The Sex-Specific Effects of Early Life Adversity and Chronic Psychosocial Stress during Adulthood on Bone Are Mitigated by Mycobacterium vaccae NCTC 11659 in Mice

Abstract

Introduction: Chronic stress is a major burden in our society and increases the risk for various somatic and mental diseases, in part via promoting chronic low-grade inflammation. Interestingly, the vulnerability for chronic stress during adulthood varies widely among individuals, with some being more resilient than others. For instance, women, relative to men, are at higher risk for developing typical stress-related diseases, including depression and posttraumatic stress disorder (PTSD). Moreover, the experience of early life adversity (ELA) may increase an individuals' vulnerability for chronic stress during adulthood (CAS), possibly due to its association with chronic inflammation. Because severe consequences of stress-induced immune activation are a dysregulated endochondral ossification, delayed long-bone growth, and bone regeneration following fracture, the aim of this study was to investigate the sexspecific effects of ELA alone or in combination with CAS on bone. As enhancement of an individuals' immunoregulatory potential by repeated administrations of a heat-inactivated preparation of Mycobacterium vaccae NCTC (National Collection of Type Cultures) 11659 has been shown to promote stress resilience in mice, we further aimed to investigate if M. vaccae NCTC 11659 also protects against the negative effects of ELA/CAS on bone. Methods: Male and female C57BL/ 6N mice were subjected to ELA using a maternal separation (MS) model. CAS was induced by either using the chronic subordinate colony housing (CSC) paradigm in males or the social instability paradigm (SIP) in females. The effects on bone were evaluated by μCT, histological, and gene expression analysis. M. vaccae NCTC 11659 was administered repeatedly s.c. prior to CAS. Results: No cumulative impact of ELA and CAS on bone could be detected. Female mice seem to be more susceptible to ELA while male mice to CAS. Importantly, repeated M. vaccae NCTC 11659 administrations were able to mitigate the negative consequences of stress on bone in both sexes. Conclusion: Our results support the hypotheses that the negative effects of ELA and CAS on bone are highly sex-dependent. Moreover, repeated s.c. administrations with immunoregulatory microorganisms might be a future therapeutic option for stress-related bone disorders.