动物营养学报 >

2026 , Vol. 38 >Issue 5: 3198 - 3208

DOI: https://doi.org/10.12418/CJAN2026.256

综述

不同来源乳酸代谢与功能的差异研究进展

  • 贾宁晖 ,
  • 王铭育 ,
  • 郑萍 , *
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  • 四川农业大学动物营养研究所, 教育部、农业农村部、四川省抗病营养重点实验室, 成都 611130
*郑 萍,教授,博士生导师,E-mail:

贾宁晖(1998—),男,山西临汾人,博士研究生,从事动物营养与饲料科学研究。E-mail:

Office editor: 菅景颖

收稿日期: 2025-10-29

  网络出版日期: 2026-05-14

基金资助

四川省重大科技专项(2021ZDZX0009)

国家自然科学基金项目(31972577)

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Research Progress on Differences in Metabolism and Functions of Lactate from Different Sources

  • JIA Ninghui ,
  • WANG Mingyu ,
  • ZHENG Ping , *
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  • Key Laboratory of Disease-Resistant Nutrition of Sichuan Province, Ministry of Education, Ministry of Agriculture and Rural Affairs, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
*professor, E-mail:

Received date: 2025-10-29

  Online published: 2026-05-14

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摘要

乳酸作为重要代谢产物,其来源分为内源性(机体细胞糖酵解产生,以L-乳酸为主)和外源性(饲粮添加、静脉输入及肠道菌群发酵膳食纤维产生,含一定比例D-乳酸)两类。内源乳酸和外源乳酸在代谢与功能上存在差异:内源乳酸依赖单羧酸转运体(MCTs)转运实现乳酸穿梭,通过线粒体氧化或糖异生快速维系能量稳态,在免疫调节中直接调控巨噬细胞极化与炎症因子释放;外源乳酸摄取受肠道pH、肝脏清除率影响,优先作为三羧酸(TCA)循环底物供能,在免疫调节中依赖组蛋白乳酸化重编程细胞功能。这些差异对动物的健康和生产性能具有重要影响。本文主要综述了内源乳酸和外源乳酸在来源、代谢、能量供应及免疫调控中的差异,以期进一步揭示不同来源乳酸代谢的分子机制,并为提高乳酸利用提供参考。

关键词： 内源乳酸; 外源乳酸; 代谢; 三羧酸循环; 免疫调节

本文引用格式

贾宁晖 , 王铭育 , 郑萍 . 不同来源乳酸代谢与功能的差异研究进展[J]. 动物营养学报, 2026 , 38(5) : 3198 -3208 . DOI: 10.12418/CJAN2026.256

Abstract

As an important metabolic product, lactate has two sources: endogenous (primarily L-lactate, produced by glycolysis in somatic cells) and exogenous (containing a certain proportion of D-lactate, derived from dietary supplementation, intravenous infusion and intestinal microbiota fermentation of dietary fiber). There are significant differences in the metabolism and physiological roles of endogenous and exogenous lactate: endogenous lactate relies on monocarboxylate transporters (MCTs)-mediated lactate shuttle to rapidly maintain energy homeostasis through mitochondrial oxidation or gluconeogenesis, and directly regulates macrophage polarization and inflammatory factor release in immune modulation; exogenous lactate uptake is affected by intestinal pH and hepatic clearance rate, it is preferentially used as a substrate for the tricarboxylic acid (TCA) cycle to supply energy, and its immune regulation depends on histone lactylation to reprogram cellular functions. These differences significantly impact animal health and production performance. This review summarized the differences between endogenous and exogenous lactate in sources, metabolism, energy supply and immune regulation, aiming to further clarify the molecular mechanisms underlying the metabolism of lactate from different sources and provide references for improving lactate utilization.

