The gut microbiota influences blood-brain barrier (BBB) permeability in mice. Germ-free mice, starting from intrauterine life, showed increased BBB permeability compared to pathogen-free mice with normal gut flora. This increased permeability was maintained into adulthood and was associated with reduced expression of tight junction proteins occludin and claudin-5, which regulate BBB function. Exposure of germ-free mice to pathogen-free microbiota decreased BBB permeability and increased tight junction protein expression. The study suggests that gut microbiota-BBB communication begins during gestation and continues throughout life. The maternal gut microbiota can influence the prenatal development of the BBB. Ingestion of infrared-labeled IgG2b antibody by pathogen-free mothers showed a shift in antibody signal from diffuse to vascularized in embryos, indicating BBB integrity. In contrast, germ-free dams showed diffuse signal in brain parenchyma, suggesting increased BBB permeability. Analysis of tight junction proteins in brain lysates showed lower expression of occludin in germ-free mice. Lack of gut microbiota is associated with increased BBB permeability in adult mice. Three techniques confirmed this: in vivo PET imaging with [11C] raclopride, extravasation of Evans blue dye, and neuronal damage after R4A antibody administration. Germ-free adult mice showed increased BBB permeability, as evidenced by higher raclopride uptake, Evans blue leakage, and neuronal damage. In contrast, pathogen-free mice did not show these effects. Vascular density and pericyte coverage were similar in germ- and pathogen-free adult mice, indicating that increased BBB permeability was not due to vascular differences. Brain endothelial tight junctions were altered in germ-free mice, with lower expression of occludin and claudin-5. Conventionalization of germ-free mice with pathogen-free microbiota or SCFAs restored BBB integrity. SCFAs or bacterial metabolites affect BBB permeability. Monoculturing germ-free mice with C. tyrobutyricum or B. thetaiotaomicron, or administering sodium butyrate, reduced BBB permeability. Sodium butyrate increased occludin expression and histone acetylation in brain lysates. The BBB is a complex structure formed by endothelial cells, pericytes, and astrocytes. Gut microbiota influences BBB integrity through tight junction protein expression. The study highlights the role of gut microbiota in regulating BBB function, with implications for neurological diseases. The findings suggest that gut microbiota may modulate BBB permeability through tight junction protein expression, with potential therapeutic applications. The study also emphasizes the importance of understanding gut-brain communication for neurological health.The gut microbiota influences blood-brain barrier (BBB) permeability in mice. Germ-free mice, starting from intrauterine life, showed increased BBB permeability compared to pathogen-free mice with normal gut flora. This increased permeability was maintained into adulthood and was associated with reduced expression of tight junction proteins occludin and claudin-5, which regulate BBB function. Exposure of germ-free mice to pathogen-free microbiota decreased BBB permeability and increased tight junction protein expression. The study suggests that gut microbiota-BBB communication begins during gestation and continues throughout life. The maternal gut microbiota can influence the prenatal development of the BBB. Ingestion of infrared-labeled IgG2b antibody by pathogen-free mothers showed a shift in antibody signal from diffuse to vascularized in embryos, indicating BBB integrity. In contrast, germ-free dams showed diffuse signal in brain parenchyma, suggesting increased BBB permeability. Analysis of tight junction proteins in brain lysates showed lower expression of occludin in germ-free mice. Lack of gut microbiota is associated with increased BBB permeability in adult mice. Three techniques confirmed this: in vivo PET imaging with [11C] raclopride, extravasation of Evans blue dye, and neuronal damage after R4A antibody administration. Germ-free adult mice showed increased BBB permeability, as evidenced by higher raclopride uptake, Evans blue leakage, and neuronal damage. In contrast, pathogen-free mice did not show these effects. Vascular density and pericyte coverage were similar in germ- and pathogen-free adult mice, indicating that increased BBB permeability was not due to vascular differences. Brain endothelial tight junctions were altered in germ-free mice, with lower expression of occludin and claudin-5. Conventionalization of germ-free mice with pathogen-free microbiota or SCFAs restored BBB integrity. SCFAs or bacterial metabolites affect BBB permeability. Monoculturing germ-free mice with C. tyrobutyricum or B. thetaiotaomicron, or administering sodium butyrate, reduced BBB permeability. Sodium butyrate increased occludin expression and histone acetylation in brain lysates. The BBB is a complex structure formed by endothelial cells, pericytes, and astrocytes. Gut microbiota influences BBB integrity through tight junction protein expression. The study highlights the role of gut microbiota in regulating BBB function, with implications for neurological diseases. The findings suggest that gut microbiota may modulate BBB permeability through tight junction protein expression, with potential therapeutic applications. The study also emphasizes the importance of understanding gut-brain communication for neurological health.