2. 中国农业科学院农业质量标准与检测技术研究所, 农业农村部农产品质量安全重点实验室, 北京 100081
2. Key Laboratory of Agri-Food Safety and Quality, Ministry of Agriculture, Institute of Quality Standards and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing 100081, China
糖脂代谢紊乱是肥胖、2型糖尿病、非酒精型脂肪肝等代谢类疾病的重要诱因及主要临床表现[1-3]。而在畜禽养殖中，糖脂代谢紊乱则会造成饲料转化率降低，畜禽产品质量下降、免疫功能受损及诱发相关疾病等问题。胆汁酸(bile acids, BAs)是由胆固醇在肝脏中通过分解代谢产生的一类化合物[4]。过往的观点认为，胆汁酸的主要功能是促进肠道中脂质乳化及吸收[5]。而自从20世纪末，胆汁酸的一系列自然配体，如法尼醇X受体(farnesoid X receptor，FXR)、孕烷X受体(pregnane X receptor，PXR)、类固醇与外源性受体(steroid and xenobiotic receptor，SXR)、本构雄激素受体(constitutive androstane receptor，CAR)和维生素D受体(vitamin D receptor，VDR)、武田G蛋白偶联受体5(Takeda G protein-coupled receptor 5，TGR5)被发现以来，胆汁酸作为信号分子参与调控宿主糖脂代谢的作用日益受到研究者重视[6-9]。胆汁酸分为初级胆汁酸(primary bile acids, PBA)(主要在肝脏合成)和次级胆汁酸(secondary bile acids, SBA)(由肠道微生物分解初级胆汁酸形成)[10]，而在不同病理生理状态下，胆汁酸谱也会发生相应变化，这些变化会影响胆汁酸的功能[11-15]。本文就胆汁酸生理、受体介导和非受体介导的糖脂代谢调控机制、与糖脂代谢相关激素的关系以及与肠道微生物的互作进行简要综述，并在文尾对未来的研究方向提出建议，以期为基于胆汁酸的动物健康营养代谢调控提供思考和理论依据。
1 胆汁酸生理胆汁酸是一组由胆固醇生成的水溶性两亲分子，其合成过程主要发生在肝细胞中，非常复杂并受到多种酶调节[4]。由于胆汁酸具有两亲特性，由胆固醇合成的初级胆汁酸会与牛磺酸或甘氨酸结合，生成牛磺结合型胆汁酸(taurine binding bile acid，TBA)或甘氨结合型胆汁酸(glycine binding bile acid，GBA)，这种修饰将它们由弱酸转化为不可渗透细胞膜的强酸，可以在胆汁或肠道中积聚，也可以阻止非结合型胆汁酸以被动扩散的方式返回肝脏。肝脏中初级胆汁酸一旦合成即与甘氨酸或牛磺酸结合，排泄入贮存于胆襄中的胆汁，需要时输送到十二指肠。初级胆汁酸在人类中主要与甘氨酸结合，在啮齿类动物中主要与牛磺酸结合[16-18]。本课题组前期研究发现，猪体内初级胆汁酸主要与甘氨酸结合[19]。初级胆汁酸在肝细胞合成后，通过三磷酸腺苷(adenosine triphosphate，ATP)依赖的胆汁酸盐输出蛋白(bile salt export pump，BSEP)分泌入肝胆管[17]。随后，胆汁酸与胆固醇、卵磷脂、钾、钠和钙等形成微胶粒，储存在胆囊中，进食刺激胆囊收缩排出胆汁进入十二指肠。在回肠末端，约有95%的胆汁酸会通过胆汁酸转运蛋白(apical sodium dependent bile acid transporter，ASBT)吸收进入肠道上皮细胞，并通过异二聚体有机溶质转运体α和β(organic solute transporters alpha and beta，OSTα/β)在基底外侧膜上分泌出来，再通过肝门静脉重吸收回肝脏，这一过程就是胆汁酸的肝肠循环。