Dietary restriction improves intestinal cellular fitness to enhance gut barrier function and lifespan in D. melanogaster.
Dietary restriction improves intestinal cellular fitness to enhance gut barrier function and lifespan in D. melanogaster.
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DOI：
10.1371/journal.pgen.1007777
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发表时间：
2018-11
期刊：
影响因子：
4.5
通讯作者：
Kapahi P
中科院分区：
文献类型：
--
作者：
Akagi K;Wilson KA;Katewa SD;Ortega M;Simons J;Hilsabeck TA;Kapuria S;Sharma A;Jasper H;Kapahi P
肠道完整性的丧失与包括炎症性肠病在内的各种人类疾病有关。然而，导致屏障功能丧失的机制仍然知之甚少。通过使用D.Blackogaster，我们证明了饮食限制(DR)通过上调肠道上皮中dMyc的表达来提高肠道细胞的适合性，从而减缓了与年龄相关的肠道完整性的下降。肠道细胞中dMyc的减少导致细胞死亡，从而导致肠道通透性增加和寿命缩短。遗传镶嵌和上位性分析表明，细胞竞争，即邻近细胞通过凋亡消除不适合的细胞，介导了肠道细胞中dMyc水平降低的细胞死亡。我们观察到肠细胞凋亡是肠道通透性增加和dMyc丢失后寿命缩短所必需的。此外，在有丝分裂后的肠母细胞和肠细胞中，dMyc的适度激活足以延长营养丰富的饮食的健康寿命。我们认为dMyc可作为肠细胞健康状况的晴雨表，影响肠道屏障功能，以应对饮食和年龄的变化。饮食限制(DR)是一种强有力的环境方法，可以延缓各种生物体的衰老和与年龄相关的疾病。在哺乳动物和果蝇中都观察到了与年龄相关的肠道完整性破坏，这是寿命的决定因素。在果蝇中，DR能够减缓与年龄相关的肠道完整性下降。虽然共生失调被认为是肠道屏障功能障碍的主要原因，但抗生素治疗并不能阻止与年龄相关的肠道通透性增加。我们发现，肠道屏障功能的内在机制是通过“细胞竞争”来调节肠道细胞的凋亡。我们发现DR上调肠道中dMyc的表达，从而增强肠细胞的适合性，防止与年龄相关的肠道完整性下降，并有助于DR诱导的寿命延长。相反，在丰富的饮食中，抑制肠细胞中的dMyc会导致细胞死亡，从而增强肠道通透性，导致全身炎症和寿命缩短。
Loss of gut integrity is linked to various human diseases including inflammatory bowel disease. However, the mechanisms that lead to loss of barrier function remain poorly understood. Using D. melanogaster, we demonstrate that dietary restriction (DR) slows the age-related decline in intestinal integrity by enhancing enterocyte cellular fitness through up-regulation of dMyc in the intestinal epithelium. Reduction of dMyc in enterocytes induced cell death, which leads to increased gut permeability and reduced lifespan upon DR. Genetic mosaic and epistasis analyses suggest that cell competition, whereby neighboring cells eliminate unfit cells by apoptosis, mediates cell death in enterocytes with reduced levels of dMyc. We observed that enterocyte apoptosis was necessary for the increased gut permeability and shortened lifespan upon loss of dMyc. Furthermore, moderate activation of dMyc in the post-mitotic enteroblasts and enterocytes was sufficient to extend health-span on rich nutrient diets. We propose that dMyc acts as a barometer of enterocyte cell fitness impacting intestinal barrier function in response to changes in diet and age. Dietary restriction (DR) is a robust environmental method to slow aging and age-related diseases in diverse organisms. Age-related disruption of gut integrity has been observed in both mammals and fruit flies and is a determinant of lifespan. In Drosophila, DR is able to slow the age-related decline in gut integrity. Although commensal dysbiosis has been proposed as a leading cause of gut barrier dysfunction, antibiotic treatment does not prevent the age-related increase in gut permeability. We identify that an intrinsic mechanism regulates gut barrier function through regulation of enterocyte apoptosis by ‘cell competition’. We show DR up-regulates dMyc expression in the gut which enhances enterocyte cellular fitness, prevents the age-related decline in gut integrity, and contributes to DR-induced lifespan extension. Conversely, on a rich diet, inhibition of dMyc in the enterocytes leads to cell death that enhances gut permeability and leads to systemic inflammation and shortened lifespan.
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影响因子：
4.5
作者：
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