动物营养学报    2021, Vol. 33 Issue (7): 3719-3725    PDF    
冬眠行为与动物肠道微生物相互作用机制的研究进展
朱宇航1 , 司华哲2 , 张玉3 , 徐超1     
1. 中国农业科学院特产研究所, 长春 130000;
2. 吉林农业大学动物科技学院, 长春 130118;
3. 吉林向海国家级自然保护区管理局, 通榆 137215
摘要: 冬眠是动物界一种十分常见的行为,在寒冷并且缺乏食物的冬季,冬眠能够帮助动物节约大量的能量。冬眠动物的肠道微生物在冬眠期和非冬眠期差异显著。本文总结了冬眠动物肠道微生物及其代谢产物在冬眠期与非冬眠期间的显著差异、冬眠期间动物肠道微生物变化与肠道免疫系统变化的联系,以期为今后冬眠动物肠道微生物的研究提供参考。
关键词: 冬眠    肠道微生物    代谢    免疫    
Research Progress on Interaction Mechanism between Animal Hibernation Behavior and Gut Microbiota
ZHU Yuhang1 , SI Huazhe2 , ZHANG Yu3 , XU Chao1     
1. Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun 130000, China;
2. College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China;
3. Jilin Xianghai National Nature Reserve, Tongyu 137215, China
Abstract: Hibernation is a very common behavior in the animal. It can help animals save a lot of energy during the cold winter when there is little food. The intestinal microorganisms of hibernating animals are significantly different between hibernating and non-hibernating periods. In order to provide reference for future research on intestinal microorganism of hibernating animals. This paper summarizes the significant differences of intestinal microorganism and its metabolites in hibernating animals during hibernation and non-hibernation. In addition, the relationship between intestinal microorganism changes and intestinal immune system changes in hibernating animals is summarized.
Key words: hibernation    gut microbiota    metabolism    immunity    

冬眠现象在动物界十分常见,能够进行冬眠的动物可分为3类:变温动物(也称外温动物),如蛇(Serpentiformes)[1]、蛙(Ranidae)[2-3]和蟾蜍(Bufonidae)[4];恒温动物(也称内温动物),如熊(Ursidae)[5]、獾(Meles meles)[6]和一些鸟类[7];异温动物,如刺猬(Erinaceinae)[8]、地松鼠(Sciuridae)[9-11]和蝙蝠(Chiroptera)[12]等。冬眠是一种适应行为,帮助动物在冬季食物短缺时降低能量的消耗。动物的冬眠状态通常伴随着代谢抑制[13],其体温根据周围环境温度而下降。在冬眠期间,动物通常会短暂的苏醒几次[14-15]。冬眠动物的食物组成具有很大的季节性变化,一般都会在夏秋季节加大自己的采食量以储存脂肪,在冬眠期间会禁食,棕熊(Ursus arctos)和叙利亚仓鼠(Mesocricetus auratus)会在短暂的苏醒期进食[5, 16-17]

哺乳动物肠道微生物附着在胃肠道黏膜和表皮细胞上,肠道微生物群落的组成具有宿主特异性,在宿主的一生中都在持续变化。研究表明,肠道微生物的组成结构及其功能对宿主的健康有着重要影响,与宿主许多生理活动,如代谢、行为、营养和免疫等密切相关[18]。宿主的习性、食物组成及周围环境变化对肠道微生物影响很大[19-20]。当宿主食物组成变化时,肠道微生物会对变化做出适应性反应,通过改善宿主的消化功能以利用新的食物组成[21]。冬眠动物如棕熊,通常在冬眠前大量进食,并在冬眠期间禁食[22],因此,肠道微生物会做出适应性改变。

冬眠引起动物食物组成的变化从而影响肠道微生物变化,肠道微生物的变化也会对冬眠宿主动物的能量代谢起到调节作用。本文综述了冬眠现象对动物肠道微生物及其代谢产物的影响和冬眠期间动物肠道微生物变化与肠道免疫系统变化的联系,以期为冬眠动物肠道微生物的研究提供参考。

1 冬眠对动物肠道微生物的影响

许多有冬眠习性的哺乳动物,如北极地松鼠(Urocitellus parryii)[11]、十三条纹地松鼠(Ictidomys tridecemlineatus)[9-10]、棕熊[5]、马铁菊头蝠(Rhinolophus ferrumequinum)[12]、两栖动物东北林蛙(Rana dybowskii)[23]和斑腿泛树蛙(Polypedates megacephalus)[3],其肠道菌群Shannon指数和Chao1指数在冬眠期间会较非冬眠期低[3, 5, 9-12, 24]。这说明冬眠期间动物肠道微生物的多样性和丰富度均降低。此外,冬眠期间动物肠道微生物的β多样性与非冬眠期相比,也存在显著差异[2, 3, 5, 9-12],表明冬眠期间动物肠道菌群的群落结构与非冬眠期相比,存在显著差异。

