Short-term caloric restriction partially reprograms immune and microbial networks during acute DSS-induced colitis.

BACKGROUND AND AIMS: The effects of caloric restriction (CR) during active colitis remain incompletely understood. We examined whether short-term CR, initiated during dextran sodium sulfate (DSS)-induced inflammation, modulates disease severity, host transcriptional responses, and gut microbiota composition. Cross-species transcriptomic analyses were used to contextualize these effects within established human ulcerative colitis (UC) signatures.

METHODS

Male C57BL/6 mice were assigned to control, CR, DSS, or DSS with concurrent CR (DSS.CR) groups. Clinical disease activity, histopathology, hematology, anxiety-like behavior, colon and spleen transcriptomes (RNA-seq), and fecal microbiota (16S rRNA) were assessed. Public UC microarray datasets were used to compare DSS and DSS.CR transcriptional profiles with human active and inactive UC.

RESULTS

Compared with DSS, DSS.CR mice showed modest but consistent improvements in stool consistency and bleeding, with limited effects on overall histopathological scores, and reduced splenic enlargement and disruption. Transcriptomic analysis revealed limited differential gene expression between DSS and DSS.CR, but gene set enrichment analysis indicated reduced activation of inflammatory pathways (e.g., NF-κB, IL-17, cytokine–cytokine receptor) and relative enhancement of epithelial renewal and proteostasis programs. CR also partially mitigated DSS-associated dysbiosis, modestly preserving microbial diversity and functional pathways linked to carbohydrate metabolism and detoxification. Human microarray meta-analyses confirmed that DSS recapitulates active UC signatures, while CR shifted these toward a remission-like profile.

CONCLUSIONS

Short-term CR during acute DSS-induced colitis partially attenuated mucosal and systemic inflammation and modestly shifted transcriptional and microbial profiles toward epithelial repair and metabolic resilience. These findings highlight CR’s potential as a non-pharmacological adjunct for modulating intestinal inflammation and support further translational evaluation of feasible dietary restriction strategies in IBD.