动物营养学报 >

2026 , Vol. 38 >Issue 8: 5660 - 5670

DOI: https://doi.org/10.12418/CJAN2026.454

综述

抗氧化类益生菌延缓雌性动物卵巢衰老的作用机制与研究进展

  • 陈美琪 , 1, 2 ,
  • 孙梦爽 1, 2 ,
  • 张晨希 1 ,
  • 王彦博 , 1, 2, *
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  • 1 内蒙古民族大学生命科学与食品学院, 通辽 028043
  • 2 内蒙古个体化用药工程技术研究中心, 通辽 028000
*王彦博,副教授,硕士生导师,E-mail:

陈美琪(2001—),女,吉林松原人,硕士研究生,从事益生菌与衰老机制研究。E-mail:

Office editor: 陈 燕

收稿日期: 2026-01-13

  网络出版日期: 2026-08-13

基金资助

国家自然科学基金项目(32360182)

内蒙古自治区高等学校青年科技英才支持计划(NJYT24053)

中央引导地方科技发展资金项目(2023ZY0015)

内蒙古自治区直属高校基本科研业务费(GXKY26Z068)

内蒙古自治区研究生教育教学改革项目(JG2025019Z)

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Mechanism and Research Progress of Antioxidant Probiotics in Delaying Ovarian Aging in Female Animals

  • CHEN Meiqi , 1, 2 ,
  • SUN Mengshuang 1, 2 ,
  • ZHANG Chenxi 1 ,
  • WANG Yanbo , 1, 2, *
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  • 1 College of Life Sciences and Food Engineering, Inner Mongolia Minzu University, Tongliao 028043, China
  • 2 Inner Mongolia Engineering and Technical Research Center for Personalized Medicine, Tongliao 028000, China
*associate professor, E-mail:

Received date: 2026-01-13

  Online published: 2026-08-13

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摘要

卵巢衰老可导致雌性动物生育能力下降和内分泌紊乱,并损害机体整体健康,其发生与氧化应激、免疫炎症、肠道微生物群失衡及下丘脑-垂体-卵巢轴功能紊乱密切相关。抗氧化类益生菌因具有抗氧化、抗炎及免疫调节等特性,已成为延缓卵巢衰老研究的前沿热点。该类益生菌可通过调节肠道稳态、修复肠道屏障、减少内毒素入血以缓解卵巢炎症;同时调控短链脂肪酸等代谢产物水平,清除活性氧并激活机体抗氧化系统,且能抑制颗粒细胞凋亡、保护卵泡储备,从多途径改善卵巢功能。本文梳理了卵巢衰老的核心机制,阐述了抗氧化类益生菌延缓雌性动物卵巢衰老的作用途径,为相关研究与应用提供参考。

关键词： 益生菌; 雌性动物; 卵巢衰老; 氧化应激; 下丘脑-垂体-卵巢轴

本文引用格式

陈美琪 , 孙梦爽 , 张晨希 , 王彦博 . 抗氧化类益生菌延缓雌性动物卵巢衰老的作用机制与研究进展[J]. 动物营养学报, 2026 , 38(8) : 5660 -5670 . DOI: 10.12418/CJAN2026.454

Abstract

Ovarian aging can lead to decreased fertility, endocrine disorders, and impaired systemic health in female animals. Its pathogenesis is closely associated with oxidative stress, immune inflammation, gut microbiota dysbiosis and hypothalamic-pituitary-ovarian axis dysfunction. Antioxidant probiotics, owing to their antioxidative, anti-inflammatory, and immunomodulatory properties, have become a frontier hotspot for research on delaying ovarian aging. These probiotics can alleviate ovarian inflammation by modulating gut homeostasis, repairing the intestinal barrier and reducing the entry of endotoxins into the bloodstream. Simultaneously, they regulate the levels of metabolites such as short-chain fatty acids, scavenge reactive oxygen species, and activate the endogenous antioxidant defense system. Furthermore, they inhibit granulosa cell apoptosis, preserve follicular reserve and improve ovarian function through multiple pathways. This review outlined the core mechanisms of ovarian aging and elaborated on the pathways through which antioxidant probiotics delay ovarian aging in female animals, aiming to provide a reference for related research and applications.

