺ dynamics and transcriptomic alterations. In particular, studies involving Lactiplantibacillus plantarum and primary cortical neuronal cultures have described bacterial adhesion to neuronal surfaces together with modulation of neuroplasticity-associated proteins and gene networks related to cellular signaling and neuronal regulation. Current models of the microbiota-gut-brain axis primarily emphasize indirect communication mediated through metabolites, immune pathways, neuroendocrine signaling, vagal pathways, extracellular vesicles, and soluble mediators. Although these mechanisms possess substantial explanatory value, certain early cellular responses observed under conditions of direct bacteria-neuron proximity may not be fully interpretable exclusively through soluble signaling mechanisms. This manuscript proposes a conceptual perspective in which the neuronal membrane is considered a dynamic cellular interface potentially sensitive to localized mechanical, physicochemical, or membrane-associated perturbations generated under conditions of direct biological proximity. Within this context, intracellular Ca²⁺ dynamics are interpreted as possible early cellular responses that may emerge in association with membrane-associated perturbation. Potential candidate mechanisms including mechanosensitive ion channels, localized membrane perturbation, adhesion-associated signaling, cytoskeletal remodeling, membrane reorganization, and local physicochemical microenvironmental alterations are discussed together with alternative explanations involving soluble mediators, immune activation, extracellular vesicles, osmotic or ionic perturbations, and generalized cellular stress responses. Importantly, the currently available evidence derives exclusively from reduced experimental systems and does not establish physiological relevance or demonstrated neuromodulation in vivo. Rather than proposing an alternative model of microbiota-brain communication, this perspective aims to refine interpretation of emerging neurobacterial interface observations by defining experimentally testable hypotheses and mechanistically plausible questions for future investigation.