丁酸梭菌与肠道上皮细胞互作的分子机制的研究
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摘要
丁酸梭菌作为益生菌已被广泛的应用于治疗肠炎、改善动物的生产性能等方面,并得到了普遍的认可。但是寄主细胞识别丁酸梭菌并由此产生的益生作用的分子机制尚不明确。本论文旨在探讨丁酸梭菌的益生机制。
试验一：用丁酸梭菌刺激HT-29细胞,然后通过测定跨膜受体TLRs(toll-like receptor)和炎性因子的表达分析丁酸梭菌诱导的信号传导途径。试验结果显示,丁酸梭菌能够显著提高TLR2mRNA的表达水平,但却没有影响TLR2、TLR4、TLR5、TLR9、MyD88(myeloid differentiation primary response protein88)的表达。同时发现,NF-κB、IL-8、TNF-α的表达量亦显著提高,说明HT-29细胞被诱导发生了免疫反应。但是与大肠杆菌相比,丁酸梭菌诱导的NF-κB (nuclear factor κB)、IL-8(interleukin-8)、TNF-α(tumor necrosis factor alpha)的表达水平却低很多。另外,丁酸梭菌能够显著提高炎性抑制因子IL-10和Hsp70(heat shock protein70)的表达量,这可能和丁酸梭菌的益生特性有关。
试验二：分别使用TLR2和MyD88特异性siRNA (small interfering RNA)敲除HT-29细胞TLR2和MyD88基因。沉默MyD88基因对丁酸梭菌诱导的NF-κB、IL-8、IL-6、TNF-α的表达没有影响,但是沉默TLR2基因却使NF-κB、IL-8、IL-6、TNF-α的表达下降,说明TLR2是丁酸梭菌的特异性受体。因此,丁酸梭菌可激活由TLR2介导的MyD88-非依赖性信号传导通路。
试验三：TLR2是识别丁酸梭菌的关键性受体,我们进一步分析了TLR2的结构和活性区域。首先,以鼠的TLR2晶体结构为模板,通过同源模建方法构建了人的TLR2的三维结构,然后采用分子对接技术模建了人的TLR2与脂磷壁酸(LTA)的相互作用模型,发现了TLR2受体识别LTA的关键性残基,这对进一步开展定点突变试验具有指导意义。
试验四：用IL-10特异性siRNA (siIL-10)(?)(?)IL-10抗体处理HT-29细胞,用以敲除和中和IL-10。试验结果显示,中和或敲除IL-10促进了丁酸梭菌诱导的NF-κB的活化和IL-8的表达。另外发现IL-10被中和和敲除后,丁酸梭菌能够诱导HT-29细胞发生严重的凋亡和坏死。试验结果说明,IL-10在肠道寄主细胞识别丁酸梭菌以及丁酸梭菌调节的免疫保护方面发挥着重要作用。
试验五：首先,测定丁酸梭菌及其SCS对EHEC(大肠杆菌)的生长、粘附的抑制作用；结果显示,丁酸梭菌及其SCS有显著抑制效果。另一方面,丁酸梭菌和其SCS能够抑制EHEC引发的CEICs(鸡胚肠道细胞)凋亡。同时发现,丁酸梭菌可通过调节XIAP(X连锁凋亡抑制蛋白)、BclXL (B-cell lymphoma-extra large)、FAS、 Bcl2(B-cell leukaemia/lymphoma-2)、BAX (Bcl2-associated X protein)、P53(Tumor protein53)的表达和抑制caspase(半胱氨酸蛋白酶)-9、caspase-3的活力缓解EHEC诱导的细胞凋亡。试验结果表明,丁酸梭菌既可直接的抑制EHEC的活力,又可间接通过调节凋亡因子的表达抑制EHEC诱导的细胞凋亡,从而发挥对EHEC诱导的肠道炎症的抑制作用；这有助于揭示丁酸梭菌的益生机理。此外,我们首次选用CEICs作为体外模型,研究丁酸梭菌对EHEC诱导的细胞凋亡的抑制作用,这为丁酸梭菌治疗鸡的大肠杆菌病提供了理论依据。
Oral administration of Clostridium butyricum as probiotics is increasingly gaining importance in the treatment of intestinal inflammations and improvement of animal performance. However, the mechanisms of host cell receptor recognition of C. butyricum and the downstream immune signaling pathways leading to these benefits remain unclear. The aim of the study was to explain the beneficial properties of C. butyricum.
