Stressor‐Enhanced Infectious Colitis is Due to Aberrant Colonic Epithelial Cell Signaling

Abstract

It has been long known that exposure to psychological stressors can exacerbate gastrointestinal disease, however the mechanism by which this occurs has not yet been fully elucidated. One hypothesis is that disruptions in the indigenous microbiota of the intestine by psychological stressors contribute to the exacerbation of disease. Recently, our laboratory has shown that exposing mice to the social stressor, namely, social disruption (SDR) significantly alters the intestinal microbiota community structure, and reduces the levels of beneficial species like Lactobacillus reuteri. These stressor‐induced changes in the microbiota can lead to increased proinflammatory cytokines (e.g., TNF‐α) and chemokines (e.g., CCL2) in the colons of mice challenged with the colonic pathogen Citrobacter rodentium. Exaggerated expression of these pro‐inflammatory cytokines and chemokines can enhance inflammatory monocyte recruitment, leading to enhanced colonic tissue damage. Thus, identifying the cellular source(s) of colonic TNF‐α and CCL2 during stressor exposure has important health implications. Due to close proximity with the colonic microbiota, we hypothesized that colonic epithelial cells (CEC) from stressor‐exposed mice would have increased expression of TNF‐α and CCL2 as compared to CEC from naïve mice. To test this hypothesis mice were exposed to SDR, which involves repeated social defeat, for 2 hours a night for 6 consecutive nights. The morning following the last night of the stressor, mice were euthanized, colons were excised, and both CEC and lamina propria cells were isolated. Results demonstrated that CEC from SDR‐exposed mice had significant increases in both TNF‐α and CCL2 gene expression as compared to CEC isolated from non‐stressed controls. Conversely, TNF‐α and CCL2 gene expression was unchanged in lamina propria cells from stressor exposed mice when compared their control counterparts. Together, these data have led to the proposed model that stressor exposure can lead to aberrant inflammatory gene expression in colonic epithelial cells, which may prime the colon for an overzealous inflammatory response when challenged with an enteric pathogen following stressor exposure.Support or Funding InformationSupported by NIH grant AT006552‐01A1 (M.T.B).