冬眠期间,动物肠道菌群中厚壁菌门(Firmicutes)相对丰度普遍下降[2, 3, 5, 10-12, 17, 25],拟杆菌门(Bacteroidetes)和变形菌门(Proteobacteria)相对丰度普遍上升[2, 3, 5, 10-11]。拟杆菌门细菌通常以淀粉、纤维素和果胶等为底物,在蛋白质的代谢中也发挥重要作用。冬眠期间,拟杆菌门相对丰度的增加可能是由于拟杆菌门细菌具有代谢宿主黏液聚糖的能力,这种能力使拟杆菌门细菌能够在缺乏食物多糖时转而代谢宿主多糖[25],也可能是由于拟杆菌门参与代谢肠道表皮提供的蛋白质和脂肪[26]。冬眠期间,木蛙(Rana sylvatica)[24]、斑腿泛树蛙[3]、十三条纹地松鼠[10]和北极地松鼠[11]肠道菌群中疣微菌门(Verrucomicrobia)的相对丰度较非冬眠期更高,然而在冬眠的棕熊和马铁菊头蝠的肠道菌群中并没有这种现象[5, 12]。此外,木蛙肠道菌群中,放线菌门(Actinobacteria)和酸杆菌门(Acidobacteria)的相对丰度在冬眠期间显著升高[24]。冬眠期间,几乎所有冬眠动物的肠道微生物中拟杆菌门、厚壁菌门和变形菌门都占据优势地位,尤其是拟杆菌门[2, 3, 5, 9-12, 17, 24],其相对丰度在冬眠的十三条纹地松鼠[10]、北极地松鼠[11]、棕熊[5]、斑腿泛树蛙[3]、东北林蛙[2]和黑龙江林蛙(Rana amurensis)[23]的肠道菌群各菌门中最高。疣微菌门、放线菌门和软壁菌门(Tenericutes)在冬眠的东北林蛙、斑腿泛树蛙、棕熊、十三条纹地松鼠、北极地松鼠、马铁菊头蝠、叙利亚仓鼠和木蛙肠道菌群中也占据优势地位[2, 3, 5, 9-12, 17, 24]

1.1 厚壁菌门及相关菌属在冬眠期间的变化

厚壁菌门相对丰度在冬眠期间的降低主要体现在梭菌纲(Clostridia)中毛螺菌科(Lachnospiracea)[9-11]和厌氧棍状菌属(Anaerotruncus)[10]相对丰度的显著降低,梭菌纲中的细菌能够以植物多糖为底物[27]。乳杆菌目(Lactobacillales)中链球菌科(Streptococcaceae)[2, 5]和乳杆菌科(Lactobacillaceae)[9-11]相对丰度较非冬眠期间显著降低,乳杆菌属(Lactobacillus)的相对丰度虽然较非冬眠期降低,但是差异并不显著。乳杆菌目的细菌具有共同的代谢和生理特性,参与碳水化合物发酵。因此,冬眠期间,动物肠道菌群梭菌纲和乳杆菌目相对丰度的降低可能是其底物的缺失导致的。然而,在棕熊中发现,粪球菌属(Coprococcus)的相对丰度在冬眠期和非冬眠期差距很小[5],这说明粪球菌属在棕熊肠道菌群中发挥着重要作用,粪球菌属能够产生丁酸,而丁酸盐的含量对肠道屏障功能十分重要[28]

1.2 拟杆菌门及相关菌属在冬眠期间的变化

拟杆菌门相对丰度在冬眠期间的升高主要体现在拟杆菌纲(Bacteroidia)中紫单胞菌科(Porphyromonadaceae)[9-10]、理研菌科(Rikenellaceae)[9-11]、拟杆菌科(Bacteroidaceae)[2, 5, 10-11]、拟杆菌科中拟杆菌属(Bacteroides)[2, 5, 10-11]和理研菌科中另枝菌属(Alistipes)[10]相对丰度较非冬眠期显著升高。然而,在冬眠期十三条纹地松鼠和北极地松鼠肠道菌群中,拟杆菌纲中的普雷沃菌属(Prevotella)[10-11]相对丰度较非冬眠期显著降低。普雷沃菌属的基因组分析表明,它缺乏降解宿主黏液多糖的能力,更适合植物多糖的降解[29]。动物冬眠期间,肠道中缺乏来自食物的多糖,因此,能够降解宿主多糖的细菌具有竞争优势,相对丰度上升;对于没有降解宿主多糖能力的细菌,由于没有代谢底物,其相对丰度显著降低。