Trial1. The HT-29cells were stimulated by C. butyricum to investigate its capability to influence the innate immune response of HT-29cells. The results showed that the C. butyricum was able to stimulate TLR (toll-like receptor)2production at mRNA level, however, TLR4, TLR5, TLR9, MyD88(myeloid differentiation primary response protein88) transcription levels were not up-regulated. The NF-κB (nuclear factor κB), IL (interleukin)-8and TNF-a (tumor necrosis factor alpha) levels in response to C. butyricum were significantly increased, indicating that HT-29cells were sensitised by C. butyricum. However, compared with Escherichia coli, the levels of NF-κB, IL-8and TNF-a induced by C. butyricum were far lower. Furthermore, we observed that the C. butyricum induced a significant increase in the levels of both IL-10and Hsp70(heat shock protein70), which may be associated with the beneficial properties of C. butyricum.
Trial2. TLR2and MyD88specific siRNA (small interfering RNA) were used to silence expression of TLR2and MyD88. Knockdown of MyD88expression using siRNA in this manner did not affect C. butyricum-induced elevated levels of NF-κB, IL-8, IL-6and TNF-α, suggesting a MyD88-independent route to TLR signaling transduction. However, a significant reduction in the levels of NF-κB, IL-8, IL-6and TNF-α was evident in the absence of TLR2expression, implying the need for TLR2in C. butyricum recognition. Hence, C. butyricum activates TLR2-mediated MyD88-independent signaling pathway in human epithelial cells.
Trial3. The TLR2is a key receptor for recognizing C. butyricum. We next analyzed the structure of TLR2and indentified its functional domain. Based on the X-ray crystal structure of mouse TLR2, a homology model of human TLR2was constructed. The human TLR2ligand agonist LTA (lipoteichoic acid) was docked into the optimized model, and the critical amino acid residues for binding were identified, which was very important for further site-directed mutagenesis study.
Trial4. HT-29cells were treated with anti-IL-10(IL-10antibody) or siIL-10(specific siRNA) to disrupt IL-10. In both cases, the effects of C. butyri cum-induced NF-κB activation and IL-8expression were enhanced. We also found that neutralization or knockdown of IL-10could induce apoptosis and necrosis of HT-29cells treated with C. butyricum compared with control cells. These findings show that IL-10serves an important role in C. butyricum-mediated immune protection, and in host recognition of C. butyricum.
Trial5. We investigated the effects of C. butyricum and its SCS (spent culture supernatants) on EHEC (Escherichia coli) growth and adherence to CEICs (chicken embryo intestinal cells). Indeed, the C. butyricum and its SCS exhibited significant inhibitory activity. On the other hand, we evaluated the potential of C. butyricum to inhibit EHEC-induced apoptosis in CEICs. Also, the C. butyricum showed significant inhibitory effect on the EHEC-induced apoptosis by modulating the expression of XIAP (X-linked inhibitor of apoptosis protein), BclXL (B-cell lymphoma-extra large), FAS, Bcl2(B-cell leukaemia/lymphoma-2), BAX (Bcl-2-associated X protein), P53(Tumor protein53) and via inhibition of caspase-9and caspase-3activation. Altogether, these results indicate that the C. butyricum possesses the ability to prevent the EHEC-induced intestinal disorders both directly through inhibiting EHEC viability and indirectly via medicating EHEC-induced apoptosis, which could help to explain the beneficial properties of C. butyricum. Furthermore, this data is novel in the case of poultry and the manner in which C. butyricum prevents the EHEC-induced apoptosis provides supportive information for the treatment of colibacilliosis.
