Targeting gut microbiota to improve circadian rhythm disorders: research progress
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摘要: 生物钟是指生物为适应外部环境的周期性变化表现出周期接近24 h的节律模式。肠道菌群是人和动物体内寄生的数量极其庞大的微生物的总和。生物钟紊乱会增加代谢性疾病的发生风险，且紊乱的发生与肠道菌群的失调相互作用。随着对“脑-肠”轴认识的不断加深，以肠道菌群为靶点改善生物钟紊乱及其引发的疾病的干预方法已经取得了较大的理论突破并部分应用于临床实践，包括饮食干预(如时间限制摄食)、微生物相关制品的开发(如益生菌和后生元)及粪菌移植等。现对肠道菌群及其昼夜节律性、靶向肠道菌群治疗生物钟紊乱的研究进展进行综述，以期为预防和治疗节律紊乱及并发疾病提供新的思路。Abstract: Biological clock is a pattern of rhythms in which organisms exhibit cycles approaching 24 h in order to adapt to periodic changes in the external environment. Gut microbiota is the sum of extremely large number of microorganisms parasitized in humans and animals. Disorders of the biological clock increase the risk of metabolic diseases, and the occurrence of these disorders is closely related to the interaction with the dysbiosis of the gut microbiota. With the deepening of the understanding of the brain-gut axis, targeting gut microbiota to ameliorate biological clock disorders and associated diseases has achieved major theoretical breakthroughs and was partially applied in clinical practice, including dietary interventions such as time restricted feeding, development of microbial-related products (probiotics and postbiotics), and fecal microbiota transplantation. This article reviews the research progress of intestinal flora and rhythmicity, as well as targeting intestinal flora for the treatment of biological clock disorders, so as to provide new ideas for the prevention and treatment of rhythm disorders and concurrent diseases.
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昼夜节律是一种生物节律，大多数生物包括细菌、真菌、动物和植物均表现出周期接近24 h的节律模式，其可以使生物体保持内部和外部环境的一致性[1]。人类的许多活动因素都可能破坏正常昼夜节律并导致节律紊乱的发生[2]，后者与脑血管病、癫痫等疾病密切相关[3]。动物研究表明，对生物钟相关基因的干扰会破坏生物钟节律并诱发一系列代谢性疾病，如脂肪肝、高血糖等[4-5]。而通过进食等措施可促进生物钟节律恢复正常，如对生物钟基因敲除小鼠采取时间限制摄食(time restricted feeding，TRF)可有效预防其肥胖和代谢综合征的发生[6]。人和动物体内寄生着一群数量极为庞大、种类多达1 000多种的微生物(主要为细菌)，这些微生物统称为肠道菌群。机体昼夜节律的紊乱及外部环境的剧烈变化均会导致肠道菌群的异常，进而引发一系列疾病，其中最典型的就是肥胖和2型糖尿病(type 2 diabetes mellitus，T2DM)[7]。
1 肠道菌群及其昼夜节律性
