Mycobacterium vaccae ATCC 15483T administered to nulliparous C57BL/6N mice prior to mating protects their male offspring against the negative consequences of prenatal stress

The prenatal period is a vulnerable phase for the offspring's development in utero and ex utero. Accordingly, negative environmental influences such as chronic maternal stress pose a major risk factor for the offspring to develop a variety of mental and physical disorders later in life. Many of these pathologies are accompanied by an over-reactive immune system and chronic low-grade inflammation, and prospective human and mechanistic animal studies strengthen the idea that an exaggerated immune (re)activity plays a causal role in their pathogenesis. In line with the latter, we have shown in mice that repeated administrations with heat-inactivated preparations of different immunoregulatory nontuberculous mycobacteria (NTM), such as M. vaccae NCTC 11659 and the closely related strain M. vaccae ATCC 15483^T promote immunoregulation and stress protection. In the current study, we extend these findings by showing that repeatedly administering M. vaccae ATCC 15483^T via the intragastric (i.g.) route to female mice prior to mating protected their male offspring against the negative consequences of prenatal stress (PS) exposure (i.e., restraint stress combined with daily alternating social instability from embryonic days 4 to 16) on the immune and musculoskeletal system. In detail, while male offspring of PS vs. noPS mothers in the vehicle (i.e., borate-buffered saline, BBS) group showed an increased splenic IgG expression, lipopolysaccharide (LPS) reactivity of isolated spleen cells and chemotactic activity of isolated white blood cells (WBCs), as well as a reduced femoral bone volume/total volume (BV/TV), trabecular tissue mineral density (TbTMD), trabecular thickness (TbTh) and trabecular number (TbN), these effects were absent in male offspring of the M. vaccae ATCC 15483^T group. The protective effects of M. vaccae ATCC 15483^T on female offspring are harder to interpret, as the latter were not as reliably affected by PS. Collectively, our findings indicate that repeated i.g. administration of M. vaccae ATCC 15483^T in an intergenerational manner is protective against the negative consequences of PS on the immune and musculoskeletal system.