Key words： probiotics; female animals; ovarian aging; oxidative stress; hypothalamic-pituitary-ovarian axis

卵巢作为雌性动物生殖系统的核心器官,是衰老进程中的“起搏器”,其功能衰退与机体整体衰老密切相关。卵巢不仅通过原始卵泡的募集、生长与产生成熟卵子,维持雌性动物生殖能力[1],还分泌雌激素、孕激素等性激素调控下丘脑-垂体-卵巢(hypothalamic-pituitary-ovarian,HPO)轴稳态[2],通过调控机体生理活动影响心血管功能[3]与大脑认知水平[4]。随着年龄增长,卵巢表现出加速衰老特征,伴随卵泡数量减少、质量下降及内分泌紊乱。而在畜牧生产中,母畜卵巢功能衰退能够导致发情不规律、受胎率降低、产仔数减少,缩短有效繁殖年限,制约产业产能与效益,进一步凸显卵巢衰老对雌性动物健康的重要影响。
卵巢衰老的机制具有复杂性,涉及多路径协同作用。氧化应激是导致卵巢衰老的核心因素之一,卵巢内活性氧(reactive oxygen species,ROS)与抗氧化系统失衡会引发颗粒细胞凋亡和卵母细胞DNA损伤,加速卵泡闭锁[5]。慢性炎症通过激活炎症小体释放促炎因子,干扰卵泡成熟与激素合成,形成衰老促进的炎症微环境[6]。益生菌近年来在调节雌性动物生殖系统稳态[7]、延缓卵巢衰老方面[8]发挥重要作用。研究发现,部分菌种能通过重塑肠道微生物群平衡[9],激活HPO轴调控功能[8],改善雌激素[10]与孕激素[11]的平衡状态,缓解氧化应激损伤[6]。因此,本文综合现有研究成果,从卵巢功能保护、代谢调节及炎症抑制等方面,深入探讨益生菌延缓雌性动物卵巢衰老的作用机制,并梳理当前研究进展与未来方向,为调控雌性动物生殖健康提供参考。

1 卵巢衰老的核心机制

卵巢衰老是一个复杂的生理过程,涉及多方面分子机制的异常调控,而HPO轴作为雌性动物生殖内分泌调节的核心轴系[12],其在生殖衰老中起着决定性作用。尽管无数研究证明卵巢和HPO轴都参与生殖衰老过程,但哪一个是诱因仍存在争议。近期研究倾向于认为,HPO轴在生殖衰老中占据主导地位,其调控机制[13]如图1所示,促性腺激素释放激素(gonadotropin-releasing hormone,GnRH)作用于垂体,促其分泌促卵泡激素(follicle stimulating hormone,FSH)与促黄体生成素(luteinizing hormone,LH),以调控卵泡发育,卵巢分泌的激素反馈调节下丘脑和垂体;下丘脑神经元通过神经递质网络精准调控GnRH释放,谷氨酸作为兴奋性递质,其水平下降及GnRH神经元对其敏感性降低会抑制GnRH分泌;γ-氨基丁酸(gamma-aminobutyric acid,GABA)通过直接结合GnRH神经元受体或间接抑制谷氨酸受体发挥双重调控作用,其与谷氨酸的平衡是GnRH正常释放的关键;KNDy细胞分泌的基斯肽(kisspeptin)、神经激肽B(neurokinin B,NKB)和强啡肽(dynorphin,DYN)构成调控环路,三者基因表达随年龄改变会导致GnRH神经元兴奋-抑制输入失衡,最终调控GnRH的脉冲式分泌节律。目前,关于“神经系统与卵巢孰先衰老”,尚未形成定论。但多数研究更倾向于HPO轴的神经内分泌功能紊乱是卵巢衰老的重要启动因素,而非卵巢自身先发生独立衰老。除此之外,卵巢衰老还伴随基因组稳定性失衡、氧化应激-慢性炎症恶性循环等问题,而益生菌可通过多轴调控,协同改善这些状况,延缓卵巢衰老[14-15]。
图1 大脑与卵巢通过HPO轴的相互作用

DYN:强啡肽 dynorphin;NKB:神经激肽B neurokinin B;Kisspeptin:基斯肽;KNDy cells:KNDy细胞kisspeptin/neurokinin B/dynorphin cells;Glu:谷氨酸 glutamic acid;GABA:γ-氨基丁酸 gamma-aminobutyric acid;GnRH:促性腺激素释放激素 gonadotropin-releasing hormone;FSH:促卵泡激素 follicle-stimulating hormone;LH:促黄体生成素 luteinizing hormone;Estrogen:雌激素;Progestin:孕激素;Inhibin:抑制素;Hypothalamus:下丘脑;Pituitary gland:垂体;Ovary:卵巢;HPO axis:下丘脑-垂体-卵巢轴 hypothalamic-pituitary-ovarian axis。