Key words： endogenous lactate; exogenous lactate; metabolism; tricarboxylic acid cycle; immune regulation

乳酸曾被认为是糖酵解的无用副产物,乳酸浓度升高被视为高强度运动或疾病状态下发生酸中毒的关键指标[1]。然而,随着乳酸穿梭理论的提出与发展,乳酸被重新定义为连接糖酵解与氧化代谢的重要“纽带”,且具有自分泌、旁分泌和内分泌样的调控作用[2-4]。越来越多的研究表明,乳酸可作为能量底物来源,在多种生理与病理过程中扮演重要角色。
乳酸可通过多条通路调节巨噬细胞极化、T细胞分化及炎性小体活性,从而缓解仔猪断奶应激所致的肠道炎症,在此基础上,能量不再被过度免疫所消耗,饲料转化效率随之提高,断奶仔猪生长性能得到改善[5-6]。然而,内源乳酸和外源乳酸在体内的代谢和作用机制不尽相同,本文总结了内源乳酸和外源乳酸在来源、代谢、能量供应及免疫调控中的差异,以期为探究不同来源乳酸的作用机理和营养调控提供参考。

1 乳酸生理

三大有机酸包括羧酸、羟基酸和酮酸,其中乳酸是最广泛的一种羟基酸,其分子式为C3H6O3。乳酸可在机体内参与多种反应得益于其分子结构中既有羟基也有羧基,其羧基在水溶液中易释放出1个质子而产生乳酸根离子。此外,乳酸分子中有1个不对称的碳原子,具有L(+)和D(-)2种构型,故其有L-乳酸(左旋)和D-乳酸(右旋)这2种旋光异构体。哺乳动物通过L-乳酸脱氢酶(L-lactate dehydrogenase,L-LDH)分解L-乳酸,D-乳酸可经D-乳酸脱氢酶(D-lactate dehydrogenase,D-LDH)催化为丙酮酸,进而进入后续代谢通路[7],正常生理条件下,血浆中D-乳酸与L-乳酸的比值约为1∶100[8]。天然的左旋偏好决定了后续L-乳酸和D-乳酸代谢通路、转运亲和及免疫调节的底物选择性。

2 内源乳酸

2.1 内源乳酸的合成

乳酸的来源可分为内源性与外源性两类。内源乳酸几乎全部为L-乳酸(>99%),其主要是机体自身细胞(如骨骼肌、红细胞、神经元等)通过糖酵解途径产生的[3,9]。在细胞质中,1分子葡萄糖可产生2分子丙酮酸,当氧供应不足时,丙酮酸被乳酸脱氢酶(lactate dehydrogenase,LDH)还原为乳酸,同时还原型烟酰胺腺嘌呤二核苷酸(NADH)被氧化为氧化型烟酰胺腺嘌呤二核苷酸(NAD+)。有氧条件下乳酸也会持续产生,其不再是传统认知中的代谢废物,而是具有代谢价值的动态燃料[4]。心肌等有氧代谢旺盛的组织不仅能通过LDH逆反应将乳酸氧化为丙酮酸再进入线粒体代谢,更有研究证实线粒体对乳酸的氧化优先级高于丙酮酸[10]。肿瘤细胞或某些增殖细胞更倾向于有氧糖酵解将丙酮酸转化为乳酸以获取能量,即瓦伯格效应(Warburg effect)[11-12]。LDH主要包括A、B和C 3种同工酶,它们的表达和功能有显著的组织特异性。A型主要在骨骼肌、肿瘤组织等无氧代谢较为活跃的组织中表达,功能是在缺氧条件下促进丙酮酸转化为乳酸;B型集中于心肌等有氧代谢组织,倾向于促进乳酸向丙酮酸的转化,有助于维持有氧条件下的能量代谢;C型仅在睾丸和精子细胞中表达,与生殖过程中的特定代谢需求相关[13-14]。这种“同工酶-组织代谢类型”的精准匹配,是内源乳酸合成适应不同生理场景的核心机制。

