Early life adversity promotes a milieu in favor of catabolic bone turnover in females: Mycobacterium vaccae NCTC 11659 proofs protective in preclinical studies.

Despite early clinical studies supporting the hypothesis that early life adversity (ELA) negatively affects the bone and despite typical ELA-associated disorders, including post-traumatic stress disorder (PTSD) and major depressive disorder (MD), are associated with osteoporosis and increased bone fracture risk, preclinical studies do not support this association. However, previous studies were only conducted in male but not female mice. In the current study we showed that ELA, induced by the classical maternal separation (MS) paradigm, facilitated femoral osteoclast activity specifically in female but not male mice. This was associated with a transient decline in both intestinal alpha diversity and Firmicutes/Bacteroidetes ratio, suggesting that the microbiome-gut-bone axis is involved in these effects. Moreover, ELA long-lastingly increased the femoral mRNA expression of the proinflammatory cytokine interleukin-6 (IL-6) and the osteoclastic markers Cathepsin K and RANKL. Importantly, all sex-specific ELA effects on bone were absent in female mice administered with M. vaccae NCTC (National Collection of Type Cultures) 11659 following ELA exposure. Finally, our clinical data indicate strong associations between ELA and development of an osteopenic/osteoporotic bone phenotype in postmenopausal women undergoing bone diagnostics. Together, our preclinical and clinical findings indicate that i) ELA negatively affects the bone, ii) these effects are specific for female sex, iii) the negative effects of ELA on female bone are associated with transient changes in the composition of the intestinal microbiome followed by long-lasting activation of the immune system and the HPA axis, together setting the stage for a facilitated catabolic bone turnover and development of an osteopenic/osteoporotic bone phenotype, iv) developing immunoregulatory approaches, such as repeated s.c. administrations with immunoregulatory microorganisms, have potential for prevention/treatment of ELA-related bone disorders.