NOD‐like Receptors: Novel Regulators of the Microbiota‐Gut‐Brain Axis in Mice

Abstract

BackgroundThe crosstalk between the gut and the brain has revealed a complex communication system responsible for maintaining a proper gastrointestinal (GI) homeostasis as well as affect emotional mood and cognitive functions. The immune system, which is recognized to maintain the symbiotic relationship between the host and the microbiota, plays a pivotal role in the regulation of the microbiota‐gut‐brain (MGB) axis. Specifically, nucleotide binding oligomerization domain (Nod)‐like receptors (NLR), which sense bacterial pathogens and initiate the innate immune response, are essential in maintaining GI homeostasis. Moreover, their expression in the brain implicates them as potential prime mediators of the MGB axis. The hypothalamic‐pituitary adrenal (HPA) axis is a critical component of the stress response, and has been shown to be closely correlated to the MGB axis.HypothesisWe hypothesized that deficiency in NLRs, (i.e. Nod1/Nod2), will dysregulate the MGB axis, including mood, cognitive behavior, and GI physiology.MethodsAdult (6–8 weeks of age) male and female Nod1/Nod2 double knockout (NodDKO) and wild type (WT; C57Bl/6) mice were utilized. Mice were subjected to behavioral tests (novel object recognition [NOR] task, light/dark box, open field test) following exposure to an acute stress (water avoidance stress [WAS]) to assess recognition memory, anxiety‐like behavior, and general health, respectively.ResultsDeletion of Nod1 and Nod2 receptors reduced cognitive performance in both male and female mice following WAS compared to WT controls. In contrast, only male NodDKO mice exhibited anxiety‐like behavior vs. WT controls. These changes in behavior were accompanied by altered mRNA expression levels of genes for stress (↓corticotropin releasing factor receptor [CRFR]1; ↑CRFR2), cognition (↑brain‐derived neurotropic factor [BDNF]) and inflammation (↑tumor necrosis factor [TNF]α; ↓interleukin [IL]10) in the hippocampus and prefrontal cortex of NodDKO mice in a sexually dimorphic manner. Stress‐induced impairment in colonic physiology (↑short circuit current [Isc] and ↑conductance [G]) were also observed in NodDKO mice in addition to altered mRNA expression for pro‐inflammatory cytokines (↑IL6) and antimicrobial peptides (↓RegIIIγ).ConclusionOur study suggests that innate immune NLRs are important for the regulation of mood, cognitive memory and GI physiology in response to acute stress in part via an impaired HPA axis, demonstrating a critical role in the maintenance of the MGB axis and homeostasis.Support or Funding InformationThis work was funded by NIH 1R01AT009365‐01 (MGG), 5R21MH108154‐01 (MGG).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.