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. 2024 Jul 22;10(15):e34932.
doi: 10.1016/j.heliyon.2024.e34932. eCollection 2024 Aug 15.

Aloe-emodin alleviates inflammatory bowel disease in mice by modulating intestinal microbiome homeostasis via the IL-4/IL-13 axis

Dong Yang  1 , Tingrui Ge  1 , Jingyi Zhou  1 , Huazhuan Li  1 , Yonggang Zhang  1
Affiliations

Aloe-emodin alleviates inflammatory bowel disease in mice by modulating intestinal microbiome homeostasis via the IL-4/IL-13 axis

Dong Yang et al. Heliyon. .

Abstract

Introduction: Inflammatory bowel disease (IBD) is a global health concern. Aloe-emodin (AE) has diverse pharmacological benefits, including anti-inflammatory effects. However, its role in IBD remains unclear, prompting our investigation of its regulatory effects and mechanisms in an IBD mouse model.

Methods: We studied the therapeutic efficacy of AE in alleviating symptoms and modulating cytokine secretion in a murine model of dextran sulfate sodium (DSS)-induced colitis. BALB/c mice were administered DSS to induce colitis and were subsequently treated with varying doses of AE. Changes in body weight, fecal lipocalin-2 (LCN2) levels, colon tissue histology, and serum cytokine concentrations were evaluated to assess the effects of AE treatment. Additionally, 16 S rRNA sequencing was used to analyze alterations in the composition of the gut microbiota following AE intervention. Finally, the database was used to analyze the signaling pathways associated with IBD in AE and to detect the expression levels of interleukin (IL)-4 pathway using real-time quantitative reverse transcription PCR. Exogenous IL-4 was used in rescue experiments to observe its effects on the disease process of IBD under AE regulation.

Results: AE treatment resulted in a dose-dependent mitigation of weight loss, reduction in fecal LCN2 levels, and amelioration of histological damage in DSS-induced colitis in mice. The levels of superoxide dismutase and catalase increased, whereas malondialdehyde decreased following AE treatment, indicating a dose-dependent alleviation of colitis symptoms. Furthermore, AE administration attenuated the secretion of pro-inflammatory cytokines, including IL-17, tumor necrosis factor-alpha (TNF-α), and chemokine ligand 1, while promoting the expression of anti-inflammatory cytokines IL-4 and IL-13. Analysis of the gut microbiota revealed that AE effectively suppressed the overgrowth of colitis-associated bacterial species and restored microbial homeostasis. Finally, we found that overexpression of IL-4 was able to reverse the therapeutic effect of AE for DSS-induced IBD.

Conclusion: AE shows promise in alleviating colitis severity, influencing inflammatory cytokines, and modulating the gut microbiota in an IBD mouse model via the IL-4/IL-13 pathway, suggesting its potential as a natural IBD remedy.

Keywords: Aloe-emodin; IL-4/IL-13 pathway; Inflammatory bowel disease; Intestinal microbiome.

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Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dong Yang reports financial support was provided by Lianyungang Traditional Chinese Medicine Science and Technology Development Plan Project. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
AE alleviates mice colitis induced by DSS. A: Changes in body weights of mice were monitored following treatment with different doses of AE in a mouse model of colitis induced by DSS.B: Intestinal inflammation marker LCN2 in feces. Levels of LCN2 in fecal samples collected from mice were measured as a marker of intestinal inflammation.C: H&E staining of colon tissue sections. Histological evaluation of colon tissue slices stained with H&E to assess tissue damage and inflammation. Representative images are shown. Data are shown as mean ± SD, ***P < 0.001: compared with control group; ##P < 0.01 and ###P < 0.001: compared with DSS group. Representative results from one out of three independent experiments.
Fig. 2
Fig. 2
AE reduces the inflammatory cytokines in the DSS-induced colitis in mice. A: Inflammatory cytokines IL-17 and TNF-α in serum detected by ELISA. B: Chemokines CXCL1 in serum detected by ELISA. C: Th17 cells in mesenteric lymph nodes detected by Flow cytometry. Data are shown as mean ± SD, ***P < 0.001: compared with control group; #P < 0.05, ##P < 0.01 and ###P < 0.001: compared with DSS group. Representative results from one out of three independent experiments.
Fig. 3
Fig. 3
AE restrains oxidative stress and improves the intestinal mucosa barrier in the DSS-induced colitis in mice. A: Concentrations of T-SOD, CAT, and MDA in the colon were measured in colon tissues of mice treated with variable doses of AE using ELISA. B: Assessment of apoptosis in colon tissue slices following treatment with AE using the TUNEL assay. Data are presented as mean ± SD, ***P < 0.001: compared with control group; #P < 0.05, ##P < 0.01 and ###P < 0.001: compared with DSS group. Representative results from one out of three independent experiments.
Fig. 4
Fig. 4
AE regulates the composition and function of intestinal microbiota in the DSS-induced colitis in mice. A: Venn diagram illustrating the overlap of intestinal flora among three groups of mice: control, DSS, and AE-treated (50 mg/kg). The diagram demonstrates comparable species diversity across the groups, with a total of 594 bacterial communities identified. B: Abundance maps of phylum classification level depicting the predominant phyla observed in each group, including Firmicutes, Bacteroidetes, Saccharibacteria, Actinobacteria, and Proteobacteria. C: Abundance maps of species classification level illustrating the impact of AE treatment (50 mg/kg) on specific bacterial species. Notably, AE treatment (50 mg/kg) effectively suppresses the overgrowth of Acetatifactor muris induced by colitis, restoring its abundance to normal levels. Representative results from one out of three independent experiments.
Fig. 5
Fig. 5
AE activates the IL-4/IL-13 pathway in the DSS-induced colitis in mice. A:Bioinformatics analysis reveals 12 common targets of AE in colitis. B:Gene Ontology analysis illustrates functional annotations of the identified targets.C:RT-PCR analysis demonstrates the expression levels of IL-4 and IL-13 in intestinal tissues of mice before and after 50 mg/kg AE treatment.D:Mouse body weight changes following IL-4 intervention in DSS-induced colitis mice, indicative of AE-like alleviation of colitis-induced weight loss.E:H&E staining and histological scoring of colon tissue sections depict the protective effect of exogenous IL-4 on DSS-induced intestinal injury. Data are presented as mean ± SD, **P < 0.01 and ***P < 0.001: compared to control group; #P < 0.05 and ##P < 0.01: compared with DSS and pc-DNA-NC + AE group. Representative results from one out of three independent experiments.
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