2.2 内源乳酸的转运

成年人体内每天约产生1.8 g/kg乳酸进入循环,其中肌肉和皮肤各占25%,红细胞和脑各占20%,肠道占10%[15]。内源乳酸在细胞间依赖溶质载体家族16(solute carrier family 16,Slc16)基因编码的单羧酸转运体(monocarboxylate transporters,MCTs)实现双向转运[16]。在MCTs家族中,MCT1~4依赖H+运输单羧酸盐以运载乳酸、丙酮酸和酮体[17]。其中,MCT1为基础稳态型,分布于多数组织,负责维持基础乳酸平衡;MCT2在肝脏、肾脏、脑和精子尾部中表达明显,且对底物亲和力远高于MCT1[18-19];MCT3分布于视网膜色素上皮和脉络丛上皮的基底膜[20],而MCT1位于视网膜色素上皮细胞顶端[21];MCT4在白色骨骼肌纤维、星形胶质细胞、白细胞、软骨细胞及胎盘中表达强烈,提示其可能在依赖高水平糖酵解来满足能量需求的组织中发挥重要作用[22-24]。这些转运蛋白依赖于质子和单羧酸的浓度梯度来决定乳酸的转运方向,例如,在炎症条件下,细胞外乳酸浓度高,MCTs利用膜两侧的乳酸浓度梯度,把乳酸顺梯度运回胞内,供线粒体氧化或转化为丙酮酸继续供能[25];而在肿瘤条件下,缺氧区肿瘤细胞几乎完全依赖糖酵解,乳酸产量激增,富氧区肿瘤细胞则通过MCT1大量摄取乳酸[26]。内源乳酸运转速率受组织代谢状态调控,在缺氧条件下,乳酸生成速率超过线粒体氧化能力,导致乳酸通过MCT4外流显著增加[25]。除MCTs介导转运外,内源乳酸的转运平衡还依赖特异性受体感知与信号通路调控。一方面,G蛋白偶联受体81(G-protein-coupled receptor 81,GPR81)作为目前已知的唯一内源乳酸受体,广泛分布于机体各组织器官[27],其可感知内源乳酸,以自分泌信号方式调控骨骼肌的乳酸代谢[28];另一方面,多种细胞信号通路也参与内源乳酸代谢调节。低氧诱导因子1(hypoxia inducible factor-1,HIF-1)包含HIF-1α亚基和HIF-1β亚基,通常在缺氧条件下被激活,HIF-1α通过调节糖酵解相关蛋白[如葡萄糖转运蛋白1(glucose transporter 1,GLUT1)、己糖激酶1(hexokinase 1,HK1)、丙酮酸激酶M1(pyruvate kinase M1,PKM1)、丙酮酸激酶M2(pyruvate kinase M2,PKM2)、乳酸脱氢酶A亚基(lactate dehydrogenase A subunit,LDHA)和丙酮酸脱氢酶激酶(pyruvate dehydrogenase kinase,PDK)家族]的表达,增加乳酸生成量,进而与MCT4的转运功能协同,维持缺氧组织的乳酸稳态[29]。

2.3 内源乳酸的分解与再利用

内源乳酸的分解主要由线粒体氧化途径完成。内源乳酸在胞质内经LDH氧化为丙酮酸,随后由丙酮酸脱氢酶(pyruvate dehydrogenase,PDH)转化为乙酰辅酶A(coenzyme A,CoA)并进入三羧酸(tricarboxylic acid,TCA)循环,经氧化磷酸化生成二氧化碳(CO2)、水(H2O)以及三磷酸腺苷(adenosine triphosphate,ATP)。内源乳酸的再利用则依赖糖异生途径。在肝脏、骨骼肌和肾脏等部位,丙酮酸由磷酸烯醇式丙酮酸羧激酶(phosphoenolpyruvate carboxykinase,PEPCK)、果糖-1,6-二磷酸激酶(fructose-1,6-bisphosphatase,FBPase)等催化,经乳酸循环(lactate cycle)重新合成葡萄糖,每2分子乳酸生成1分子葡萄糖需消耗6分子ATP[30]。PDH活性受E1α亚基的磷酸化修饰及线粒体NAD+/NADH比值双重调控,当线粒体NAD+/NADH比值升高时,E1α亚基发生去磷酸化,进而介导PDH活化[31-32],丙酮酸大量转化为乙酰CoA并进入TCA循环;线粒体NAD+/NADH比值下降时,PDH活性受抑,丙酮酸更多流向乳酸生成途径,生成的乳酸主要经血液循环转运至肝脏,通过糖异生途径合成葡萄糖[33]。乳酸过度累积(>5 mmol/L)可能诱发酸中毒,进而导致高乳酸血症及多器官功能障碍[34]。因此,内源乳酸在组织中的快速代谢与清除对维持机体稳态至关重要。