Fig.1 Interaction between brain and ovary through HPO axis[13]

1.1 免疫炎症与卵巢微环境改变

免疫炎症调控异常与卵巢微环境失衡是卵巢衰老的核心机制之一,老年马的免疫衰老研究显示,淋巴细胞增殖、抗体产生及疫苗应答能力随年龄下降,同时伴随促炎状态,这种与年龄相关的免疫功能改变,为理解动物免疫衰老和器官衰老之间的关联提供了参考[16]。在Vav-iCre+/-Ercc1-/fl小鼠模型中发现,特异性敲除小鼠造血细胞内切除修复交叉互补基因组1(excision repair cross-complementation group 1,Ercc1)基因可导致免疫细胞提前衰老,p16、p21蛋白等衰老标志物及衰老相关分泌表型(senescence-associated secretory phenotype,SASP)因子高表达[17]。系统性炎症直接破坏卵巢微环境稳态,由此证实免疫炎症对卵巢衰老的驱动作用,卵巢局部微环境中,卵巢纤维炎症反应会导致白细胞介素-1β(interleukin-1β,IL-1β)、ROS等炎症因子在局部积累,同时伴随血管化不足、胶原沉积,还会促使泡沫状巨噬细胞生成[18]。在老年小鼠的卵巢中,仍保留着极小胚胎样干细胞(very small embryonic-like stem cells,VSELs)、卵原干细胞(oogonial stem cells,OSCs)以及生殖细胞巢,但由于卵巢微环境内氧化应激增强、基质纤维化等年龄相关变化的影响,干细胞分化过程受阻,生殖细胞巢停滞于减数分裂前期,无法进一步组装为成熟卵泡[19]。Shank3b突变小鼠作为自闭症模型,相关研究主要集中于神经发育相关炎症,该模型存在基因型依赖的系统性炎症,具体表现为骨髓、脾脏中干扰素-γ(interferon-γ,IFN-γ)、白细胞介素-6(interleukin-6,IL-6)等细胞因子出现异常,进而表明全身性的免疫炎症能够跨组织地对器官微环境产生影响,为理解卵巢衰老的免疫调控网络提供了证据[20]。卵巢微环境发生改变会引发氧化应激反应以及血管稳态失衡现象[21]。与此同时,雌性衰老小鼠远端输卵管多纤毛细胞出现空泡化[22]。进而表明随着年龄增长,生殖系统整体微环境发生变化,这些发现进一步说明卵巢功能衰退并非孤立发生,而是受到生殖系统整体微环境衰老影响的系统性过程[22]。

1.2 细胞凋亡与卵泡储备量减少

卵巢衰老主要表现为卵泡储备耗竭与细胞异常凋亡,其内在驱动力源于关键调控因子表达异常及信号通路失衡,而外源性因素则进一步加速了这一进程。成年野生型雌鼠体内p53诱导的磷酸酶1(wild-type p53-induced phosphatase 1,WIP1)蛋白的低表达会触发WIP1/p53/B细胞淋巴瘤-2相关X蛋白(B-cell lymphoma-2-associated X protein,Bax)信号通路诱导颗粒细胞凋亡以及磷脂酰肌醇3激酶(phosphatidylinositol 3-kinase,PI3K)/蛋白激酶B(protein kinase B,Akt)/核糖体蛋白S6(rpS6)信号通路驱动原始卵泡过度激活。该双重作用加剧了卵泡闭锁与储备耗竭,最终表现为动情周期紊乱及生育力减退[23]。谷胱甘肽过氧化物酶4(glutathione peroxidase 4,GPX4)低表达使细胞抗氧化能力下降,导致丙二醛(malondialdehyde,MDA)积累及线粒体形态异常,进而影响颗粒细胞功能和卵母细胞质量,加剧卵泡储备减少[14]。而卵泡闭锁的核心机制在于颗粒细胞凋亡,卵巢衰老状态下抗凋亡蛋白与促凋亡蛋白的表达平衡被打破,B细胞淋巴瘤-2相关X蛋白(B-cell lymphoma-2-associated X protein,Bax)表达升高、B细胞淋巴瘤-2(B-cell lymphoma-2,Bcl-2)表达降低,导致凋亡细胞增多,进一步缩减卵泡储备[15,24-25]。
此外,环磷酰胺等化疗药物会损伤卵巢线粒体功能,降低ATP水平、导致ROS升高,并激活半胱天冬蛋白酶-3(cysteine-dependent aspartate-specific protease-3,Caspase-3)等凋亡因子,加剧了颗粒细胞和卵母细胞凋亡[25]。然而,葛根素能够通过上调Bcl-2、下调Bax和Caspase-3基因表达逆转该过程[15]。绵羊、山羊等动物模型证实,增龄性原始卵泡池衰减与卵巢基质中多核巨细胞的累积密切相关,这类细胞进一步加剧了卵泡储备的耗竭[26]。龙胆紫、杨梅素等物质可通过调控凋亡相关蛋白诱导卵巢癌细胞凋亡,在正常卵巢组织中此类凋亡通路异常激活会加速衰老[24,27]。