1.3 疣微菌门及相关菌属在冬眠期间的变化

疣微菌门相对丰度在冬眠期间的升高主要体现在疣微菌科(Verrucomicrobiaceae)和嗜黏蛋白阿克曼菌(Akkermansia muciniphila),其在斑腿泛树蛙、木蛙、叙利亚仓鼠和十三条纹地松鼠肠道中升高[3, 9-11, 17, 24]。疣微菌科和嗜黏蛋白阿克曼菌相对丰度的升高,可能是由于它们能够以宿主胃肠黏液多糖或宿主肠道中的黏液蛋白为底物[30]

1.4 放线菌门及相关菌属在冬眠期间的变化

放线菌门中的一些菌属的相对丰度在冬眠期间会下降。在棕熊中,微球菌属(Micrococcus)的相对丰度虽然较非冬眠期降低,但是差异并不显著[5]。在十三条纹地松鼠和东北林蛙中发现,红椿菌科(Coriobacteriaceae)的相对丰度较非冬眠期显著降低[2, 10]。通过与碳水化合物活性酶数据库(Carbohydrate-Active Enzyme Database,CAZy)进行比对发现,微球菌属和红椿菌科的成员含有一些能够催化果胶、纤维素和淀粉等碳水化合物降解的酶,因此,红椿菌科相对丰度在十三条纹地松鼠和东北林蛙肠道菌群中显著降低,可能是冬眠期间动物的禁食行为导致的。冬眠棕熊肠道菌群中微球菌属的相对丰度较非冬眠期降低,但是差异并不显著,可能与棕熊在冬眠期间的短暂苏醒期进食有关[5, 16]

在东北林蛙和木蛙中,变形菌门中假单胞菌属(Pseudomonas)相对丰度在冬眠期间显著升高[2, 24]。在冬眠棕熊中,肠杆菌科(Enterobacteriaceae)的相对丰度较非冬眠期显著增加。假单胞菌属的成员具有广泛的代谢多样性,肠杆菌科细菌能够发酵糖类产生乳酸,它们相对丰度的显著增加可能是因为它们也能够代谢肠黏液多糖[31]。此外,冬眠期间肠道菌群多样性和丰富度的降低,尤其是一些有益菌的减少,对病原菌的抑制作用下降,导致肠杆菌科相对丰度在冬眠期显著增加。

2 冬眠对肠道微生物代谢产物的影响

动物冬眠时,其肠道微生物会自发的重组,改变菌群的结构,在长时间的禁食和低温条件下,始终与宿主保持一种互利关系。这使肠道菌群能够为宿主提供代谢产物,这些代谢产物对宿主在冬眠期间保持免疫和代谢稳态至关重要[32]。短链脂肪酸(short fatty acids,SCFAs)是肠道菌群代谢的主要产物,可以被转换作为葡萄糖,或者促进糖异生,此外,其新陈代谢能够促进腺嘌呤核苷三磷酸(adenosine triphosphate,ATP)合成[33]。由于动物在冬眠期间禁食,导致肠道内SCFAs的含量降低[9, 17],低水平的SCFAs可能是小肠黏膜萎缩和肠屏障通透性增加的主要原因[9]

肠道中丁酸盐的含量与厚壁菌门的相对丰度呈正相关,厚壁菌门相对丰度在冬眠动物肠道菌群中普遍降低[2, 3, 5, 10-12, 17, 24],这导致了肠道中丁酸盐含量的降低[34]。丁酸盐是肠上皮细胞的首选能量来源,可以通过刺激上皮细胞增殖和恢复,调节细胞凋亡并参与黏液产生以维持肠道屏障的完整性,降低炎症反应[35-37]。动物冬眠期间,肠道菌群中产乳酸的细菌,例如乳酸杆菌[9-11]和微球菌属[5, 38],其相对丰度的降低会导致肠道中乳酸水平的降低。一般认为,乳酸盐是处于运动状态的肌肉在氧供应不足时的代谢产物,但是,在有氧条件下也能够产生乳酸盐[41]。乳酸盐可作为一种重要的能量来源,并在有氧环境下调节脂质和碳水化合物代谢[39]。同样,冬眠期间琥珀酸含量的增加与产琥珀酸细菌如肠杆菌科的相对丰度增加有关[5]。琥珀酸是三羧酸循环的中间物质,在ATP生成中起着重要作用[40]。然而,宿主也能产生乳酸和琥珀酸,因此宿主代谢的季节性变化也可能导致乳酸和琥珀酸的差异。