3 外源乳酸

3.1 外源乳酸的来源

外源乳酸非机体自身产生,其来源主要包括:饲粮中直接添加的乳酸制剂、临床静脉输入的乳酸以及肠道微生物发酵饲粮中纤维生成的乳酸。乳酸是最常用的有机酸化剂之一,广泛应用于畜牧生产中,在抑制有害菌繁殖、提高畜禽生长性能等方面有明显优势[35-38]。外源添加2%液体乳酸还可缓解葡聚糖硫酸钠(dextran sulfate sodium,DSS)诱导的仔猪肠道损伤[39]。在急性肠炎、失血性或感染性休克状态下,乳酸钠林格液(sodium lactate Ringer’s injection,LRS)是临床常用药物,可迅速扩充血容量并纠正代谢性酸中毒[40]。肠道中的乳杆菌和双歧杆菌通过发酵膳食纤维和未被消化吸收的碳水化合物以产生乳酸(D-乳酸为主)[41]。肠道微生物代谢产生的短链脂肪酸也可间接影响乳酸生成,丙酸可通过糖异生转化为葡萄糖,间接影响乳酸生成[42-43]。

3.2 外源乳酸的吸收与转运

直接摄入的外源乳酸需先经消化道吸收进入循环系统,再通过转运体介导进入靶细胞,其吸收效率与转运特性共同决定体内乳酸的利用效率。肠道是外源乳酸的主要吸收部位,吸收效率与肠道pH密切相关。酸性环境可显著促进外源乳酸吸收,绵羊空肠-回肠灌流试验显示,将含6.25~12.5 mmol/L外源乳酸的测试液pH由6.3降至4.3,其肠道吸收速率提升约6倍[44],这可能与酸性条件下乳酸分子更易通过肠道上皮细胞的被动扩散或载体介导转运有关。此外,肠道菌群代谢产生的乳酸,可直接在肠道局部被吸收或经门静脉进入肝脏代谢[41]。
外源乳酸依赖MCTs导入细胞,转运速率与MCTs亚型表达丰度、细胞类型及器官清除能力直接相关,且不同组织依赖的MCTs亚型存在显著差异。在小胶质细胞中,25 mmol/L乳酸钠处理24 h可显著上调MCT4编码基因Slc16a3的表达,而特异性敲除Slc16a3基因后乳酸摄取能力显著降低[45]。而肠道上皮细胞的主要乳酸转运体为MCT1,Wang等[46]利用肠道特异性敲除MCT1编码基因Slc16a1的小鼠模型证实,Slc16a1基因缺失会显著降低肠道间质液中的乳酸浓度。肝脏代谢功能也会影响外源乳酸的转运利用,在内毒素休克绵羊模型中,尽管总肝血流量维持正常甚至升高,但静脉推注1 mmol/kg BW 外源乳酸后,其肝脏清除率仍下降90%,门静脉与肝静脉乳酸浓度近乎相等[47],提示肝脏对外源乳酸的代谢障碍会导致清除效率下降。