1.3 氧化应激-慢性炎症恶性循环

氧化应激与慢性炎症构成卵巢衰老微环境恶化的核心分子网络,将直接损伤颗粒细胞与卵母细胞功能[28-29]。随着年龄增长,卵巢的抗氧化能力下降,导致卵巢中超氧化物歧化酶(superoxide dismutase,SOD)活性、谷胱甘肽(glutathione,GSH)水平降低,ROS水平升高。然而,过量的ROS优先攻击颗粒细胞线粒体,进而氧化损伤线粒体DNA(mitochondrial DNA,mtDNA)触发“ROS恶性循环”,导致呼吸链功能受损、线粒体膜电位破坏,促进细胞色素c释放以激活内源性凋亡通路[28]。此外,ROS通过氧化修饰DNA碱基形成8-羟基-2'-脱氧鸟苷(8-hydroxy-2'-deoxyguanosine,8-OHdG),降低DNA修复基因表达,加剧基因组不稳定性[30]。ROS能够显著上调炎症因子IL-1β表达,并激活诱导核因子-κB(nuclear factor kappa-B,NF-κB)信号通路[31]。研究发现,通过对37周龄衰老模型小鼠灌胃7或70 mg/kg的亚麻木酚素二葡萄糖苷,能够抑制氧化应激,提升卵巢的营养摄取与代谢水平,增加卵泡刺激素受体的表达,进而改善卵巢的储备功能[32]。每日腹腔注射10 mg/kg BW芍药苷并连续给药7周,可激活线粒体自噬,抑制氧化应激、促进颗粒细胞增殖,改善过氧化氢致小鼠卵巢发育延迟[33]。维生素C可通过修复氧化损伤的卵巢组织,增强颗粒细胞抗氧化防御能力[34]。
目前,上述内容在卵巢衰老进程中的作用及机制已得到广泛研究。衰老、吸烟、高糖饮食等多种因素均可诱导机体的氧化应激,进而通过激活细胞凋亡、加剧炎症反应、损伤线粒体功能等关键机制,加速卵巢衰老进程[35-37]。氧化应激抑制策略已初步证实能够改善卵巢衰老表型,但仍需进一步研究以明确其是否能够改善卵巢衰老动物的妊娠结局。

2 益生菌的种类及特性

不同类型的益生菌因其生物学特性和作用机制的差异,在机体中展现出不同的功能潜力。依据其代谢特征和来源,益生菌通常可分为乳酸菌类(lactic acid bacteria,LAB)和非乳酸菌类(non-LAB)两大类[38]。不同菌株在抗氧化、抗炎、免疫调节等方面存在差异,这种差异可能直接对衰老产生影响。表1总结了不同种类益生菌特征,包括其延缓衰老的抗氧化、抗炎机制,可为延缓雌性动物生殖衰老的菌株筛选提供参考。从卵巢衰老的核心机制来看,益生菌需具备强抗氧化、抗炎及适配免疫调节的功能。表格内容揭示了益生菌的抗氧化、抗炎及免疫调节功能与延缓衰老的关联,为雌性动物生殖衰老防护提供参考。卵巢衰老核心与氧化应激、局部炎症及免疫紊乱相关,适配益生菌需具备针对性功能。后续可筛选戊糖片球菌、植物乳杆菌等适配菌株,通过功能互补进一步提升益生菌对卵巢衰老的延缓,为雌性动物生殖健康维护提供更好的参考方案。
表1 不同种益生菌的特性

