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Abstract：
OBJECTIVE: The abdominal discomfort experienced by patients with colitis may be attributable in part to the presence of small intestinal dysmotility, yet mechanisms linking colonic inflammation with small-bowel motility remain largely unexplored. We hypothesize that colitis results in small intestinal hypomotility owing to a loss of enteroendocrine cells (EECs) within the small intestine that can be rescued using serotonergic-modulating agents.
METHODS: Male C57BL/6J mice, as well as mice that overexpress (EECOVER) or lack (EECDEL) NeuroD1+ enteroendocrine cells, were exposed to dextran sulfate sodium (DSS) colitis (2.5% or 5% for 7 days) and small intestinal motility was assessed by 70-kilodalton fluorescein isothiocyanate-dextran fluorescence transit. EEC number and differentiation were evaluated by immunohistochemistry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining, and quantitative reverse-transcriptase polymerase chain reaction. Mice were treated with the 5-hydroxytryptamine receptor 4 agonist prucalopride (5 mg/kg orally, daily) to restore serotonin signaling.
RESULTS: DSS-induced colitis was associated with a significant small-bowel hypomotility that developed in the absence of significant inflammation in the small intestine and was associated with a significant reduction in EEC density. EEC loss occurred in conjunction with alterations in the expression of key serotonin synthesis and transporter genes, including Tph1, Ddc, and Slc6a4. Importantly, mice overexpressing EECs revealed improved small intestinal motility, whereas mice lacking EECs had worse intestinal motility when exposed to DSS. Finally, treatment of DSS-exposed mice with the 5-hydroxytryptamine receptor 4 agonist prucalopride restored small intestinal motility and attenuated colitis.
CONCLUSIONS: Experimental DSS colitis induces significant small-bowel dysmotility in mice owing to enteroendocrine loss that can be reversed by genetic modulation of EEC or administering serotonin analogs, suggesting novel therapeutic approaches for patients with symptomatic colitis.
METHODS: Male C57BL/6J mice, as well as mice that overexpress (EECOVER) or lack (EECDEL) NeuroD1+ enteroendocrine cells, were exposed to dextran sulfate sodium (DSS) colitis (2.5% or 5% for 7 days) and small intestinal motility was assessed by 70-kilodalton fluorescein isothiocyanate-dextran fluorescence transit. EEC number and differentiation were evaluated by immunohistochemistry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining, and quantitative reverse-transcriptase polymerase chain reaction. Mice were treated with the 5-hydroxytryptamine receptor 4 agonist prucalopride (5 mg/kg orally, daily) to restore serotonin signaling.
RESULTS: DSS-induced colitis was associated with a significant small-bowel hypomotility that developed in the absence of significant inflammation in the small intestine and was associated with a significant reduction in EEC density. EEC loss occurred in conjunction with alterations in the expression of key serotonin synthesis and transporter genes, including Tph1, Ddc, and Slc6a4. Importantly, mice overexpressing EECs revealed improved small intestinal motility, whereas mice lacking EECs had worse intestinal motility when exposed to DSS. Finally, treatment of DSS-exposed mice with the 5-hydroxytryptamine receptor 4 agonist prucalopride restored small intestinal motility and attenuated colitis.
CONCLUSIONS: Experimental DSS colitis induces significant small-bowel dysmotility in mice owing to enteroendocrine loss that can be reversed by genetic modulation of EEC or administering serotonin analogs, suggesting novel therapeutic approaches for patients with symptomatic colitis.
摘要：
目的：结肠炎患者的腹部不适可能部分归因于小肠动力障碍的存在，然而，将结肠炎症与小肠运动联系起来的机制仍未被研究。我们假设结肠炎由于小肠内的肠内分泌细胞（EEC）的损失而导致小肠运动不足，这可以使用5-羟色胺能调节剂来挽救。
方法：雄性C57BL/6J小鼠，以及过度表达（EECOVER）或缺乏（EECDEL）NeuroD1+肠内分泌细胞的小鼠，暴露于DSS结肠炎（2.5％或5％，持续7天），并通过70kdFITC-葡聚糖荧光转运评估小肠运动性。通过免疫组织化学评估EEC的数量和分化，TUNEL染色,和qRT-PCR。小鼠用5-HT4激动剂普鲁卡洛必利(5mg/kg口服，每天）恢复血清素信号。
结果：DSS诱导的结肠炎与在小肠中没有明显炎症的情况下发生的显著小肠动力不足相关，并且与EEC密度的显著降低相关。EEC丢失与关键5-羟色胺合成和转运蛋白基因表达的改变有关，包括Tph1、Ddc、还有Slc6a4.重要的是,小鼠过度表达肠内分泌细胞显示出改善的小肠运动，而缺乏EECs的小鼠在暴露于DSS时肠道动力较差。最后,用5-HT4激动剂普鲁卡洛必利治疗暴露于DSS的小鼠可恢复小肠运动并减轻结肠炎。
结论：实验性DSS结肠炎由于肠内分泌损失而在小鼠中诱导显著的小肠动力障碍，这可以通过EEC的遗传调节或施用5-羟色胺类似物来逆转，为有症状的结肠炎患者提供新的治疗方法。
方法：雄性C57BL/6J小鼠，以及过度表达（EECOVER）或缺乏（EECDEL）NeuroD1+肠内分泌细胞的小鼠，暴露于DSS结肠炎（2.5％或5％，持续7天），并通过70kdFITC-葡聚糖荧光转运评估小肠运动性。通过免疫组织化学评估EEC的数量和分化，TUNEL染色,和qRT-PCR。小鼠用5-HT4激动剂普鲁卡洛必利(5mg/kg口服，每天）恢复血清素信号。
结果：DSS诱导的结肠炎与在小肠中没有明显炎症的情况下发生的显著小肠动力不足相关，并且与EEC密度的显著降低相关。EEC丢失与关键5-羟色胺合成和转运蛋白基因表达的改变有关，包括Tph1、Ddc、还有Slc6a4.重要的是,小鼠过度表达肠内分泌细胞显示出改善的小肠运动，而缺乏EECs的小鼠在暴露于DSS时肠道动力较差。最后,用5-HT4激动剂普鲁卡洛必利治疗暴露于DSS的小鼠可恢复小肠运动并减轻结肠炎。
结论：实验性DSS结肠炎由于肠内分泌损失而在小鼠中诱导显著的小肠动力障碍，这可以通过EEC的遗传调节或施用5-羟色胺类似物来逆转，为有症状的结肠炎患者提供新的治疗方法。
