Gut Microbiome

Integrated multi-omics, network pharmacology, and experimental validation reveal the protective mechanisms of curcumol against DSS-induced ulcerative colitis.

TL;DR

Curcumol exerted protective effects in DSS-induced ulcerative colitis by reducing inflammation and mucosal barrier injury, partially normalizing gut microbial and metabolic profiles, and attenuating SPP1/CD44/PI3K/Akt-related signaling.

Key Findings

Curcumol significantly ameliorated DSS-induced body weight loss, reduced disease activity index scores, preserved colon length, and alleviated histopathological injury in C57BL/6J mice.

  • A mouse model of UC was established using 3% DSS in C57BL/6J mice.
  • CUR or 5-aminosalicylic acid (5-ASA) was administered once daily beginning on the first day of DSS exposure, with 5-ASA serving as a phenotypic positive control.
  • Protective effects were evaluated based on body weight change, disease activity index (DAI), colon length, and histopathological alterations.
  • Protective effects were generally more pronounced in the high-dose CUR group, with significant between-dose differences observed for selected endpoints (P < 0.05).

Curcumol decreased levels of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-17 in DSS-induced colitis mice.

  • Inflammatory cytokine levels were measured as part of pharmacodynamic evaluation.
  • Reductions were observed in all four measured cytokines: TNF-α, IL-1β, IL-6, and IL-17.
  • These effects were part of the broader anti-inflammatory and immunomodulatory activities attributed to CUR.
  • High-dose CUR group was selected for subsequent mechanistic studies based on pharmacodynamic and phenotypic evaluation.

Curcumol restored goblet cell abundance and partially restored protein expression of mucosal barrier molecules MUC2, claudin-1, ZO-1, and occludin.

  • Goblet cell abundance was assessed as a marker of mucosal integrity.
  • Barrier-related molecules evaluated included MUC2, claudin-1, ZO-1, and occludin.
  • The restoration of these barrier components indicates partial recovery of epithelial barrier function.
  • These findings suggest CUR reduces mucosal barrier injury in DSS-induced UC.

High-dose curcumol partially restored gut microbial diversity and reshaped community structure in DSS-treated mice.

  • Gut microbiota was assessed using fecal 16S rRNA gene sequencing.
  • Analysis was performed specifically in the high-dose CUR group selected based on pharmacodynamic evaluation.
  • CUR partially restored microbial diversity that had been reduced by DSS exposure.
  • Reshaping of community structure was observed alongside partial reversal of DSS-induced metabolic disturbances.

High-dose curcumol partially reversed DSS-induced fecal metabolic disturbances as assessed by untargeted metabolomics.

  • Fecal untargeted metabolomics was performed on the high-dose CUR group.
  • DSS-induced metabolic disturbances were partially reversed by CUR treatment.
  • This metabolomic analysis was part of a multi-omics approach that also included 16S rRNA sequencing and colonic transcriptome sequencing.
  • Metabolic findings were integrated with microbiome and transcriptomic data in the overall analysis.

Integrative analysis of mouse colonic transcriptomics, public human UC transcriptomic datasets, and network pharmacology converged on SPP1 and CD44 as candidate hub genes.

  • Three complementary analytical approaches were integrated: mouse colonic transcriptome sequencing, analysis of public human UC transcriptomic datasets, and network pharmacology.
  • SPP1 (secreted phosphoprotein 1) and CD44 were identified as candidate hub genes.
  • The PI3K/Akt signaling pathway was implicated as a key candidate pathway altered by DSS exposure and modulated by CUR.
  • PIK3CB was identified as a candidate component of this pathway.

Experimental validation confirmed that high-dose curcumol reduced expression of SPP1, CD44, and PIK3CB and decreased p-p85/p85 and p-Akt/Akt ratios.

  • Protein expression of SPP1, CD44, and PIK3CB was reduced following high-dose CUR intervention.
  • Phosphorylation ratios p-p85/p85 and p-Akt/Akt were decreased, indicating attenuation of PI3K/Akt pathway activation.
  • These findings validate the network pharmacology and transcriptomic predictions.
  • Results suggest the SPP1/CD44/PI3K/Akt signaling network contributes to CUR-mediated protection against DSS-induced UC.

Multiplex immunofluorescence showed a reduction in the macrophage-associated fraction of SPP1-positive cells after high-dose curcumol intervention.

  • Multiplex immunofluorescence was used to characterize cell-type-specific SPP1 expression.
  • The macrophage-associated fraction of SPP1-positive cells was specifically reduced by high-dose CUR.
  • This finding links CUR's immunomodulatory effects to macrophage-associated SPP1 signaling.
  • The result provides cellular-level specificity to the observed reduction in SPP1 expression.

What This Means

This research suggests that curcumol, a natural compound with anti-inflammatory properties, can protect against ulcerative colitis (UC) in a mouse model. When mice were treated with curcumol alongside a chemical that induces colitis (DSS), they experienced less weight loss, lower disease severity scores, better-preserved colon length, and less tissue damage compared to untreated colitis mice. Curcumol also reduced levels of inflammatory proteins (TNF-α, IL-1β, IL-6, IL-17), helped restore the gut's protective mucus-producing cells, and partially recovered the molecular 'glue' that holds the intestinal lining together — molecules like MUC2, claudin-1, ZO-1, and occludin. Higher doses of curcumol showed stronger effects than lower doses. Using a combination of advanced techniques including gut microbiome analysis, metabolite profiling, gene expression studies in mice, examination of human UC datasets, and computational network pharmacology, the researchers identified two proteins — SPP1 and CD44 — and a signaling pathway called PI3K/Akt as likely key targets through which curcumol works. Laboratory validation confirmed that curcumol reduced the activity of these proteins and dampened PI3K/Akt pathway signaling. Specialized imaging further showed that the reduction in SPP1 was specifically occurring in immune cells called macrophages, which play a central role in intestinal inflammation. This research suggests that curcumol may protect against colitis through multiple coordinated mechanisms: calming inflammation, strengthening the gut barrier, rebalancing the gut microbiome and its metabolites, and suppressing a specific immune signaling network (SPP1/CD44/PI3K/Akt). These findings provide a scientific basis for further investigation of curcumol as a potential therapeutic agent for UC, though further research including human clinical studies would be needed before any clinical application could be considered.

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Citation

Shu F, Chen K, Song Y, Li J, Shen M, Guo Z, et al.. (2026). Integrated multi-omics, network pharmacology, and experimental validation reveal the protective mechanisms of curcumol against DSS-induced ulcerative colitis.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1852138