Psychological stress modifies in vivo microbiota host-interactions in colonic epithelial cells. SUMATRA

Chronic psychological stress (PS) contributes to the evolution of chronic diseases via gut dysfunctions such as altered intestinal permeability, which has been linked to altered intestinal epithelial cell (IEC)-microbiota interactions. However, the impact of PS and associated microbiota changes on alterations of key IEC functions such as proliferation, differentiation or cell death remains largely unknown. Combining in vivo multi-omics approaches with an organoid model we aimed to characterize the impact of PS on both functional and transcriptomic response of IEC and their interactions with microbiota composition and diversity. We showed that repeated acute water avoidance stress (WAS) induced a region-specific remodeling of the gut epithelium transcriptome across four segments (jejunum, ileum, proximal and distal colon), with an upregulation of pro-proliferative/pro-regenerative functions in the distal colon. Using in situ approaches, we further showed that WAS increased the number of Ki67 and Casp3 immunoreactive (IR) cells in the crypts of the colonic distal epithelium as compared to controls. Next, we showed that WAS increased the luminal microbiota diversity and changed the composition of luminal and adherent-associated bacteria. These compositional changes were associated with a significant decrease in cecal concentrations of butyrate, acetate, and propionate as compared to control. We further demonstrated that fecal supernatant derived from WAS mice, as compared to controls, enhanced HT-29 cell proliferation in vitro. Finally, using multi-omics approaches based on covariance analysis that, in the colon, WAS-induced cell proliferation and cell death were associated with specific sets of host genes, involved in microtubule destabilization, actin structure and luminal and epithelial-associated bacteria such as Lachnospiraceae NK4A136g (L. NK4136g) or Bilophila. Altogether our study demonstrate that WAS induces in the distal colon a pro-proliferative response driven by associated microbial and intestinal epithelial transcriptomic signatures. Pharmacological and/or pre-probiotic targeting of these signatures might provide novel strategies to prevent WAS induced gut dysfunctions.