The gut microbiota influences blood-brain barrier permeability in mice

Abstract

Pivotal to brain development and function is an intact blood-brain barrier (BBB), which acts as a gatekeeper to control the passage and exchange of molecules and nutrients between the circulatory system and the brain parenchyma. The BBB also ensures homeostasis of the central nervous system (CNS). We report that germ-free mice, beginning with intrauterine life, displayed increased BBB permeability compared to pathogen-free mice with a normal gut flora. The increased BBB permeability was maintained in germ-free mice after birth and during adulthood and was associated with reduced expression of the tight junction proteins occludin and claudin-5, which are known to regulate barrier function in endothelial tissues. Exposure of germ-free adult mice to a pathogen-free gut microbiota decreased BBB permeability and up-regulated the expression of tight junction proteins. Our results suggest that gut microbiota–BBB communication is initiated during gestation and propagated throughout life.

Microbiota and the control of blood-tissue barriers

“…72 These defects in permeability persisted into adulthood, as demonstrated by leakage of Evans blue dye into the brain parenchyma 71 and seminiferous tubules of the testis of mature mice. 72 This leakiness was associated with reduced expression of TJ proteins 71,72 : in the BBB, expression of claudin-5 and occludin was lower, while that of ZO-1 was unchanged; and in the BTB, expression of occludin and ZO-2 was lower. 72 Moreover, electron microscopy revealed that TJ in the brain of GF adult mice were disorganized.…”

“…Remarkably, these barriers could be "sealed" by recolonizing their intestines with fecal material from the control mice. Colonization with bacterial strains that produce only butyrate (Clostridium Tyrobutyricum) or acetate/probionate (Bacteroides thetaiotaomicron) restored the integrity of the brain parenchyma 71 and seminiferous tubules of the testis 72 as shown by exclusion of Evans blue dye. Furthermore, the protein components of the TJ complexes in these barriers were restored to control levels by either such colonization or butyrate alone.…”

“…In germ-free (GF) pregnant mouse dams, maturation of the fetal BBB was delayed 71 as was tubules formation in the postnatal testis. 72 These defects in permeability persisted into adulthood, as demonstrated by leakage of Evans blue dye into the brain parenchyma 71 and seminiferous tubules of the testis of mature mice.…”

“…In this system, butyrate elevated the levels of claudin-1, 3, 4, and 5, the latter by almost 300%. Furthermore, butyrate can enhance histone acetylation in the BBB in vivo 71 as well as in dendritic cells in vitro. 74 However, butyrate acts not only on the cells that form the barrier.…”

“…Furthermore, the protein components of the TJ complexes in these barriers were restored to control levels by either such colonization or butyrate alone. 72,71 Short-chain fatty acids (SCFA), provided either as pure sodium butyrate or generated by SCFA-producing bacteria, reestablished barrier functions in previously GF mice, but the underlying mechanism(s) remains unclear. One possibility we explored in the case of the BBB involves epigenetic modification in the form of enhanced histone acetylation stimulated by butyrate.…”