Background and Aims

Gut bacteria-derived short-chain fatty acids (SCFAs) play crucial roles in the maintenance of intestinal homeostasis. However, how SCFAs regulate epithelial turnover and tissue repair remain incompletely understood. In this study, we investigated how the SCFA propionate regulates cell migration to promote epithelial renewal and repair.

Methods

Mouse small intestinal epithelial cells (MSIE) and human Caco-2 cells were used to determine the effects of SCFAs on gene expression, proliferation, migration, and cell spreading in vitro. Video microscopy and single cell tracking were used to assess cell migration kinetically. 5-bromo-2’-deoxyuridine (BrdU) and hydroxyurea were used to assess the effects of SCFAs on migration in vivo. Lastly, an acute colitis model using dextran sulfate sodium (DSS) was used to examine the effects of SCFAs in vivo.

Results

Using video microscopy and single cell tracking, we found that propionate promoted intestinal epithelial cell migration by enhancing cell spreading and polarization, which led to increases in both cell speed and persistence. This novel function of propionate was dependent on inhibition of class I histone deacetylases (HDAC) and GPR43 and required signal transducer and activator of transcription 3 (STAT3). Furthermore, using 5-bromo-2’-deoxyuridine (BrdU) and hydroxyurea in vivo, we found that propionate enhanced cell migration up the crypt-villus axis under homeostatic conditions, while also protecting against ulcer formation in experimental colitis.

Conclusion

Our results demonstrate a mechanism by which propionate stimulates cell migration in an HDAC inhibition, GPR43, and STAT3 dependent manner, and suggest that propionate plays an important role in epithelial migration independent of proliferation.

中文翻译：

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丙酸盐提高细胞速度和持久性以促进肠上皮细胞更新和修复

背景和目标

肠道细菌衍生的短链脂肪酸 (SCFA) 在维持肠道稳态中发挥着至关重要的作用。然而，SCFAs 如何调节上皮周转和组织修复仍不完全清楚。在这项研究中，我们研究了 SCFA 丙酸盐如何调节细胞迁移以促进上皮更新和修复。

方法

小鼠小肠上皮细胞 (MSIE) 和人 Caco-2 细胞用于确定 SCFA 对体外基因表达、增殖、迁移和细胞扩散的影响。视频显微镜和单细胞跟踪用于动态评估细胞迁移。5-bromo-2'-deoxyuridine (BrdU) 和羟基脲用于评估 SCFA 对体内迁移的影响。最后，使用硫酸葡聚糖钠 (DSS) 的急性结肠炎模型来检查短链脂肪酸在体内的作用。

结果

使用视频显微镜和单细胞跟踪，我们发现丙酸盐通过增强细胞扩散和极化来促进肠上皮细胞迁移，从而提高细胞速度和持久性。丙酸盐的这种新功能依赖于 I 类组蛋白脱乙酰酶 (HDAC) 和 GPR43 的抑制，并且需要信号转导和转录激活因子 3 (STAT3)。此外，在体内使用 5-bromo-2'-deoxyuridine (BrdU) 和羟基脲，我们发现丙酸盐在稳态条件下增强了细胞沿隐窝绒毛轴的迁移，同时还可以防止实验性结肠炎中的溃疡形成。

结论

我们的研究结果证明了丙酸盐以 HDAC 抑制、GPR43 和 STAT3 依赖性方式刺激细胞迁移的机制，并表明丙酸盐在不依赖于增殖的上皮迁移中起重要作用。