剩余的5%未进入肝肠循环的胆汁酸，一部分经过肠道菌群的分解代谢生成次级胆汁酸，被动的由后肠重新吸收；另一部分则是经粪便排出体外[4, 20]。次级胆汁酸的疏水性、临界胶束浓度、膜渗透性、与受体或转运载体结合能力复杂多样。通过自建的方法，本课题组初步鉴定出猪体内存在16种胆汁酸，猪的初级胆汁酸主要包括胆酸(cholic acid, CA)、鹅脱氧胆酸(chenodeoxycholic acid，CDCA)、甘氨胆酸(glycocholic acid，GCA)、甘氨鹅脱氧胆酸(glycochenodeoxycholic acid，GCDCA)、牛磺胆酸(taurocholic acid，TCA)和牛磺鹅脱氧胆酸(taurine chenodeoxycholic acid，TCDCA)，而次级胆汁酸主要包括石胆酸(lithocholic acid，LCA)、猪胆酸(hyocholic acid，HCA)、熊脱氧胆酸(ursodeoxycholic acid，UDCA)、猪脱氧胆酸(hyodeoxycholic acid，HDCA)和脱氧胆酸(deoxycholic acid，DCA)[21]。
1.1 非受体介导作用胆汁酸的主要生理作用就是促进脂质的乳化吸收。胆汁酸可以与极性磷脂相结合，将食糜脂质更好地融合于肠腔内胶束溶液中。该过程增加肠腔内脂质与水解酶接触的表面积，促进脂肪水解消化吸收[22]。胆汁酸的这一生理特性对于脂质吸收与全身系统能量平衡至关重要。不同种类胆汁酸促进脂质消化的能力有所差异[23-24]。胆汁酸促进脂质吸收的能力主要受到其胶束形成能力(micelle-forming properties)[25]和通过肠上皮细胞不动水层(unstirred water layer)能力的影响[26]。有研究还表明肠上皮细胞内胆固醇的酯化作用也受到胆汁酸调节，但其潜在机制仍未可知[27]。
近年来的研究发现，胆汁酸可与一些特定蛋白质结合并调节其活性。举例来说，N-酰基磷脂酰乙醇胺磷脂酶D(N-acylphosphatidylethanolamine-phospholipases D，NAPE-PLD)，它是一种在脑和肠中发现的酶，可将膜脂转化为专门的生物活性脂[28]。花生四烯酰乙醇酰胺(anandamide)和油酰乙醇酰胺(oleoylethanolamide)是NAPE-PLD的主要代谢产物，两者都参与调控采食量并且油酰乙醇酰胺可以促进胰高血糖素样肽-1(glucan-like peptide-1，GLP-1)的分泌，而通过对NAPE-PLD晶体结构的解析，研究人员发现DCA可以结合该酶并促进其活性[29-31]。
1.2 受体介导作用胆汁酸可以激活多种核受体与膜受体。核受体主要包括FXR、PXR、SXR、CAR和VDR，而膜受体主要包括TGR5、鞘氨醇-1-磷酸受体2(sphingosine-1-phosphate receptor 2，S1PR2)[4]。FXR和PXR在肝脏和肠道中大量表达，而VDR在胰腺、皮肤、肠道和肝脏等大多数组织中广泛分布。FXR是胆汁酸发挥生理作用的主要传感器。胆汁酸的结构，特别是碳链中羟基的位置，决定了它们结合和激活FXR的能力。通常，胆汁酸越疏水，它对FXR的亲和力就越高，初级胆汁酸对FXR的激活作用最强，将胆汁酸按激活强度排序，依次为CDCA>TCA>DCA=牛磺石胆酸(taurine lithocholic acid，TLCA)；而牛磺-α-鼠胆酸(tauro-α-muricholic acid，T-α-MCA)、牛磺-β-鼠胆酸(tauro-β-muricholic acid，T-β-MCA)和UDCA对FXR则具有明显的拮抗作用[32-33]。而次级胆汁酸比初级胆汁酸具有更高的TGR5结合能力，胆汁酸对TGR5的结合能力排序为LCA>DCA>CDCA>CA[34-35]。
