Mechanisms underlying the intergenerational effects of Mycobacterium vaccae ATCC 15483T to promote stress resilience in mice.

• Applicant: Professor Dr. Stefan O. Reber
• Subject Area: Biological Psychiatry
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450542225

According to the "Old Friends" hypothesis, reduced exposure, particularly during early pre- and postnatal life, to immunoregulatory microorganisms contributes to the increased prevalence of stress-associated disorders in urban concrete landscapes of high-income countries. Accordingly, our own preclinical studies demonstrate that non-pathogenic rapid-growing mycobacteria (RGMs), including M. vaccae NCTC 11659 and M. vaccae ATCC 15483T, have immunoregulatory and stress-protective effects when administered repeatedly prior or during stressor exposure. Own unpublished preclinical findings revealed within the framework of a currently still ongoing DFG grant proposal advance these findings by showing that repeated administrations (i.g.) of female C57BL/6N mice with a heat-killed preparation of M. vaccae ATCC 15483T provide even intergenerational stress protection. Their male offspring, despite never being directly administered with RGMs, were resilient against multiple negative consequences of chronic psychosocial stress (i.e., chronic subordinate colony housing, CSC) during adulthood. Moreover, correlational analyses suggest the gut microbiome as potential mediator, as M. vaccae ATCC 15483T intergenerationally facilitated α-diversity and relative abundance of short-chain fatty acids (SCFAs) producing bacterial taxa. As adult female offspring of M. vaccae ATCC 15483T-administered mothers also showed an ameliorated immobilization stress-induced rise in plasma cytokine levels, it is likely that the intergenerational stress-protective effects of M. vaccae ATCC 15483T are independent of sex. Given that M. vaccae ATCC 15483T had opposite effects on the maternal gut microbiome (i.e., reduced SCFAs producing taxa only at weaning), it is one aim of the current proposal to unravel the role of the maternal gut microbiome and respective gut microbiome-derived SCFAs in the intergenerational effects of M. vaccae ATCC 15483T on the gut microbiome (investigated so far only in male offspring) and the facilitated stress resilience (reported in male and female offspring). Another aim is to investigate the role of maternal Tregs in the postpartum developing differences in the gut microbiome between vehicle and M. vaccae ATCC 15483T-administered mothers and, consequently, in the facilitated stress resilience of their male and female offspring. As intragenerational stress-protective effects of M. vaccae NCTC 11659 are at least partly mediated by Tregs, the final aim is to investigate the role of offspring's Tregs in the intergenerational stress protective effects of M. vaccae ATCC 15483T.

• DFG Programme: Research Grants