3.3 外源乳酸的代谢

外源乳酸中的L-乳酸进入TCA循环主要依赖定位于线粒体外膜附近的乳酸脱氢酶B亚基(lactate dehydrogenase B subunit,LDHB)[48],其对乳酸的亲和力远高于丙酮酸,与外源乳酸的MCTs输入通道耦联。外源乳酸代谢速率可能受其进入细胞的效率和细胞内代谢通路饱和度的影响。当LDHB被敲除时,心脏、肝脏等高氧化能力组织的乳酸氧化受阻,细胞被迫转向糖酵解供能,导致乳酸堆积[49]。外源乳酸的代谢途径存在组织差异化。以心肌细胞为例,心肌线粒体丰度在肌膜下表面最大,当外源乳酸进入心肌细胞时,极易被转运到线粒体并进入TCA循环[50],研究显示,MCT1介导的外源乳酸是单核细胞内产生乙酰CoA的重要来源[51]。然而,当以25~50 mmol/L乳酸持续处理24~48 h可能会导致单核细胞内NAD+水平降低,其机制是大量乳酸进入细胞后,需通过LDH催化为丙酮酸,该过程会消耗NAD+,引起氧化还原失衡,导致甘油醛-3-磷酸脱氢酶(glyceraldehyde-3-phosphate dehydrogenase,GAPDH)活性降低,进而抑制糖酵解,细胞内代谢通路过载最终影响其代谢速率[16]。在哺乳动物中,D-乳酸来源于α-酮醛甲基乙二醛(methylglyoxal,MGO)生成过程中碳水化合物和脂质分解[52]以及肠道微生物发酵[41]。正常情况下,肠道内产生的D-乳酸会被其他细菌转化为乙酸盐和短链脂肪酸,不会造成机体酸碱失衡。然而,在肠屏障功能障碍(如短肠综合征)时,肠道微生物产生的D-乳酸可能会增加,诱发D-乳酸酸中毒[53]。与L-乳酸可被LDHB高效氧化不同,D-乳酸主要通过D-LDH代谢,该酶的催化活性仅为L-LDH的5%~10%[7],且需要D-乳酸/H+共转运体和D-乳酸/丙酮酸反向转运体,故具有代谢速率慢、易蓄积的特点[54]。
综上可知,乳酸是联系能量、信号与免疫调控的枢纽分子,内源乳酸和外源乳酸在吸收起点、代谢速率和途径、代谢机制等方面存在显著差异。内源乳酸由骨骼肌、脑、红细胞等依赖氧含量经LDH生成,经MCTs进行细胞间乳酸穿梭,并在肝脏、肾脏、心肌处通过TCA循环或糖异生途径被迅速清除,维持氧化还原稳态;外源乳酸则经外部摄入及肠道菌群进入宿主,其吸收速率受MCTs表达量和肠腔pH等因素调控,是产生乙酰CoA的重要来源。

