Alterations in the Histamine Axis Are Associated with Increased BBB Permeability and Streptococcus suis Invasion

Streptococcus suis (S. suis) is a zoonotic pathogen capable of causing meningitis and other diseases. However, the molecular mechanisms underlying its ability to cross the blood brain barrier (BBB) and invade the central nervous system remain incompletely understood. In this study, non-targeted metabolomics was used to investigate the effects of S. suis type 2 strain HA9801 infection on the metabolic profile of human brain microvascular endothelial cells (hBMECs), and to examine associations between key metabolites and BBB permeability. The results showed that HA9801 infection induced changes in the metabolic profile of hBMECs, with significant enrichment of the histidine metabolism pathway. Notably, several histamine-related metabolites were altered. Changes in HDC and HNMT gene expression, together with alterations in histamine-related metabolites detected by non-targeted metabolomics, were consistent with changes in histamine-related metabolism. These observed metabolic alterations were accompanied by significant accumulation of endogenous histamine, which was accompanied by reduced expression of tight junction protein genes (TJP1, OCLN, and CLDN5) and increased BBB permeability. Moreover, elevated histamine levels were associated with increased invasion and translocation of S. suis across the BBB. This study suggests that S. suis impairs BBB integrity in association with alterations in the host histidine–histamine metabolic axis, which were accompanied by increased histamine levels, reduced expression of tight junction protein genes, and enhanced bacterial invasion and translocation. These findings identify histamine-associated signaling as a potential pathway for further investigation in S. suis-associated BBB dysfunction.