Table 1 Characteristics of different probiotics

益生菌种类
Probiotic
species		 抗氧化能力
Antioxidant
capacity		 抗炎能力
Anti-inflammatory
capacity		 核心功能总结
Summary of core
functions		 参考文献
References
嗜热链球菌
Streptococcus
thermophilus		 ★★★ ▲▲△ 每日灌胃D-半乳糖诱导的衰老小鼠20 mL/kg
发酵代谢产物(含1×108 CFU/mL菌株),持续2个月。
可提升体内超氧化物歧化酶(SOD)活性、降低丙二醛
(MDA)水平,延长白细胞及肝脏端粒长度,
进而缓解细胞衰老		 [39]
乳酸乳球菌
Lactococcus
lactis		 ★★☆ ▲▲▲ 每日灌胃小鼠1×109 CFU热灭活菌株,持续75周。
通过细菌DNA激活Toll样受体9/髓样分化因子88
(TLR9/MyD88)信号通路,维持树突状细胞活性,抑制
白细胞介素-1β(IL-1β)转录,调节免疫平衡,
增强肠道黏膜免疫及抗病毒应答		 [40]
戊糖片球菌
Pediococcus
pentosaceus		 ★★★ ▲▲▲ 每日灌胃小鼠1×109 CFU菌株,持续4~8周。通过
分泌细菌素、胞外聚合物(EPS)等物质,清除
自由基、抑制脂质过氧化作用;还能中和脂多糖
(LPS),下调促炎因子表达,抑制致病菌生长		 [41]
布拉氏酵母菌
Saccharomyces
boulardii		 ★★☆ ▲▲▲ 每日灌胃小鼠1×109 CFU菌株,持续3~7 d。
降低细胞内活性氧(ROS)水平以减轻氧化损伤,
调节肠道微生物群;同时,调节肠道黏膜免疫功能,
下调免疫球蛋白E水平减轻过敏反应,
增强肠道屏障功能		 [42]
马克斯克鲁维
酵母菌
Kluyveromyces
marxianus		 ★★☆ ▲▲△ 向秀丽隐杆线虫模型中添加1×106 CFU/μL
菌株30 μL,持续7 d。减轻氧化应激诱导的细胞损伤,
同时降低血清白细胞介素-6(IL-6)水平,促进
有益菌增殖,以缓解肠道局部炎症		 [43]
植物乳杆菌
Lactobacillus
plantarum		 ★★★ ▲▲▲ 每日灌胃小鼠1×109 CFU菌株,持续4周。
通过分泌短链脂肪酸及植物乳杆菌素,
清除自由基、抑制脂质过氧化并提高抗氧化酶活性;
调节促炎[肿瘤坏死因子-α(TNF-α)、IL-6]/
抗炎[白细胞介素-10(IL-10)]因子平衡,
减轻肠道及全身炎症		 [41]

★★★表示抗氧化能力强,能够多途径抗氧化,可分泌抗氧化物质或激活宿主抗氧化通路,显著改善抗氧化性能指标;★★☆表示抗氧化能力中等,抗氧化途径单一,对氧化应激的改善效果温和或仅在特定场景有效;▲▲▲表示抗炎能力强,能够显著抑制炎症通路,调控促炎/抗炎因子平衡,有效缓解炎症损伤;▲▲△表示抗炎能力中等,抗炎范围局限,对系统性炎症改善有限,调控炎症指标幅度较弱。

★★★ indicates strong antioxidant capacity, capable of exerting antioxidant effects through multiple pathways, secreting antioxidant substances or activating host antioxidant signaling pathways, and significantly improving antioxidant performance indicators; ★★☆ indicates moderate antioxidant capacity, with a single antioxidant pathway and mild improvement in oxidative stress, effective only under specific conditions; ▲▲▲ indicates strong anti-inflammatory capacity, capable of significantly suppressing inflammatory pathways, regulating the balance of pro-inflammatory and anti-inflammatory factors, and effectively alleviating inflammatory damage; ▲▲△ indicates moderate anti-inflammatory capacity, with a limited spectrum of anti-inflammatory action, limited efficacy against systemic inflammation, and weak modulation of inflammatory markers.

