Metformin Improves Ileal Epithelial Barrier Function in Interleukin-10 Deficient Mice.
Metformin Improves Ileal Epithelial Barrier Function in Interleukin-10 Deficient Mice.
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DOI：
10.1371/journal.pone.0168670
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Zhu MJ
中科院分区：
文献类型：
--
作者：
Xue Y;Zhang H;Sun X;Zhu MJ
肠上皮屏障功能受损是炎症性肠病的主要病因。肠上皮细胞的增殖和分化是维持肠道完整性的关键。二甲双胍是一种常见的抗糖尿病药物。目的是使用白细胞介素-10缺陷（IL 10 KO）小鼠评价二甲双胍对回肠上皮屏障完整性的保护作用。野生型和IL 10 KO小鼠在含/不含二甲双胍的情况下喂食6周，然后收集回肠进行分析。通过体外功能获得和丧失的研究，进一步验证了AMPK的介导作用。与野生型小鼠相比，IL 10 KO小鼠回肠组织中的增殖增加，杯状细胞和潘氏细胞谱系分化减少，这伴随着隐窝扩张增加。补充蛋氨酸可减轻肠细胞增殖，恢复绒毛/隐窝比，增加杯状细胞和潘氏细胞分化，改善屏障功能。此外，在IL 10 KO小鼠中补充二甲双胍可抑制巨噬细胞促炎活性，如M1巨噬细胞丰度降低和促炎细胞因子IL-1β、TNF-α和IFN-γ表达降低所示。作为二甲双胍的靶点，AMPK磷酸化在二甲双胍治疗的小鼠中增强，与小鼠基因型无关。与此相关，在补充二甲双胍的IL 10 KO小鼠中，分化调节因子（包括bmp 4、bmpr 2和math 1）的mRNA水平也增加，这可能解释了二甲双胍增强的IL 10 KO小鼠上皮分化。一致地，在Caco-2细胞中，二甲双胍促进紧密连接蛋白-3和E-cadherin组装，并减轻TNF-α诱导的紧密连接蛋白片段化。AMPK功能获得和丧失试验也证实AMPK与上皮细胞分化和增殖有关。补充二甲双胍促进分泌细胞谱系分化，抑制炎症，并可能通过激活AMPK改善IL 10 KO小鼠的上皮屏障功能，显示其对肠道上皮的有益作用。
The impairment of intestinal epithelial barrier is the main etiologic factor of inflammatory bowel disease. The proper intestinal epithelial proliferation and differentiation is crucial for maintaining intestinal integrity. Metformin is a common anti-diabetic drug. The objective is to evaluate the protective effects of metformin on ileal epithelial barrier integrity using interleukin-10 deficient (IL10KO) mice. Wild-type and IL10KO mice were fed with/without metformin for 6 weeks and then ileum was collected for analyses. The mediatory role of AMP-activated protein kinase (AMPK) was further examined by gain and loss of function study in vitro. Compared to wild-type mice, IL10KO mice had increased proliferation, reduced goblet cell and Paneth cell lineage differentiation in the ileum tissue, which was accompanied with increased crypt expansion. Metformin supplementation mitigated intestinal cell proliferation, restored villus/crypt ratio, increased goblet cell and Paneth cell differentiation and improved barrier function. In addition, metformin supplementation in IL10KO mice suppressed macrophage pro-inflammatory activity as indicated by reduced M1 macrophage abundance and decreased pro-inflammatory cytokine IL-1β, TNF-α and IFN-γ expressions. As a target of metformin, AMPK phosphorylation was enhanced in mice treated with metformin, regardless of mouse genotypes. In correlation, the mRNA level of differentiation regulator including bmp4, bmpr2 and math1 were also increased in IL10KO mice supplemented with metformin, which likely explains the enhanced epithelial differentiation in IL10KO mice with metformin. Consistently, in Caco-2 cells, metformin promoted claudin-3 and E-cadherin assembly and mitigated TNF-α-induced fragmentation of tight junction proteins. Gain and loss of function assay also demonstrated AMPK was correlated with epithelial differentiation and proliferation. Metformin supplementation promotes secretory cell lineage differentiation, suppresses inflammation and improves epithelial barrier function in IL10KO mice likely through activation of AMPK, showing its beneficial effects on gut epithelial.
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影响因子：
9.8
作者：
Fellermann, Klaus;Stange, Daniel E.;Stange, Eduard F.
通讯作者：
Stange, Eduard F.
影响因子：
14.2
作者：
Groschwitz, Katherine R.;Hogan, Simon P.
通讯作者：
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影响因子：
4.9
作者：
Keubler LM;Buettner M;Häger C;Bleich A
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Bleich A
DOI：
10.1016/j.bbrc.2010.12.099
发表时间：
2011-01-28
影响因子：
3.1
作者：
Jang, Won Gu;Kim, Eun Jung;Koh, Jeong-Tae
通讯作者：
Koh, Jeong-Tae
影响因子：
64.8
作者：
JARRIAULT, S;BROU, C;ISRAEL, A
通讯作者：
ISRAEL, A