1.2.1 核受体介导作用作为第1个被发现的胆汁酸天然内源性配体，FXR在不同物种中基因进化的保守性和相似性很高，其在体内糖脂代谢稳态中的作用已被多项研究所验证[36-37]。FXR激活会降低肝脏脂蛋白的合成、血浆甘油三酯和胆固醇的含量，这是因为FXR激活会诱导脂蛋白代谢或清除基因的表达，同时会抑制甘油三酯合成基因的表达[38]。胆汁酸通过激活肝脏FXR，诱导靶基因小异二聚体配体(small heterodimer partner，SHP)表达，SHP抑制转录因子固醇调节因子结合蛋白-1c(sterol regulatory element-binding protein-1c，SREBP-1c)及其下游肝脏脂质合成基因表达，减少肝脏脂质合成[39]。除此之外，SHP的表达还可以通过抑制磷酸烯醇式丙酮酸羧激酶和果糖二磷酸酶-1等减少肝脏的糖异生[40]。与野生型小鼠相比，FXR敲除小鼠的空腹葡萄糖耐量显著受损，而注射FXR激动剂GW4064可显著改善ob/ob和db/db小鼠腹腔葡萄糖和胰岛素耐量测试中的血糖漂移[41-42]。FXR激动剂Fexaramine可显著改善血糖水平，并减少饮食诱导的体重增加[12, 43]。FXR激活可以促进脂蛋白的清除，导致载脂蛋白C(apolipoprotein C，APOC)和血管生成素样蛋白3(angiopoietin-like protein 3，ANGPTL3)表达量的降低，这2个蛋白都会抑制脂蛋白脂酶的活性。此外，FXR的激活还会诱导过氧化物酶体增殖物激活受体α(peroxisome proliferator-activated receptor α，PPARα)的表达，从而促进脂肪酸β氧化[44]。FXR经胆汁酸激活后，诱导产生的成纤维细胞生长因子15(fibroblast growth factor 15，FGF15)改变初级胆汁酸与次级胆汁酸的比例，增强胆汁的亲水性，进而通过ATP结合盒转运蛋白G5(ATP binding cassette transport G5，ABCG5)和ATP结合盒转运蛋白G8(ATP binding cassette transport G8，ABCG8)使胆固醇排入肠腔，可以使经肠腔排出方式排出的胆固醇达到吸收胆固醇的60%以上[45]。除此之外，FXR的激活还可以通过调控肝脏脂肪代谢保护骨骼肌免于出现脂毒性的症状[46]，通过调控肠道微生物的组成促进GLP-1和胰岛素的分泌[43]。
有意思的是，一些研究发现FXR的抑制也会对机体糖脂代谢产生显著影响。全身FXR敲除的小鼠和肠道缺乏FXR的小鼠口服葡萄糖耐量显著改善，体重降低[47-49]。高脂饮食条件下，与对照组相比，GW 4064组小鼠体重增加显著，空腹血糖和胰岛素含量增加，并且葡萄糖和胰岛素耐受性受损[50]。FXR抑制改善糖脂代谢的机制主要包括：1)通过肠道FXR介导的血清神经酰胺生成影响肝脏丙酮酸羧化酶活性及肝脏糖异生[48]；2)FXR依赖性抑制的GLP-1前体物质生成增加，从而促进葡萄糖刺激的GLP-1生成[49]；3)增加肠上皮细胞葡萄糖磷酸化水平，延迟肠道葡萄糖吸收[51]；4)FXR依赖性抑制的肝脏糖酵解基因表达量增加[52]。综上所述，FXR介导的糖脂代谢调控机制值得进一步深入研究。
除FXR之外，VDR也可以被LCA等激活，通过影响胰岛[53]、巨噬细胞[54]或内皮细胞[55]参与糖脂代谢的调控。但是由于这些胆汁酸很难吸收进入到细胞，并且相较于活化类型的维生素D，这些胆汁酸结合核受体VDR的能力较弱，体内需要较高水平的LCA才可以激活VDR且多发生在维生素D缺乏的情况下[56]。目前对于胆汁酸-VDR信号对宿主糖脂代谢稳态的有关研究仍较少，需进一步深入研究。
