Yu S et al. (2023), Sea Cucumber Peptides Ameliorate DSS-Induced Ul...

ECB-ART-52700

Nutrients 2023 Nov 17;1522:. doi: 10.3390/nu15224813.

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Sea Cucumber Peptides Ameliorate DSS-Induced Ulcerative Colitis: The Role of the Gut Microbiota, the Intestinal Barrier, and Macrophage Polarization.

Yu S , Guo H , Ji Z , Zheng Y , Wang B , Chen Q , Tang H , Yuan B .

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The incidence of ulcerative colitis (UC) is increasing annually. There are few treatments for UC patients, and some drugs have serious side effects. Sea cucumber peptide (SCP) has anti-inflammatory, antioxidant and other biological activities, and various sea cucumber species are in pharmaceutical development. However, relevant studies on the effects of SCP on UC progression are still lacking. In this study, a mouse model of acute colitis was induced by 3% dextran sulfate (DSS), and the effect of 500 mg/kg SCP on colitis was investigated. The results showed that SCP can alleviate DSS-induced colon damage and intestinal barrier damage. SCP significantly inhibited the expression of inflammatory factors and oxidative stress in UC mice. SCP reversed the intestinal microbiota dysregulation induced by DSS, inhibited the growth of Sutterella, Prevotella_9 and Escherichia-Shigella harmful bacteria, and increased the abundance of Lachnospiraceae_NK4A136_group. At the same time, SCP treatment significantly inhibited the LPS-induced polarization of M1 macrophages, which may be mediated by two monopeptides, IPGAPGVP and TGPIGPPGSP, via FPR2. In conclusion, SCP can protect against colitis by modulating the intestinal microbiota composition and the intestinal barrier and inhibiting the polarization of M1 macrophages.

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	Figure 1. Effect of SCP on colitis model mice. (A) Establishment of a mouse model of enteritis. (B) Body weight changes in mice after 7 days of modeling. (C) Comparison of changes in body weight on day 7 between different groups. (D) DAI scores of mice at 7 days of modeling. (E) Comparison of changes in DAI scores on day 7 between different groups. (F) Schematic diagram of the length of the colon. (G) Comparison of colon length between different groups. (H) H&E staining between different groups. Data are shown as the mean ± SEM (n = 8), * p < 0.05, p < 0.01, ** p < 0.0001.
	Figure 2. Effect of SCP on colonic inflammation in mice. (A–C) Expression of IL-6, IL-1β, and TNF-α mRNA in colonic tissues. (D) Secretion of IL-6, IL-1β and TNF-α in colon homogenates. (E) Secretion of IL-6, IL-1β and TNF-α in mouse serum. Data are shown as the mean ± SEM (n = 3), ns, p > 0.5, p < 0.01, * p < 0.001, **** p < 0.0001.
	Figure 3. Effect of SCP on oxidative stress indicators in DSS-induced colitis mice. (A) Changes in indicators of oxidative stress in colon homogenates. (B) Changes in indices of oxidative stress in serum. Data are shown as the mean ± SEM (n = 3), p < 0.01, * p < 0.001, **** p < 0.0001.
	Figure 4. Effect of SCP on DSS-induced intestinal damage. (A) Representative Western blotting images of the tight junction proteins ZO-1, Occludin and Claudin-1. (B) Relative expression of the ZO-1 protein. (C) Relative expression of the occludin protein. (D) Relative expression of the claudin-1 protein. (E) AB-PAS staining of the colon samples from different groups. Data are shown as the mean ± SEM, ns p > 0.5, * p < 0.05, p < 0.01, ** p < 0.0001.
	Figure 5. Effect of SCP on the intestinal flora of colitis mice. (A–C) Dilution curves the for Chao1, Shannon, and Simpson indices. (D–F) The Chao1, Shannon, and Simpson indices for alpha diversity analysis. (G–I) Beta diversity analysis. (J) Histogram of community distribution at the portal level. (K) Histogram of genus level community distribution. (L–O) The abundance of bacterial genera. Data are shown as the mean ± SEM (n = 6), ns p > 0.5, * p < 0.05, **** p < 0.0001.
	Figure 6. Correlation of the gut flora and UC indicators. Blue: negative correlation, red: positive correlation. * p < 0.05, ** p < 0.0001. Correlation network analysis was performed using the OmicStudio tools at https://www.omicstudio.cn/tool, accessed on 20 October 2023.
	Figure 7. Effect of SCP on cell proliferation and macrophage polarization. (A,B) Detection of the viability of Raw 264.7 (left) and HT29 (right) cells. (C–E) Expression of the relevant inflammatory factors IL-6, IL-1β and TNF-α. (F–H) Graphs of macrophage polarization results in different treatment groups. All data are shown as the mean ± SEM, ns p > 0.5, * p < 0.05, p < 0.01, * p < 0.001, **** p < 0.0001.
	Figure 8. Identification of small peptides in SCP and molecular docking. (A) Mass spectra of the GIPGAPGVP small peptide. (B) Predicted molecular docking of GIPGAPGVP with FPR2. (C) Mass spectra of the TGPIGPPGSP small peptide. (D) Predicted molecular docking of TGPIGPPGSP with FPR2.