试验一：用丁酸梭菌刺激HT-29细胞,然后通过测定跨膜受体TLRs(toll-like receptor)和炎性因子的表达分析丁酸梭菌诱导的信号传导途径。试验结果显示,丁酸梭菌能够显著提高TLR2mRNA的表达水平,但却没有影响TLR2、TLR4、TLR5、TLR9、MyD88(myeloid differentiation primary response protein88)的表达。同时发现,NF-κB、IL-8、TNF-α的表达量亦显著提高,说明HT-29细胞被诱导发生了免疫反应。但是与大肠杆菌相比,丁酸梭菌诱导的NF-κB (nuclear factor κB)、IL-8(interleukin-8)、TNF-α(tumor necrosis factor alpha)的表达水平却低很多。另外,丁酸梭菌能够显著提高炎性抑制因子IL-10和Hsp70(heat shock protein70)的表达量,这可能和丁酸梭菌的益生特性有关。
试验二：分别使用TLR2和MyD88特异性siRNA (small interfering RNA)敲除HT-29细胞TLR2和MyD88基因。沉默MyD88基因对丁酸梭菌诱导的NF-κB、IL-8、IL-6、TNF-α的表达没有影响,但是沉默TLR2基因却使NF-κB、IL-8、IL-6、TNF-α的表达下降,说明TLR2是丁酸梭菌的特异性受体。因此,丁酸梭菌可激活由TLR2介导的MyD88-非依赖性信号传导通路。
试验三：TLR2是识别丁酸梭菌的关键性受体,我们进一步分析了TLR2的结构和活性区域。首先,以鼠的TLR2晶体结构为模板,通过同源模建方法构建了人的TLR2的三维结构,然后采用分子对接技术模建了人的TLR2与脂磷壁酸(LTA)的相互作用模型,发现了TLR2受体识别LTA的关键性残基,这对进一步开展定点突变试验具有指导意义。
试验四：用IL-10特异性siRNA (siIL-10)(?)(?)IL-10抗体处理HT-29细胞,用以敲除和中和IL-10。试验结果显示,中和或敲除IL-10促进了丁酸梭菌诱导的NF-κB的活化和IL-8的表达。另外发现IL-10被中和和敲除后,丁酸梭菌能够诱导HT-29细胞发生严重的凋亡和坏死。试验结果说明,IL-10在肠道寄主细胞识别丁酸梭菌以及丁酸梭菌调节的免疫保护方面发挥着重要作用。
试验五：首先,测定丁酸梭菌及其SCS对EHEC(大肠杆菌)的生长、粘附的抑制作用；结果显示,丁酸梭菌及其SCS有显著抑制效果。另一方面,丁酸梭菌和其SCS能够抑制EHEC引发的CEICs(鸡胚肠道细胞)凋亡。同时发现,丁酸梭菌可通过调节XIAP(X连锁凋亡抑制蛋白)、BclXL (B-cell lymphoma-extra large)、FAS、 Bcl2(B-cell leukaemia/lymphoma-2)、BAX (Bcl2-associated X protein)、P53(Tumor protein53)的表达和抑制caspase(半胱氨酸蛋白酶)-9、caspase-3的活力缓解EHEC诱导的细胞凋亡。试验结果表明,丁酸梭菌既可直接的抑制EHEC的活力,又可间接通过调节凋亡因子的表达抑制EHEC诱导的细胞凋亡,从而发挥对EHEC诱导的肠道炎症的抑制作用；这有助于揭示丁酸梭菌的益生机理。此外,我们首次选用CEICs作为体外模型,研究丁酸梭菌对EHEC诱导的细胞凋亡的抑制作用,这为丁酸梭菌治疗鸡的大肠杆菌病提供了理论依据。
Oral administration of Clostridium butyricum as probiotics is increasingly gaining importance in the treatment of intestinal inflammations and improvement of animal performance. However, the mechanisms of host cell receptor recognition of C. butyricum and the downstream immune signaling pathways leading to these benefits remain unclear. The aim of the study was to explain the beneficial properties of C. butyricum.