1.2.2 膜受体介导作用TGR5是研究最为深入的膜结合G蛋白偶联受体，其在体内多个组织中均有表达，胆汁酸是目前已知的TGR5的唯一内源性配体[57]。目前报道最为广泛的机制是胆汁酸激活TGR5，启动环磷酸腺苷(cyclic adenosine monophosphate，cAMP)及其下游相关信号通路[脱碘酶2(type 2 iodothyronine deiodinase，DIO2)或Ca2+-钙调磷酸酶-活化T细胞核因子3(nuclear factor of activated T-cells 3)-前蛋白转化酶1/3(proprotein convertases 1/3)[58-59]或哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin，mTOR)信号通路[60]，刺激肠道L细胞分泌GLP-1，同时胰岛素分泌量增加[61-63]；减少CCAAT增强子结合蛋白β(CCAAT enhancer binding protein β, CLEBPβ)介导的巨噬细胞在白色脂肪组织的炎症性浸润[64]以及增加能量消耗[65]。胆汁酸通过FXR和TGR5受体介导调节宿主代谢的机制见图 1。
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RXR：维甲酸受体retinoic acid X receptor；LRH-1：肝脏受体类似物1 liver receptor homologue 1；cAMP：环磷酸腺苷cyclic adenosine monophosphate；FXR:法尼醇X受体farnesoid X receptor；TGR5：武田G蛋白偶联受体5 Takeda G protein-coupled receptor 5；ASBT：胆汁酸转运蛋白apical sodium dependent bile acid transporter；GLP-1：胰高血糖素样肽-1 glucan-like peptide-1；FGF15/19：成纤维细胞生长因子15/19 fibroblast growth factor 15/19；LCA：石胆酸lithocholic acid；DCA：脱氧胆酸deoxycholic acid；ωMCA：ω-鼠胆酸ω-mice cholic acid；HCA：猪胆酸hyocholic acid；UDCA：熊脱氧胆酸ursodeoxycholic acid；TCDCA：牛磺鹅脱氧胆酸taurine chenodeoxycholic acid；GCDCA：甘氨鹅脱氧胆酸glycine chenodeoxycholic acid；TCA：牛磺胆酸taurocholic acid；GCA：甘氨胆酸glycocholic acid；T-α/β-MCA：牛磺-α/β-鼠胆酸tauro-α/β-mice cholic acid；JNK/ERK：c-Jun氨基末端激酶/细胞外调节激酶c-Jun N-terminal kinase/extracellular regulated protein kinases；T3：三碘甲状腺原氨酸triiodothyronine；T4：四碘甲状腺原氨酸tetraiodothyronine；SHP：小异二聚体配体small heterodimer partner；DIO2：脱碘酶2 type 2 iodothyronine deiodinase；OSTα/β：有机溶质转运体α和β organic solute transporters alpha and beta。 图 1 胆汁酸-微生物轴通过FXR与TGR5影响宿主代谢的机制 Fig. 1 Bile acid-microbial axis affects host metabolism via FXR and TGR5[66] |
