Mycobacterium vaccae NCTC 11659 attenuates early life adversity (ELA)-induced hippocampal neuroinflammation in mice

Early life adversity (ELA) is a potent risk factor for negative mental health outcomes, in part through its enduring effects on neuroimmune function. The hippocampus is particularly sensitive to stress across the lifespan, and neuroinflammatory signaling has been implicated as a mediator linking a life stress history to vulnerability. Accordingly, we hypothesized that ELA, in particular when followed by chronic psychosocial stress during adulthood (CAS), would enhance expression of inflammatory genes in the hippocampus and that these effects would be ameliorated by intervention with Mycobacterium vaccae (M. vaccae), a soil-derived mycobacterium with immunoregulatory properties. To test this, newborn male and female mice were exposed to the maternal separation (MS) paradigm between postnatal days (PNDs) 1-14 (i.e., 3h/day) before receiving repeated (3x) weekly (i.e., starting 1-2 weeks following weaning) subcutaneous (s.c.) administrations with sterile borate-buffered saline (BBS) as vehicle or a heat-killed preparation of M. vaccae NCTC (National Collection of Type Cultures) 11659 (0.1 mg/0.1 mL per s.c. injection) in sterile BBS. At the age of 7-8 weeks CAS was induced in males by the chronic subordinate colony housing (CSC) paradigm and in females by the social instability paradigm (SIP), before all mice were euthanized and hippocampal tissue was isolated by micropunch for RNA extraction and quantitative PCR analysis of neuroinflammatory markers. Among the panel of genes assessed, ELA significantly increased hippocampal expression of Iba1, CCL2, and IL-1β in vehicle- but not M. vaccae NCTC 11659-administered male and female mice. Surprisingly, CAS exposure alone did not affect hippocampal gene expression and even abrogated the reported ELA-induced expression changes. Together, these findings highlight hippocampal neuroimmune pathways as a mechanism by which predominantly ELA shapes long-term vulnerability, and support M. vaccae NCTC 11659 as a promising strategy for mitigating ELA-induced neuroinflammation.