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	Figure 1. Effect of SCP on colitis model mice. (A) Establishment of a mouse model of enteritis. (B) Body weight changes in mice after 7 days of modeling. (C) Comparison of changes in body weight on day 7 between different groups. (D) DAI scores of mice at 7 days of modeling. (E) Comparison of changes in DAI scores on day 7 between different groups. (F) Schematic diagram of the length of the colon. (G) Comparison of colon length between different groups. (H) H&E staining between different groups. Data are shown as the mean ± SEM (n = 8), * p < 0.05, p < 0.01, ** p < 0.0001.
	Figure 2. Effect of SCP on colonic inflammation in mice. (A–C) Expression of IL-6, IL-1β, and TNF-α mRNA in colonic tissues. (D) Secretion of IL-6, IL-1β and TNF-α in colon homogenates. (E) Secretion of IL-6, IL-1β and TNF-α in mouse serum. Data are shown as the mean ± SEM (n = 3), ns, p > 0.5, p < 0.01, * p < 0.001, **** p < 0.0001.
	Figure 3. Effect of SCP on oxidative stress indicators in DSS-induced colitis mice. (A) Changes in indicators of oxidative stress in colon homogenates. (B) Changes in indices of oxidative stress in serum. Data are shown as the mean ± SEM (n = 3), p < 0.01, * p < 0.001, **** p < 0.0001.
	Figure 4. Effect of SCP on DSS-induced intestinal damage. (A) Representative Western blotting images of the tight junction proteins ZO-1, Occludin and Claudin-1. (B) Relative expression of the ZO-1 protein. (C) Relative expression of the occludin protein. (D) Relative expression of the claudin-1 protein. (E) AB-PAS staining of the colon samples from different groups. Data are shown as the mean ± SEM, ns p > 0.5, * p < 0.05, p < 0.01, ** p < 0.0001.
	Figure 5. Effect of SCP on the intestinal flora of colitis mice. (A–C) Dilution curves the for Chao1, Shannon, and Simpson indices. (D–F) The Chao1, Shannon, and Simpson indices for alpha diversity analysis. (G–I) Beta diversity analysis. (J) Histogram of community distribution at the portal level. (K) Histogram of genus level community distribution. (L–O) The abundance of bacterial genera. Data are shown as the mean ± SEM (n = 6), ns p > 0.5, * p < 0.05, **** p < 0.0001.
	Figure 6. Correlation of the gut flora and UC indicators. Blue: negative correlation, red: positive correlation. * p < 0.05, ** p < 0.0001. Correlation network analysis was performed using the OmicStudio tools at https://www.omicstudio.cn/tool, accessed on 20 October 2023.
	Figure 7. Effect of SCP on cell proliferation and macrophage polarization. (A,B) Detection of the viability of Raw 264.7 (left) and HT29 (right) cells. (C–E) Expression of the relevant inflammatory factors IL-6, IL-1β and TNF-α. (F–H) Graphs of macrophage polarization results in different treatment groups. All data are shown as the mean ± SEM, ns p > 0.5, * p < 0.05, p < 0.01, * p < 0.001, **** p < 0.0001.
	Figure 8. Identification of small peptides in SCP and molecular docking. (A) Mass spectra of the GIPGAPGVP small peptide. (B) Predicted molecular docking of GIPGAPGVP with FPR2. (C) Mass spectra of the TGPIGPPGSP small peptide. (D) Predicted molecular docking of TGPIGPPGSP with FPR2.