4 不同来源乳酸在能量代谢与免疫调节中的差异

4.1 乳酸与能量代谢

乳酸在哺乳动物线粒体中显著富集,其作为能量底物和线粒体信号分子,通过激活线粒体电子传递链(electron transport chain,ETC)以增强ATP合成,该作用独立于LDH代谢途径[55-56]。乳酸在能量代谢中扮演重要角色,而内源乳酸和外源乳酸参与能量代谢的差异主要体现在供能优先级、对糖酵解的反馈调控和组织特异性作用等方面。
内源乳酸主要通过乳酸穿梭机制以维系能量稳态。在大脑内,星形胶质细胞-神经元乳酸穿梭(astrocyte-to-neuron lactate shuttle,ANLS)机制刺激神经末梢释放谷氨酸,之后通过氨基酸转运蛋白被星形胶质细胞吸收,转化为谷氨酰胺或谷胱甘肽,此过程刺激星形胶质细胞线粒体酸化以启动糖酵解,储存的糖原降解为丙酮酸,转化为乙酰CoA直接用于星形胶质细胞TCA循环,或通过LDH转化为L-乳酸[57-58],其在不同组织和细胞间穿梭以调节能量代谢,例如,内源乳酸在糖酵解活跃的骨骼肌细胞中产生后,可经MCTs转运到心肌或大脑,并在这些组织中被氧化生成ATP[59]。
当葡萄糖供应不足时,补充外源乳酸可成为额外燃料以供给能量[60]。乳酸钠通过羧酸转运蛋白Slc5a12进入细胞后,可提供酸化环境,并下调HK1的表达,进而抑制糖酵解[61],从而实现对葡萄糖的补充。外源乳酸还可替代葡萄糖作为能量底物维持大鼠海马切片中突触功能,直接支持神经元活动[62]。此外,在运动后摄入0.3%液体外源乳酸可以显著降低运动后恢复期的呼吸交换率(respiratory exchange ratio,RER),同时增加脂肪氧化水平,这表明外源乳酸有助于运动后的能量供应和快速恢复[63]。补充外源乳酸可改变细胞代谢模式,细胞可能会优先利用外源乳酸作为能量来源。Cai等[51]在比较葡萄糖和乳酸影响乙酰CoA生成的研究中发现,乳酸盐可诱导β-葡聚糖调节乙酰CoA的生成,从而促进TCA循环。值得注意的是,外源乳酸具有作为肠道糖异生前体物的潜力,在大鼠门静脉持续输注外源乳酸[6.8 μmol/(kg·min)]可显著诱导肠道糖异生,贡献量约为全身内源性葡萄糖的5%~7%[64],其机制与激活胰高血糖素-环磷酸腺苷(cyclic adenosine monophosphate,cAMP)轴相关——外源乳酸通过该轴上调糖异生限速酶葡萄糖-6-磷酸酶(glucose-6-phosphatase,G6Pase)和PEPCK的表达[65-66]。然而,过量的乳酸会导致代谢紊乱,低氧时,较高的乳酸浓度可诱导丙酮酸激酶乳酸化,进一步通过正反馈促进糖酵解,从而加剧能量代谢失衡[67]。
以上研究表明,内源乳酸经细胞糖酵解产生后,通过乳酸穿梭机制在组织内循环转运;外源乳酸可作为“额外燃料”,替代葡萄糖供能,尤其在大脑和肌肉等组织中发挥重要作用;心肌和神经元优先切换外源模式,骨骼肌仍以内源乳酸为主。