3 益生菌抗卵巢衰老的作用机制

3.1 益生菌的调节作用

益生菌通过调节肠道微生物群平衡、调控激素代谢、改善免疫功能及抑制炎症反应等多环节协同作用于卵巢抗衰过程,具体过程如图2所示。其调节肠道微生物群组成,增加有益菌丰度,减少致病菌定植,通过分泌β-葡萄糖醛酸酶调控雌激素的去结合过程,维持循环雌激素水平稳定,进而影响卵巢颗粒细胞增殖、卵泡发育和卵母细胞成熟。益生菌代谢产物短链脂肪酸(short-chain fatty acids,SCFAs)可通过环磷酸腺苷(cAMP)信号通路调节孕酮与雌二醇的分泌,改善卵巢内分泌功能[44-46]。随后抑制促炎因子[如肿瘤坏死因子-α(TNF-α)、IL-6]释放、增强抗炎因子[如白细胞介素-4(interleukin-4,IL-4)、IL-10]表达,减轻卵巢局部炎症反应[47],减少颗粒细胞凋亡和卵泡闭锁,降低脂多糖(lipopolysaccharides,LPS)入血引发的全身性炎症对卵巢的损伤,这一免疫调节作用在早衰小鼠模型中已得到证实,因此,通过益生菌的调节作用可以改善雌性早衰小鼠的卵巢储备功能[47-49]。HPO轴相关激素(如FSH、LH)的分泌也受益生菌调控,其通过调节卵泡刺激素介导的线粒体功能保护信号通路,改善卵巢线粒体能量代谢、减少ROS产生,同时通过调节非编码RNA的表达,参与线粒体和细胞核的双向通讯,减轻线粒体损伤,延缓卵巢衰老[48,50]。此外,通过粪便微生物移植(fecal microbiota transplantation,FMT)将年轻个体的健康肠道微生物群转移至衰老个体,能够重塑肠道微环境,促进卵巢颗粒细胞增殖、进而减少卵泡凋亡,改善卵巢衰老[45,48]。
图2 益生菌在体内的作用通路

Granule cell:颗粒细胞;Maintain stable estrogen levels:维持稳定雌激素水平;Beneficial bacteria:有益菌;Harmful bacteria:有害菌;Mitochondrial damage:线粒体损伤;Probiotics:益生菌;FSH:促卵泡激素 follicle-stimulating hormone;LH:促黄体生成素 luteinizing hormone;ROS:活性氧 reactive oxygen species;IL-4:白细胞介素-4 interleukin-4;IL-10:白细胞介素-10 interleukin-10;Ovarian inflammation:卵巢炎症;Granule cell apoptosis:颗粒细胞凋亡;TNF-α:肿瘤坏死因子-α tumor necrosis factor-α;IL-6:白细胞介素-6 interleukin-6;Fecal microbiota transplantation:粪便微生物移植;Young individuals:青年体;Aging individuals:老年体;Follicular atresia:卵泡闭锁;Promote reaction:促进反应;Inhibitory response:抑制反应;pathway of probiotics in the body:益生菌在体内的作用途径。

Fig.2 The action pathway of probiotics in vivo

近年来,益生菌在抗衰老领域的研究不断深入,不仅揭示了其多维度的调控机制,还进一步证实了益生菌与益生元、抗衰活性物质[如β-烟酰胺单核苷酸(β-nicotinamide mononucleotide,NMN)]之间存在显著的协同增效作用。例如,研究发现,0.1 mg/mL NMN组小鼠肠道内丁酸产生菌[瘤胃球菌科UCG-014(Ruminococcaceae UCG-014)、普雷沃氏菌科NK3B31群(Prevotellaceae NK3B31 group)]及嗜黏蛋白阿克曼菌(Akkermansia muciniphila)等益生菌丰度提升,有害菌[嗜胆菌属(Bilophila)、颤螺菌属(Oscillibacter)]丰度下降,同时粪便中胆酸、牛磺脱氧胆酸等胆汁酸相关代谢物水平升高,NMN干预还能提升肠道微生物群指数,增强肠道屏障功能[51]。鼠李糖乳酪杆菌GG(Lacticaseibacillus rhamnosus GG,ATCC 53103)可结合菊粉、菠萝汁制成益生元合成饮料,其靶向调节肠道微生态、抑制氧化应激并激活自噬通路,菠萝多酚则发挥抗氧化、抗炎作用,三者协同可从肠道微生物群平衡、氧化损伤修复与细胞衰老调控多维度抗衰,且该益生菌需按特定剂量(D-半乳糖致衰小鼠模型中108~1010 CFU为有效剂量,1010 CFU为最优剂量)、通过灌胃方式摄入,有效发挥与菊粉、菠萝多酚的协同抗衰作用[52]。

