UC San Diego

The association between intestinal diseases, mood disorders and cognitive deficits is increasingly recognized. Previous studies from our lab suggest that chronic intestinal diseases, such as infection with an enteric pathogen, in combination with an acute psychological stressor (water avoidance stress [WAS]), can induce anxiety-like behavior and memory defects in mice. In our current study, we hypothesized that nucleotide binding oligomerization domain (Nod) receptors, as important modulators of homeostasis between the host immune system and the gut microbiota, are integral regulators of the microbiota-gut-brain (MGB) axis. Using Nod1/Nod2 double knockout (NodDKO) mice, we performed behavioral testing, qPCR analysis of stool bacterial DNA, and serum corticosterone analysis. Compared to wild type (WT) controls (C57BL/6), NodDKO mice displayed anxiety- like behaviors (light/dark box test, p<0.001) and deficits in recognition memory (novel object recognition [NOR] test, p<0.001) following exposure to a single session of WAS. WT and NodDKO mice differed in the composition of their microbiota in 4 of 7 bacterial groups studied by qPCR, indicating the presence of intestinal dysbiosis in NodDKO mice. Baseline elevated levels of serum corticosterone were also observed in NodDKO mice. To evaluate a potential role for the microbiota in mediating these effects given the presence of dysbiosis in NodDKO mice, WT and NodDKO mice were co-housed at weaning and behavior assessed in adulthood. Co-housing indicated that Nod1/Nod2 receptors are important for recognition memory and anxiety-like behavior, with defects remaining despite partial microbiota normalization. Interestingly, co-housing also ameliorated the WAS-induced spike in corticosterone levels in co-housed WT and NodDKO mice. Therefore, our study indicates that Nod receptors serve as key signaling molecules, potentially acting via the hypothalamic- pituitary-adrenal (HPA) axis, to modulate the MGB axis in mice