4.2 乳酸与免疫调节

免疫细胞在免疫应答激活时显著增强糖酵解,葡萄糖大量消耗,以满足其能量需求和支持其免疫功能,但在免疫应激期间补充葡萄糖可能加剧免疫紊乱。在巨噬细胞中,糖酵解的增强促进了M1型巨噬细胞的激活和免疫效应的发挥[68]。而在免疫应激下,G6Pase和PEPCK的表达受限,抑制了糖异生过程[69]。研究发现,免疫应激患者细胞因子白细胞介素-6(interleukin-6,IL-6)和肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)水平与疾病严重程度之间呈正相关[70]。然而,训练过的单核细胞更倾向于将乳酸而非葡萄糖作为TCA循环的底物,内源乳酸或外源乳酸通过促进TCA循环和组蛋白乳酸化来支持训练免疫[51]。这提示乳酸对免疫调节具有重要意义。
内源乳酸对免疫调节的影响主要包括调节巨噬细胞极化和细胞因子水平。内源乳酸积累可激活低氧诱导因子(hypoxia inducible factors,HIFs),上调M2型关键基因精氨酸酶1的表达[71],进而诱导M1型巨噬细胞向M2型转化[72],促进炎症消退。内源乳酸还可抑制树突状细胞成熟并减少脂多糖(lipopolysaccharide,LPS)诱导的细胞因子产生[73]。组蛋白去乙酰化酶(histone deacetylase,HDAC)抑制剂通过促进非组蛋白乙酰化以发挥抗炎作用,而内源乳酸即可作为HDAC抑制剂以改善炎症[74]。此外,内源乳酸还可通过GPR81抑制NLRP3炎症小体(NLRP3 inflammasome),减少白细胞介素-1β(interleukin-1β,IL-1β)介导的促炎反应[75]。GPR81还可诱导抗炎因子白细胞介素-10(interleukin-10,IL-10)的产生以维系肠道健康[76]。在某些条件下,内源乳酸也可促进炎症反应。缺氧时,内源乳酸通过激活快速加速纤维肉瘤(rapidly accelerated fibrosarcoma,RAF)-细胞外信号调节激酶(extracellular signal-regulated kinase,ERK)信号通路促进炎症反应和血管生成[77]。在类风湿关节炎中,内源乳酸通过诱导CD4+T细胞在炎症部位的积累,促进促炎亚群1型辅助性T细胞(T helper type 1 cells,Th1)、17型辅助性T细胞(T helper type 17 cells,Th17)的产生[78-79]。
外源乳酸影响免疫调节主要是通过促进TCA循环以及组蛋白乳酸化影响免疫细胞功能。乳酸盐可诱导β-葡聚糖调节的乙酰CoA生成[51]。组蛋白乳酸化是乳酸摄入后信号传导的关键[80],L-乳酸通过乳酰基转移酶p300转移乳酰基,并转化为酰基辅酶,D-乳酸通过S-D-乳酰谷胱甘肽将乳酰基转移[81-82]。外源乳酸在M1巨噬细胞中通过组蛋白H3的乳酸化和表观遗传机制的代谢重编程来诱导产生M2表型,以释放更多的抗炎因子[80,83]。外源乳酸对免疫细胞功能的影响因细胞类型和代谢状态而异,其对不同T细胞亚群的影响也有所不同。在激活的高糖酵解CD8+T细胞中,外源乳酸不会改变组蛋白乳酸化,但在低糖酵解条件下,外源乳酸能显著增加组蛋白H3赖氨酸18乳酸化(histone H3 lysine 18 lactylation,H3K18la)和组蛋白H3赖氨酸9乳酸化(histone H3 lysine 9 lactylation,H3K9la)的水平[84]。正常情况下,外源乳酸可经GPR81激活Wnt/β-连环蛋白(β-catenin)信号通路以增强线粒体呼吸,进而促进肠上皮细胞的增殖和更新[85]。在免疫应激时,外源乳酸降低肠上皮细胞的Toll样受体(Toll-like receptor,TLR)表达和IL-1β依赖性核因子-κB(nuclear factor-kappa B,NF-κB)活化[86],通过抗炎和修复以维持肠黏膜形态。饲粮中添加2%乳酸可缓解DSS诱导的仔猪肠道炎症,缓解肠道形态损伤,促进肠道细胞增殖[39]。当CD4+T细胞中的乳酸转运蛋白Slc5a12和CD8+T细胞中的乳酸转运蛋白Slc16al受到抑制时,T细胞移动受阻,炎性因子增加,T细胞分化为Th17亚群,慢性炎症延长[87]。外源乳酸(特别是D-乳酸)能够显著增强巨噬细胞的炎症反应。D-乳酸可以增加一氧化氮(nitric oxide,NO)的产生和IL-6的分泌,从而促进炎症反应[88]。在炎症性肠病中,肠道微生物群落失调导致外源乳酸积累,导致有害菌大量繁殖,肠黏膜通透性增加,肠道屏障受损,进一步加剧肠道炎症反应[89]。此外,乳酸盐是肿瘤微环境(tumor microenvironment,TME)的主成分,外源乳酸促进成纤维细胞产生透明质酸,诱导肿瘤细胞表面CD44表达,减少细胞间黏附以促进细胞迁移和侵袭,且可通过MCTs在胞内转运,刺激NF-κB,上调促炎因子的表达[90]。
综上所述,不同来源乳酸对免疫调节作用的差异来源于代谢途径、对免疫细胞状态的影响及细胞因子的调节。内源乳酸直接参与胞内进程,在免疫细胞功能调节中发挥更直接的作用;外源乳酸则通过细胞膜上的MCTs进入细胞,通过组蛋白修饰,重编程细胞代谢模式,间接影响免疫细胞的功能;内源乳酸对细胞因子产生的调节作用更依赖于细胞内的代谢状态,而外源乳酸的影响则更依赖于细胞外的微环境。

