PROJECT SUMMARY/ABSTRACT:
Inflammatory bowel diseases (IBD) are becoming more prevalent in the US and represent a major societal health
concern. Exposure to psychosocial stressors increases the likelihood of developing IBD in genetically
predisposed individuals, implicating a brain-gut axis in the IBD etiological framework. An emerging line of work
has established that stress-induced disruptions to the gut microbiota (i.e. dysbiosis) may be the most proximate
cause of stress-induced IBD predisposition. This includes data from our laboratory where we showed that a
mouse adaptive pathogen (C. rodentium) was more effective at colonizing and inducing colitis in mice colonized
by a microbiota from mice exposed to a chronic social defeat stressor. Moreover, our new preliminary data
provides evidence stress exacerbates chronic, immune mediated (T-cell) colitis. However, how the gut
microbiota and mucosal layer becomes dysregulated in response to stressors and why those changes
predispose worsened colitis, is not yet understood. We recently demonstrated that stress induces large shifts in
intestinal epithelial cell (IEC) activity that tightly corresponded to changes in gut microbiota function and thinning
of the mucus layer. Of those changes observed in IECs, our preliminary data indicate that the reactive-oxygen
species (ROS)-generating capacity of IECs may be the most proximate causes of stress-induced dysbiosis and
mucosal disruption. Signs of stress in IECs were absent in germ-free (GF) mice at baseline, thus implicating the
microbiota in IEC responsiveness. Nevertheless, IECs were still primed to respond differentially to an ex vivo
bacterial challenge (evidenced by an increased expression in the ROS-generating enzyme dual oxidase
(DUOX2), suggesting that host stress signaling molecules and the gut microbiota are together involved in
regulating IEC activity. Intriguingly, the upregulation in DUOX2 and ROS activity in IECs corresponded to
expansion of ROS-resistant bacteria that are capable of mucus degradation. These data led us to build a
cohesive framework underlying this proposal, whereby stress hormones ‘prime’ IECs to respond to endogenous
microbiota signaling/adhesion through heightened ROS generation. This enhanced ROS activity at the mucosal
interface creates a unique niche for mucosal associated microbes that are resistant to ROS activity and survive
by degrading mucus glycans that normally provide a barrier against both endogenous microbes and pathogens.
We hypothesize that this IEC-directed expansion of ROS-resistant, mucus-degrading endogenous microbes is
what underlies IBD susceptibility in organisms exposed to chronic, unabated stress.
