Microbial Legacy: Mycobacterium vaccae ATCC 15483T intergenerationally diversifies the microbiome and enhances stress resilience in male mice

Abstract According to the “Old Friends” hypothesis, the increased prevalence of stress-associated disorders in urban concrete landscapes of high-income countries is at least in part due to a reduced exposure to immunoregulatory microorganisms. The latter is particularly impactful when occurring during early prenatal and postnatal life. Accordingly, our own preclinical studies demonstrate that non-pathogenic rapid-growing mycobacteria, including Mycobacterium ( M.) vaccae NCTC 11659 and M. vaccae ATCC 15483 T , have immunoregulatory and stress-protective effects when administered repeatedly prior to or during stressor exposure. Here, we advance these findings by showing that repeated intragastric (i.g.) administration of a heat-killed preparation of M. vaccae ATCC 15483 T to female C57BL/6 N mice provides intergenerational stress protection. Their male offspring, despite never directly receiving administration of rapid-growing mycobacteria, were protected against multiple adverse consequences of chronic stress in adulthood. Moreover, correlational analyses implicate the fecal microbiome as a potential mediator of these effects, with M. vaccae ATCC 15483 T intergenerationally facilitating α-diversity and increasing the relative abundance of bacterial taxa known to be potent short-chain fatty acid producers.