早在20世纪末，研究人员已经发现蓝藻在昼夜节律周期与外界光暗周期同步时具有显著的竞争优势，证实了细菌存在昼夜节律性[8]。随着对肠道菌群研究的不断深入，目前认为其主要存在3种形式的节律：组成、功能和定植。Zarrinpar等[9]对小鼠粪便微生物群进行了16S rRNA测序分析并将序列聚类到操作分类单元(operational taxonomic unit，OTU)，发现肠道菌群在门水平上表现出周期性波动。随后研究发现其在目水平上同样表现出周期性波动，而敲除小鼠周期昼夜节律调节器1/2(period circadian regulator 1/2，Per1/2)基因可导致其肠道共生细菌丰度的节律性波动完全消失以及维生素、核苷酸代谢功能的消失[10]。此外，肠道菌群的定植也具有节律性。肠上皮定植细菌数量存在明显的昼夜变化，暗相的上皮层黏附性比光相高10倍[11]。
宿主机体的改变及外部环境的变化，尤其是宿主饮食规律及结构的变化，会对其节律性产生较大的影响，在24 h内就能引起肠道菌群的明显变化[12]。Thiass等[10]研究发现，Per1/2－/－小鼠昼夜进食节律大幅减弱，表现出24 h内持续消耗食物而非优先在黑暗阶段进食;对持续2周昼夜颠倒喂养的小鼠肠道菌群进行分析，发现大部分菌群周期性OTU表现出接近12 h的相位转移，这表明进食时间控制了肠道菌群的节律。与此同时，宿主的饮食结构也会影响菌群的节律。高脂饮食会引起宿主再生胰岛衍生蛋白3γ表达失调，对关键肠道菌的丰度和昼夜节律具有次要驱动作用[13]。同样地，采用高蔗糖饮食同样会造成宿主肠道菌群昼夜节律的不良改变，相伴随的还有α多样性的降低以及厚壁菌/拟杆菌比值的下降[14]。
肠道菌群可以调节宿主的昼夜节律和代谢稳态——其本身及其代谢产物均具有节律性[11, 15]，可通过接触(细菌与宿主细胞相互作用)和非接触(细菌产物如短链脂肪酸)途径调节宿主的昼夜节律和新陈代谢[7]。肠道菌群可直接接触宿主肠上皮细胞调控其生物钟基因的表达水平[16]，也可通过组蛋白脱乙酰酶3在小肠中进行昼夜节律的编程，进而间接调节宿主的昼夜节律[17]。
2 靶向肠道菌群治疗生物钟紊乱的理论探索及应用前景
人们不良的生活方式如熬夜以及暴露于不良外部环境如倒班均会导致昼夜节律的紊乱，增加节律紊乱相关疾病如代谢性疾病的发生风险。肠道菌群对机体的生理及营养具有巨大影响，可以作用于宿主的昼夜节律，因而被认为是节律紊乱及相关疾病的潜在治疗靶点。其中，改变菌群的丰度及组成是较为常见的一类干预措施。目前研究已经证实，通过抗生素直接作用于菌群可以消除时差反应小鼠出现的肥胖和糖耐量降低[10]，但是长期抗生素的服用会使得菌群对抗生素产生抗性，相较而言，TRF体现出十分明显的优势。采用TRF的高脂饮食小鼠表现出与正常饮食小鼠相近的体脂率和同步的乳酸杆菌属周期性变化(其与肥胖相关代谢紊乱关系密切)，且其颤螺菌属(Oscillibacter)水平显著高于未采用TRF的高脂饮食小鼠[9]。此外，TRF还可促进扭链瘤胃球菌(Ruminococcus torques)富集进而通过抑制肠道中的缺氧诱导因子2α-神经酰胺通路逆转非酒精性脂肪性肝病(nonalcoholic fatty liver disease，NAFLD)[18]。除了改变菌群的丰度外，TRF也可改变菌群的功能。Palomba等[19]研究发现，TRF可改变乳酸杆菌和嗜黏蛋白阿克曼氏菌(Akkermansia muciniphila)的功能，增加碳水化合物和蛋白质代谢相关酶(如琥珀酰辅酶A合成酶、磷酸烯醇式丙酮酸羧激酶)的表达。TRF对菌群节律建立的效应在临床研究中也得到印证。Zeb等[20]基于TRF对健康男性进行分组并对其粪便细菌进行16S rRNA测序，结果发现TRF组被试肠道菌群丰度明显增强，普雷沃氏菌和拟杆菌进一步富集，这提示TRF对肠道菌群的昼夜节律具有显著调节作用。下面主要介绍饮食(主要是TRF)、微生物相关制品和粪菌移植(fecal microbiota transplantation，FMT)3种干预手段的应用前景。
2.1 饮食干预
目前已经开展了许多针对TRF疗效评估的临床试验。Sutton等[21]针对糖尿病患者进行了较早时间段TRF(early TRF, eTRF;8：00－14：00进食，其余时间禁食)的疗效评估，结果发现eTRF可以改善糖尿病患者的胰岛素敏感性(显著降低负荷后胰岛素水平，P＜0.01)、β细胞反应性[胰岛素生成指数提高(14±7)U/mg，P＝0.05]及氧化应激反应水平，并且对心脏代谢的健康状况也具有改善作用。Hutchison等[22]评估了具有罹患T2DM风险的男性人群接受TRF(8：00－17：00进食或12：00－21：00进食，其余时间禁食)的获益，结果发现TRF将葡萄糖增量AUC降低了36%，显著改善了患者的糖耐量。Wilkinson等[23]在代谢综合征患者中进一步探讨了TRF(保持10 h进食窗，其余时间禁食)和药物的联合干预效果，发现TRF与药物服用在改善代谢综合征患者的心脏代谢健康方面具有协同作用，降低了患者的体重、血压及动脉粥样硬化发生率。Cienfuegos等[24]进一步探究了限制进食时间为4 h及6 h的TRF对肥胖患者的益处，结果发现4 h和6 h TRF均使患者体重显著下降(＞3%)，并且两者在改善氧化应激及胰岛素抵抗方面的作用相当。最近的研究表明，即使对于无肥胖的健康受试者，eTRF对其空腹血糖、体重及炎症反应都具有改善作用[25]。这些临床试验结果充分说明TRF在改善代谢性疾病患者预后方面的巨大潜力。有趣的是，Berry等[26]研究发现不同个体摄入相同餐食后血液甘油三酯、葡萄糖及胰岛素水平具有较大程度的变异，这提示应当进一步探究如何针对不同个体制定“一人一策”的饮食策略。
