Colonic Epithelial Differentiation-associated Remodeling and Gut Barrier Damage are Associated with Depressive-like Behaviors Under Chronic Stress
Jingwen Gao, Shanyao Xiao, Zhe Gao, Aoxue Yang, Jinqian Cheng, Jiayu Wen, Honghao Zhou, Guangji Wang, Jiye Aa, Yue ZhangIntroduction:
Major depressive disorder and gastrointestinal dysfunction are frequently comorbid in clinical populations, but the colonic epithelial programs that accompany stress-associated behavioral changes remain incompletely defined. The cellular heterogeneity of the intestinal epithelium further limits high-resolution dissection of stress-induced colonic dysfunction. We therefore profiled crypt-enriched colonic epithelium from a Chronic Social Defeat Stress (CSDS) model in male mice at single-cell resolution.
Methods:
We assessed behavior, colonic histology, permeability, and crypt-enriched single-cell transcriptomes during CSDS. Separate intervention experiments used systemic DAPT, a γ-secretase inhibitor, or intramucosal AAV-mediated Occludin expression; an antibiotic-depletion experiment was also performed.
Results:
Early CSDS was accompanied by social avoidance and detectable colonic inflammation, crypt injury, and barrier dysfunction, before the broader multidomain behavioral phenotype observed at day 10. Stress was associated with expansion of cycling colonic stem and transit-amplifying cells, impaired secretory-lineage maturation, disrupted tight-junction-associated programs, mucus-barrier impairment, bacterial encroachment, and enrichment of a Reg3b-high epithelial state. In the specific interventions used here, systemic pharmacological Notch inhibition or local AAV-mediated Occludin expression was accompanied by improvement in selected barrier-related readouts and stress-associated behavioral phenotypes.
Discussion:
These findings identify temporally coordinated colonic epithelial remodeling and barrier damage in male mice exposed to CSDS and support an association between epithelial homeostasis and depressive-like behaviors. This crypt-enriched dataset should therefore be interpreted as a cell-state-resolved resource that generates hypotheses for future epithelial-specific, lineage-tracing, and mechanistic studies.
Conclusion:
Colonic epithelial remodeling and barrier damage are associated with CSDS-associated depressive-like behaviors in male mice.