5 小结

不同来源乳酸在代谢途径、能量调控和免疫调节等方面存在显著差异。内源乳酸主要由糖酵解产生,由MCTs介导,通过乳酸穿梭机制实现细胞间能量调控,并通过调节巨噬细胞极化和细胞因子水平,在免疫调节中发挥重要作用;外源乳酸则依赖于MCTs进入细胞,优先作为TCA循环底物以供能,并作为组蛋白修饰信号分子,重编程免疫细胞功能。为清晰呈现二者核心差异,结合全文研究结论系统总结见表1。
表1 不同来源乳酸的核心特征对比

Table 1 Comparison of core characteristics between different sources of lactate

核心特征
Core characteristics		 内源乳酸
Endogenous lactate		 外源乳酸
Exogenous lactate
主要来源
Main source		 机体自身糖酵解产物(L-乳酸为主),
主要源于骨骼肌、红细胞、神经元及
免疫细胞等[3,9]		 饲粮添加、静脉输入及肠道菌群发酵
膳食纤维产物(含D-乳酸)[39-43]
转运机制
Transport mechanism		 依赖单羧酸转运体(MCTs)家族介导,实现
细胞/组织间乳酸穿梭[16,25,27]		 肠道吸收依赖pH调控、MCT1介导[46];
入血后以MCT1/MCT4为载体[47]
代谢途径
Metabolic pathway		 优先经Cori循环在肝脏异生为葡萄糖;或在
心肌等组织经乳酸脱氢酶B亚基(LDHB)氧化为
丙酮酸进入三羧酸(TCA)循环[30,33-34]		 L-乳酸经LDHB催化入TCA循环彻底
供能;D-乳酸经D-乳酸脱氢酶
(D-LDH)缓慢代谢,易蓄积[7,53]
能量作用
Energy effect		 维系糖酵解活跃组织与氧化代谢组织间能量分配,
如星形胶质细胞至神经元的乳酸转运[57-58]		 补充能量缺口,可替代葡萄糖支持
神经元活动,诱导糖异生[62,64]
免疫调控
Immune regulation		 调控巨噬细胞极化;抑制NLRP3炎症小体;
作为组蛋白去乙酰化酶(HDAC)抑制剂
改善炎症[74-75]		 通过组蛋白乳酸化重编程免疫细胞功能;
G蛋白偶联受体81(GPR81)通路修复
肠道屏障[80-83,85]
虽然现阶段在乳酸调控肠道健康领域已取得部分进展,但仍存在以下关键科学空白亟待填补:1)断奶仔猪肠道发育未成熟,普遍能量供应不足,且易受应激导致肠道糖异生能力紊乱。外源乳酸能否作为肠道糖异生的关键碳源,通过调控限速酶(PEPCK、G6Pase)表达弥补能量缺口,并缓解应激性炎症,其机制尚不明确;2)当前无抗养殖中,乳酸型添加剂常因“剂量不精准”导致效果波动,L-乳酸与D-乳酸对猪与禽肠道干细胞增殖、屏障功能的剂量-时间效应曲线尚缺系统数据,精准用量缺乏科学依据;3)在猪与禽生产中,饲粮中乳酸添加量与肠道、肌肉等组织的MCT1~4表达量缺乏关联模型,核心原因是MCT1~4启动子区乳酸应答元件尚未定位,导致无法通过调控MCTs表达以提升乳酸转运效率。未来应结合同位素示踪、单细胞代谢组学和基因敲除模型,系统解析不同来源乳酸的代谢和功能,为精准乳酸营养干预提供理论依据。

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