2.2 微生物相关制品
目前应用于临床和保健的微生物相关制品主要为益生菌(probiotics)和后生元(postbiotics)两大类，前者主要指一些活的、摄入后可以给宿主带来益处的微生物，而后者主要为可为宿主带来益处的无生命的微生物或其成分[27]。益生菌主要通过增强肠道屏障功能以及提升有益菌的比例对宿主菌群产生有利影响[28-29]。既往有较多研究探究了补充益生菌对代谢综合征表型(如体重、腰围等)的影响。Solito等[30]研究发现，对肥胖儿童和青少年补充短双歧杆菌8周后可观察到明显的腰围减小。Famouri等[31]开展的一项随机对照试验(randomized controlled trial，RCT)也获得了类似的结果，发现患有NAFLD的受试者在使用益生菌混合物(嗜酸乳杆菌、乳酸双歧杆菌、双歧杆菌和鼠李糖乳杆菌)治疗12周后腰围显著减小。
Laue等[32]通过一项RCT比较了益生菌补充与否对受试者体重的影响，结果显示相较于安慰剂对照组，补充发酵乳杆菌(Lactobacillus fermentum)的代谢综合征患者体重变化显著大于安慰剂组[(－0.61±1.94)kg vs (0.13±1.64)kg，P＝0.04]。Bernini等[33]研究发现乳双歧杆菌HN019能够降低代谢综合征患者的体重、血脂水平及炎症标志物(如IL-6)水平，对减少心血管不良事件的发生具有积极意义。Parnell等[34]研究发现益生元补充剂低聚果糖可以降低超重人群血浆脂多糖浓度及炎症相关标志物IL-6水平。对于T2DM患者，益生菌的服用可显著降低其糖化血红蛋白水平并减少菌群移位[35-36];相较于单纯服用益生菌，联合使用抑菌剂可进一步降低患者的糖化血红蛋白水平[37]。目前尚不明确益生菌是否会影响受试者血压。Wastyk等[38]基于一项为期18周的前瞻性研究分析发现，补充益生菌的代谢综合征患者只有一部分表现出获益(甘油三酯和舒张压显著改善)。Solito等[30]基于一项双盲、交叉RCT明确了益生菌补充剂对青少年舒张压的改善作用，但这种作用在短双歧杆菌组和安慰剂组中均有出现，表明该结果可能与生活方式的改善而非益生菌的使用有关，益生菌补充对血压是否具有改善作用仍需进一步探究。除了益生菌之外，后生元也可抑制病原体生长[39]，且可以通过调节肠道pH值和增强特定部位黏附能力促进有益菌繁殖[40]，从而对宿主菌群产生有益影响。多项临床研究证实了后生元在改善代谢综合征方面的有益作用。补充丁酸盐可显著提升超重成年男性的能量消耗和脂肪代谢水平[41];在肥胖儿童群体中同样观察到类似结果，丁酸盐补充剂降低了肥胖儿童的BMI并改善了其葡萄糖代谢水平[42]。
2.3 FMT
FMT将来自健康人群的粪便菌群通过口服胶囊、小肠镜、结肠镜等方式移植到罹患疾病个体的肠道中，可直接靶向性改善其肠道菌群丰度进而起到治疗疾病的作用。动物研究结果提示，FMT可通过改变菌群驱动生物钟重编程和节律改变。Xia等[43]发现将TRF小鼠的肠道菌群移植到NAFLD小鼠中可保护移植小鼠免受疾病的侵害并且恢复菌群的节律。将昼夜节律紊乱的小鼠菌群移植到抗生素预处理的小鼠中，接受移植的小鼠表现出与供体小鼠相似的菌群、肠道通透性增加和内脏超敏反应增强(腹壁撤退反射评分增加、疼痛阈值降低)[44]。将肝脏缺血再灌注损伤小鼠菌群移植到无菌的假手术受体小鼠中，其表现出与供体小鼠类似的反应(具有节律性的认知障碍)[45]。
较多临床研究展示了FMT对代谢综合征的治疗价值。与自体FMT相比，同种异体FMT(供者为正常BMI个体)对代谢综合征患者具有积极作用，显著改善了其胰岛素敏感性，并且这种改善作用与γ-氨基丁酸密切相关[46]。Allegretti等[47]通过供者为正常BMI个体的FMT与安慰剂的疗效对比，进一步证明了同种异体FMT对代谢综合征患者的积极作用，并且这种移植会导致受体肠道菌群谱和胆汁酸谱趋向正常的持续转变。尽管临床研究揭示了FMT在治疗代谢综合征方面的应用价值，但是目前其作用机制以及对宿主生物钟的具体影响仍需进一步探究。虽然Smillie等[48]通过机器学习方法在治疗艰难梭菌感染的FMT疗法中揭示了部分决定肠道菌群定植的因素并将其成功外推到代谢综合征患者，但是未来还需要进一步探究细菌在肠道内定植的原理，以更好地发展针对昼夜节律紊乱疾病的细菌疗法。
3 小结
外部环境的改变与内在条件的变化都会对哺乳动物的新陈代谢产生重要影响。昼夜节律紊乱会导致肠道菌群组成、功能及定植节律的异常变化，而肠道菌群的异常变化也会对宿主节律产生不良影响，两者的变化对节律紊乱相关疾病的发生发展具有重要意义。目前，通过饮食干预、微生物相关制品及FMT治疗节律紊乱相关疾病已取得一定的效果，但是很多疗法的机制仍不明确，针对不同个体疗效的差异仍存在疑问。未来还需要进一步探究肠道菌群失调与宿主节律紊乱及相关疾病发生的具体联系、靶向肠道菌群治疗相关疾病的具体机制，以更好地预防和治疗节律紊乱及并发疾病。
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