3.2 抑制氧化应激与激活抗氧化系统

氧化应激抑制通过减少ROS生成[53]以避免卵巢组织氧化损伤,抗氧化系统激活则是调动体内酶类或非酶类抗氧化物质,增强卵巢自身抵御氧化应激的能力,二者互作可减轻卵巢颗粒细胞、卵泡膜细胞及卵母细胞的损伤,维持卵泡储备与激素分泌平衡。乳杆菌、双歧杆菌通过合成并分泌GSH、SOD、过氧化氢酶(catalase,CAT)等抗氧化物质,如植物乳杆菌CCFM1019可在卵巢局部释放GSH,中和ROS生成的脂质过氧化物,减少颗粒细胞DNA氧化损伤,鼠李糖乳酪杆菌GG能诱导卵巢组织中SOD活性提升,将超氧阴离子转化为无害的水和氧气,维持卵巢稳态;其通过调节肠道微生物群结构促进短链脂肪酸生成,激活G蛋白偶联受体41(G protein-coupled receptor 41,GPR41)通路,上调卵巢组织中核因子E2相关因子2(nuclear factor erythroid 2-related factor 2,Nrf2)的表达,进一步诱导抗氧化酶基因激活,强化卵巢自身抗氧化防御系统,同时降低肠道LPS水平,减少LPS介导的卵巢炎症与ROS协同损伤,形成“肠道微生物群-SCFAs-卵巢抗氧化”的保护轴[54]。
含维生素D益生菌混合物[动物双歧杆菌乳亚种BSO1(Bifidobacterium animalis subsp. lactis BSO1)、罗伊氏乳杆菌LRE02(Lactobacillus reuteri LRE02)、植物乳植杆菌LP14(Lactobacillus plantarum LP14)]能提升谷胱甘肽还原酶、谷胱甘肽过氧化物酶活性,增加还原型GSH水平,降低氧化型谷胱甘肽(oxidized glutathione,GSSG)比例及脂质过氧化物水平,改善机体状态[55],还可抑制HPO轴炎症反应,减少炎症相关因子生成,减轻卵巢氧化损伤[56]。

3.3 免疫炎症调控与卵巢微环境改善

免疫炎症调控与卵巢微环境改善是一个多环节协同过程,通过调控体内炎症因子水平,降低内毒素引发的全身性炎症[57],改善卵巢局部低炎状态,减少颗粒细胞凋亡、促进卵泡成熟。同时保护肠道屏障完整性间接维持卵巢功能。在衰老卵巢中,促炎因子积聚会加速颗粒细胞凋亡、抑制卵泡成熟,而益生菌能调节肠道微生物群平衡,产生短链脂肪酸等代谢产物,经HPO轴调控机体炎症通路、抑制促炎细胞因子释放,同时改善胰岛素抵抗与肠道屏障功能,间接调节卵巢甾体激素合成及HPO轴激素分泌,进而改善多囊卵巢综合征相关的卵巢内分泌与代谢异常[58]。
衰老过程中肠道通透性增加,LPS等内毒素易位入血引发全身性炎症[59],进一步加重卵巢衰老,可释放白细胞介素-22(IL-22)的基因工程罗伊氏黏液乳杆菌(Limosilactobacillus reuteri releasing IL-22,LR-IL-22)可通过多途径调节肠道微环境、缓解卵巢组织炎症,进而延缓卵巢衰老进程。研究发现,灌胃109~1010 CFU LR-IL-22,可在肠道隐窝部位实现IL-22的局部释放。该细胞因子通过调控肠道干细胞基因表达,上调肠道紧密连接相关蛋白的表达水平,从而增强肠道上皮屏障功能,有效减少LPS的易位入血;同时,IL-22的代谢调控作用可抑制肠道炎症反应,进一步降低循环系统中LPS水平;这种双重作用机制减少了LPS介导的炎症因子向卵巢组织的浸润,从而减轻卵巢组织的慢性炎症损伤,维持卵泡发育所需的低炎症微环境;这种保护作用可避免炎症过度激活导致的卵泡耗竭和卵巢功能衰退;此类益生菌在雌性动物模型均表现出稳定的肠道屏障保护和抗炎效应,为通过肠道-卵巢轴途径干预卵巢衰老提供了新的科学依据[60]。

