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

Mol Psychiatry. 2026 May 22. doi: 10.1038/s41380-026-03638-9. Online ahead of print.

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. Repeated intragastric (i.g.) administration of a heat-killed preparation of Mycobacterium (M.) vaccae ATCC 15483^T (MvacATCC)vs. its vehicle borate-buffered saline (BBS) to adult nulliparous female C57BL/6N mice was intergenerationally protective against multiple negative physiological and immunological consequences of chronic subordinate colony housing (CSC; compared with respective single-housed control (SHC) mice), including adrenal hypertrophy, splenomegaly, thymus involution, and tibia growth reduction as well as increased splenic toll-like receptor (TLR) 2 and TLR4 protein concentrations and splenocyte ex vivo (re)activity, but also decreased splenic ex vivo glucocorticoid sensitivity, regulatory T cell (Treg) counts and Treg suppression capacity in their male offspring. In contrast, CSC-induced increase in splenic myeloid cell counts as well as of neutrophilic chemotactic activity was not affected intergenerationally by MvacATCC. Moreover, fecal microbiome analyses before and after CSC showed that MvacATCC intergenerationally facilitated α-diversity and relative abundance of bacterial taxa known to be potent short-chain fatty acid (SCFA) producers. Of note, we abstained from showing respective data of female offspring in the graphical abstract (*), as the intergenerational resilience effects of MvacATCC on female offspring were difficult to interpret. The latter was due to the fact that chronic adult stressor exposure (i.e., social instability paradigm, SIP) per se did not affect any of the physiological and immunological readouts reported in females. The graphical abstract was created with Biorender.com.

PMID:42174231 | DOI:10.1038/s41380-026-03638-9