夜晚光線之照射以及自主感光視神經細胞參予小鼠腸道菌相的調控

Light Exposure at Night and Intrinsically Photosensitive Retinal Ganglion Cells (ipRGCs) Modulate the Gut Microbiota in Mice

鄒硯芳(Yan-Fang Zou)

指導教授 ： 陳示國

國立臺灣大學/生命科學院/生命科學系/碩士(2016年)

https://doi.org/10.6342/NTU201600241

摘要

打亂正常生理時鐘常會提高罹患代謝相關疾病的風險，例如胰島素不耐症、肥胖、高血脂等等的代謝問題可能導致嚴重的第二型糖尿病。研究顯示光線到達視網膜訊息除了與視覺的形成有關，也會透過自主感光視神經節細胞參與非視覺形成的生理時鐘的功能。雖然現階段研究認為生理時鐘在調控能量代謝中扮演重要的角色，但光線究竟如何影響生理代謝的功能仍不清楚。由於近年許多證據顯示腸道菌相對身體的代謝狀態有直接的影響，故本研究欲探討來自視網膜的光線訊息是否會透過改變腸道菌相來調控能量代謝的功能。我們建立了野生基因型及黑視素(melanopsin)剔除小鼠總體基因體學的腸道菌樣本，利用次世代定序技術得到在夜晚接受光照的小鼠腸道菌相。本研究發現不同腸道部位有不同的菌相分布，支持前人研究結果。我們也發現夜晚光照改變了腸道菌的組成及節律，黑視素剔除也會造成腸道菌相的改變，而夜晚光照引起的肥胖則與特定菌相總量的增減有關，代表腸道菌相確實在光照影響代謝的途徑上扮演重要角色。總結上述，本研究顯示腸道菌相在光照影響能量代謝途徑的重要調控功能，並提供一解釋生理時鐘與能量代謝交互作用的機制，並為日後研究光照引起之代謝疾病的解決方案奠定基礎。

關鍵字

腸道菌 ； 黑視素 ； 夜晚光照 ； 生理時鐘 ； 次世代定序 ； 總體基因體學

並列摘要

It has long been revealed that the environmental light signals influence non-image forming physiological functions, such as pupillary light reflex and phototaxis. It has been shown that these physiological functions were mediated through the melanopsin –expressing intrinsically photosensitive retina ganglion cells (ipRGCs). The ipRGCs also synchronize numerous physiological homeostasis and behaviors, including circadian rhythm, activity cycle, hormone release, and body temperature, to the external light dark cycle. Recent studies suggests that the circadian rhythm is involved in modulation of physiological regeneration and storage of energy. The disrupted circadian rhythm in mammals is also found to be related to higher risks of acquiring metabolic disorders, such as insulin resistance, obesity and hyperlipidemia, which could further develop into severe diseases including type II diabetes. However, the mechanism responsible for the manipulation of metabolism by light signals remains unknown. There are evidences showing that the gut microbiota has a direct impact on the metabolic status of mammals. Thus, we want to determine whether the ipRGC -mediated light signal transduction from the retina would affect body metabolism through the alterations of gut microbiota.
By constructing a metagenomics library of gut microbiota from wild-type and melanopsin knock-out (MKO) mice and performing next generation sequencing(NGS), our findings shows distinct microbial categories in different compartments of digestive track in mice. This finding indicates the importance of investigating gut microtiota along the total digestive track instead of examining stool. Also, we discover distinct gut microbiota in wild-type and MKO mice that are exposed to dim light during the night time, comparing to the mice living in normal light-dark cycle. This finding indicates that the gut microbiota being a critical modulator of the bidirectional relationships between metabolism and light signal transduction. In addition, we find diverse composition of gut microbiota in the MKO mice when compared to wildtype mice even in the normal light-dark cycle. It also provides evidence for a new phenotype of MKO mice. Furthermore, we investigate the correlation between dim-light-exposure-at-night (dLAN) induced obesity and the altered gut microbiota. We show the diversified amount of some specific gut microbes may contribute to dLAN induced obesity. To sum up, our results suggest that the gut microbiota is a critical modulator of the dLAN induced metabolic disorder, and we provide possible mechanisms of the circadian-metabolic converges.

並列關鍵字

gut microbiota ； melanopsin ； dim-light-at-night ； circadian rhythm ； next generation sequencing ； metagenomics

參考文獻

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