SCFA含量虽然在冬眠期间较夏季降低[9],但是其相对比例在冬眠期间反而会升高,如乙酸。肠道上皮细胞和外周肠道组织可利用乙酸盐作为能量来源,转运到肝脏中的乙酸盐还可以用于合成脂肪酸和胆固醇[41-42]。此外,肝脏和肠上皮细胞还可将乙酸盐转变为酮体[43]。冬眠动物可利用酮体作为大脑、肌肉和心脏组织的能量来源[44],使心脏不受缺血再灌注损伤,并在冬眠动物苏醒时促进动物从低耗氧状态转变到高耗氧状态[44]。乙酸盐相对比例在冬眠期间的升高可能是嗜黏蛋白阿克曼菌[3, 9-11, 17, 24]相对丰度的升高导致的,嗜黏蛋白阿克曼菌能够将黏液蛋白转化为乙酸盐[30]。高脂饮食会破坏肠道表皮的完整性,对于高脂饲养的小鼠,嗜黏蛋白阿克曼菌不仅可以阻止其体重增加,还能够帮助小鼠恢复肠道表皮的完整性[45]。这可能是由于嗜黏蛋白阿克曼菌产生的乙酸盐能够为肠道表皮细胞提供能量。嗜黏蛋白阿克曼菌在改善肥胖和糖尿病时能够发挥有益作用[45-46],口服经过巴氏消毒的嗜黏蛋白阿克曼菌能够减轻食物引起的肥胖[47]。此外,经过巴氏消毒后,嗜黏蛋白阿克曼菌降低小鼠机体脂肪含量,改善胰岛素抵抗和血脂异常的能力显著增强[48]。在其他一些疾病中,嗜黏蛋白阿克曼菌也能够发挥抗炎作用[49-50]并减轻鸡沙门氏菌感染[48]

3 冬眠期间肠道免疫系统的变化与肠道微生物变化的联系

肠道黏膜微生物可通过产生有机酸降低pH[51]、分泌抗微生物化合物[52]、与病原菌竞争营养和附着位点帮助宿主组织防止微生物入侵[53-54]。与病原微生物和肠腔内的微生物相比,黏膜微生物与肠道上皮更近,更有可能通过直接与细胞互作,或通过微生物相关分子模式(microorganism-associated molecular patterns,MAMPs)或其代谢物的扩散间接调节免疫系统[55]。宿主可通过病原识别受体(pathogen recognition receptors,PRRs)识别MAMPs,PRRs可分为跨膜型、胞质型和分泌型3种类型[55],最具特征的跨膜类PRRs是Toll样受体(Toll like receptors, TLRs)[56-57]。在十三条纹地松鼠中,Toll样受体4(Toll like receptor 4, TLR4)在冬眠期的表达要低于在夏季的表达,Toll样受体5(Toll like receptor 5, TLR5)在冬眠期的表达要高于在夏季的表达[10]。TLR4通过与其配体脂多糖的结合,能够破坏下游炎症反应[58]。相比之下,TLR5通过其配体鞭毛蛋白的激活,可产生保护性的抗炎反应并维护肠道屏障功能[59]。上皮细胞TLRs的表达会影响黏膜微生物群的组成,同时,微生物群的存在也会影响TLRs在上皮细胞的表达[60]。在冬眠后期,TLR4和TLR5的表达发生改变,虽然还没有发现直接的因果关系,这可能是冬眠期间肠道环境的改变引起的一种保护反应,包括上皮通透性的增加以及黏膜和肠腔内菌群的改变[9]。冬眠期间, 由于禁食,冬眠动物肠道上皮通透性增加[61],增加细菌迁移和免疫系统过度激活的风险。

4 小结与展望

综上所述,冬眠会改变动物肠道微生物的组成,进而影响肠道微生物的代谢活动,最终影响宿主的代谢及健康状态。研究冬眠动物的肠道微生物变化,可以更好地对动物进行保护和利用。在动物冬眠状态下,肠道微生物的变化与健康状态的维持密切相关,禁食会增加肠道通透性、调节肠道免疫、改变肠道内短链脂肪酸的含量并因此降低炎症反应或提供能量,因此,对其中具体的作用机制进行研究,或许能为畜禽养殖提供帮助。目前,大多数研究关注肠道微生物及宿主生理对冬眠现象的反应,应进一步通过添加抗生素或微生物移植验证微生物在冬眠现象中的作用,并研究其中的作用机制。此外,一些具有半冬眠现象的动物如黑貉,关于其肠道微生物在冬眠现象中作用的研究仍未见报道,研究半冬眠现象对黑貉肠道微生物的影响可更好地利用这一重要的经济动物。

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