Trial1. The HT-29cells were stimulated by C. butyricum to investigate its capability to influence the innate immune response of HT-29cells. The results showed that the C. butyricum was able to stimulate TLR (toll-like receptor)2production at mRNA level, however, TLR4, TLR5, TLR9, MyD88(myeloid differentiation primary response protein88) transcription levels were not up-regulated. The NF-κB (nuclear factor κB), IL (interleukin)-8and TNF-a (tumor necrosis factor alpha) levels in response to C. butyricum were significantly increased, indicating that HT-29cells were sensitised by C. butyricum. However, compared with Escherichia coli, the levels of NF-κB, IL-8and TNF-a induced by C. butyricum were far lower. Furthermore, we observed that the C. butyricum induced a significant increase in the levels of both IL-10and Hsp70(heat shock protein70), which may be associated with the beneficial properties of C. butyricum.
Trial2. TLR2and MyD88specific siRNA (small interfering RNA) were used to silence expression of TLR2and MyD88. Knockdown of MyD88expression using siRNA in this manner did not affect C. butyricum-induced elevated levels of NF-κB, IL-8, IL-6and TNF-α, suggesting a MyD88-independent route to TLR signaling transduction. However, a significant reduction in the levels of NF-κB, IL-8, IL-6and TNF-α was evident in the absence of TLR2expression, implying the need for TLR2in C. butyricum recognition. Hence, C. butyricum activates TLR2-mediated MyD88-independent signaling pathway in human epithelial cells.
Trial3. The TLR2is a key receptor for recognizing C. butyricum. We next analyzed the structure of TLR2and indentified its functional domain. Based on the X-ray crystal structure of mouse TLR2, a homology model of human TLR2was constructed. The human TLR2ligand agonist LTA (lipoteichoic acid) was docked into the optimized model, and the critical amino acid residues for binding were identified, which was very important for further site-directed mutagenesis study.
Trial4. HT-29cells were treated with anti-IL-10(IL-10antibody) or siIL-10(specific siRNA) to disrupt IL-10. In both cases, the effects of C. butyri cum-induced NF-κB activation and IL-8expression were enhanced. We also found that neutralization or knockdown of IL-10could induce apoptosis and necrosis of HT-29cells treated with C. butyricum compared with control cells. These findings show that IL-10serves an important role in C. butyricum-mediated immune protection, and in host recognition of C. butyricum.
Trial5. We investigated the effects of C. butyricum and its SCS (spent culture supernatants) on EHEC (Escherichia coli) growth and adherence to CEICs (chicken embryo intestinal cells). Indeed, the C. butyricum and its SCS exhibited significant inhibitory activity. On the other hand, we evaluated the potential of C. butyricum to inhibit EHEC-induced apoptosis in CEICs. Also, the C. butyricum showed significant inhibitory effect on the EHEC-induced apoptosis by modulating the expression of XIAP (X-linked inhibitor of apoptosis protein), BclXL (B-cell lymphoma-extra large), FAS, Bcl2(B-cell leukaemia/lymphoma-2), BAX (Bcl-2-associated X protein), P53(Tumor protein53) and via inhibition of caspase-9and caspase-3activation. Altogether, these results indicate that the C. butyricum possesses the ability to prevent the EHEC-induced intestinal disorders both directly through inhibiting EHEC viability and indirectly via medicating EHEC-induced apoptosis, which could help to explain the beneficial properties of C. butyricum. Furthermore, this data is novel in the case of poultry and the manner in which C. butyricum prevents the EHEC-induced apoptosis provides supportive information for the treatment of colibacilliosis.
引文
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