3.4 细胞凋亡抑制与卵泡储备保护

细胞凋亡与卵泡保护是指通过调控细胞凋亡相关通路、改善线粒体功能等方式,减少颗粒细胞过度凋亡和卵母细胞衰老,维持卵泡的数量与质量,进而延缓卵巢衰老的生理调控过程,也是保护雌性动物生殖功能的关键环节。研究发现,干酪乳杆菌39可激活PI3K/Akt信号通路,抑制颗粒细胞凋亡,靶向抑制凋亡相关基因表达并激活抗凋亡基因Bcl-2,减少卵泡闭锁[61]。通过灌胃0.1 mL粪上清液大肠杆菌Nissle 1917可调节小鼠肠道微生物群及代谢,促进肠道免疫因子IL-22表达,进而改善多囊卵巢综合征模型小鼠颗粒细胞的线粒体损伤,抑制线粒体自噬,减少颗粒细胞凋亡[62]。
连续30 d对成年雌性大鼠每日灌胃植物乳杆菌ATCC 8014(107 CFU/mL),可有效缓解由煎炸油喂养引起的卵巢损伤,增加卵泡数量、减少闭锁卵泡,同时调节与卵泡生成相关基因的表达,进而改善激素水平[63]。以饮水方式持续4个月,每天按400 mg/kg剂量给小鼠补充烟酰胺核糖(nicotinamide riboside,NR),能够提高卵巢内烟酰胺腺嘌呤二核苷酸(NAD+)水平,改善卵巢线粒体功能,增加卵泡数量[64]。其中原始、初级卵泡数量提升至原来的3.8倍,次级、窦卵泡数量增加80%,同时增强排卵潜力;此外,还能减少卵母细胞中ROS的生成,降低纺锤体异常发生率,最终提高卵母细胞质量;NR作为NAD+前体发挥的卵巢抗衰老作用,与肠道微生物群存在紧密的调控联系,而且肠道微生物群和卵巢功能相互调控,共同参与NAD+代谢的核心环节[64]。
动物衰老进程加速以及衰老相关健康问题的凸显,已然成为影响动物健康养殖的关键因素。在此背景下,益生菌凭借其与宿主广泛且复杂的相互作用关系,逐渐被视为预防和治疗动物衰老相关问题的途径之一。然而,上述内容仍不能明确阐明益生菌在卵巢中调控的深层机制。因此,仍需开展更为深入的研究,以解释益生菌-肠道微生物-卵巢三者间的复杂互作关系,为延缓动物衰老提供关键理论依据。

4 小结与展望

本文系统综述了抗氧化类益生菌延缓雌性动物卵巢衰老的作用及潜在机制。益生菌因具抗炎、抗氧化和免疫调节特性,可作用于卵巢衰老多环节,推测其能多方面改善卵巢储备功能、延缓卵巢衰老。目前,多数研究虽集中于其抗炎、抗氧化及代谢调节能力,但对于益生菌及其代谢产物在延缓雌性个体卵巢衰老进程中的具体作用机制,以及它们与雌性个体衰老过程中健康状况之间的内在关联尚未解释清楚。不过,本文通过对既有成果的总结,为后续深入探究作用机制指明了方向。总体而言,益生菌对雌性机体的调节作用为开发延缓卵巢衰老的相关策略提供了研究基础,兼具科学研究价值与实际应用潜力。
未来,针对益生菌与卵巢衰老的研究可多方面深入推进。借助多种先进组学技术,明确不同益生菌菌株或组合对雌性动物卵巢衰老中的具体作用差异与协同机制。此外,还可探索益生菌与其他针对卵巢抗衰老的方法(如特定药物治疗、卵巢局部微环境调控等)联合应用的效果,分析其协同作用机制,以便更有效地延缓雌性动物卵巢衰老,改善其卵巢功能与生殖健康状况,为解决动物卵巢衰老相关问题提供新的研究思路与方法。

感谢内蒙古民族大学生命科学与食品学院韩哲老师为论文提出宝贵意见。

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