胰岛素是机体内唯一降低血糖的激素，也是唯一同时促进糖原、脂肪、蛋白质合成的激素，在体内糖脂代谢中起到至关重要的作用，胰岛素敏感性异常是导致体内糖脂代谢紊乱的重要原因之一。多项研究分析了胆汁酸浓度与胰岛素敏感性之间的关系，结果表明胰岛素抵抗与初级胆汁酸和12α羟基化型胆汁酸[主要由关键酶细胞色素P450 8b1(cytochrome P450 family 8 subfamily B member 1，Cyp8b1)催化生成]的浓度有关[13, 67-68]。存在胰岛素抵抗程度的肥胖和2型糖尿病患者中血浆12α羟基化胆汁酸浓度显著高于健康人群；在饮食诱导肥胖小鼠中，尽管产热和耗氧量没有发生变化，但敲除Cyp8b1基因可以减少体重，降低餐后胰岛素含量，改善葡萄糖耐量。Cyp8b1敲除小鼠粪便中脂质含量较高，说明在该基因敲除小鼠肠道中脂质吸收能力降低。除此之外，12α羟基化胆汁酸通过激活肠道FXR生成神经酰胺(ceramide)和FGF15，进而抑制肝脏PPARα-成纤维细胞生长因子21(fibroblast growth factor 21，FGF21)信号通路，从而导致胰岛素抗性[69-71]。Cyp8b1敲除小鼠回肠L细胞数量增加，因此回肠上皮中GLP-1和肽YY(peptide YY，PYY)含量提高，这可能是由于脂质吸收与脂质感受器激活受损[72]。脂质组学结果显示，Cyp8b1的敲除会增加粪便中脂质(如单酰基甘油)的排出，而单酰基甘油是脂质感受器G蛋白偶联受体119(G protein-coupled receptor 119，GPR119)的激活剂。GPR119多分布于肠内分泌细胞特别是L细胞表面，并介导脂质诱导的GLP-1分泌。Cyp8b1敲除小鼠回肠中GLP-1和PYY含量较高，胃排空速度减缓，采食量与体重下降，而这些症状可通过敲除GPR119得到缓解[72]。因此，12α羟基化胆汁酸的含量变化会影响脂质吸收、肠道激素分泌和脂质感受器的激活，从而影响胰岛素敏感性和糖脂代谢。牛磺熊脱氧胆酸(tauroursodeoxycholic acid，TUDCA)可以激活小鼠胰岛β细胞FXR，抑制ATP敏感性K+通道(ATP-sensitive potassium channel，KATP)的亚单位磺脲类受体1(sulphonylurea receptor 1，SUR1)的活性，减少外流的K+，促进细胞质Ca2+浓度增加，增加胰岛素分泌[73]。而胰腺α细胞中TGR5的激活可诱导胰高血糖素转化酶原-1的表达，催化胰高血糖素原生成GLP-1，接着迁移到β细胞，并与其膜上的GLP-1受体相结合，增强β细胞的分泌胰岛素功能[74]。
进食诱导产生的成纤维细胞生长因子19(fibroblast growth factor 19，FGF19)和空腹诱导产生的FGF21是具有不同生理功能的代谢调节激素，但两者在改善能量代谢和胰岛素敏感性以及通过直接作用中枢神经系统降低体重方面具有相似的作用[75]。FGF15(啮齿类动物)和FGF19(人类)在回肠上皮细胞中表达量较高，可由胆汁酸通过FXR或TGR5激活分泌，是一种控制肝脏中胆汁酸合成与宿主糖脂代谢稳态的重要内分泌激素[76]。肠道FXR激活后生成的FGF15可通过肝脏成纤维细胞生长因子受体4(fibroblast growth factor receptor 4，FGFR4)通路影响过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptor γ，PPARγ)通路，减少脂肪沉积与胆固醇、甘油三酯的合成，抑制肝脏脂质合成。FGF15和FGF19可通过调控糖异生转录因子cAMP反应元件结合蛋白6(cAMP responsive element binding protein 6, CREB6)的去磷酸化，减少肝脏的糖异生[77]；激活细胞外信号调节激酶(extracellular regulated protein kinase，ERK)-糖原合激酶(glycogen synthase kinase)GSK3a/p的磷酸化级联反应，促进肝糖原合成[78]；通过增加棕色脂肪组织中β-Klotho依赖性交感神经活动，从而增加代谢率，减少体重[79]。而在下丘脑神经元中，FGF15或FGF19会激活ERK信号通路，从而促进非胰岛素依赖性的葡萄糖含量降低[79-81]。血浆中FGF19的含量在2型糖尿病和肥胖患者中显著下降，而注射重组FGF19蛋白可以显著改善db/db和饮食诱导肥胖小鼠的代谢紊乱[82]。FGF21是一种在肝细胞中产生的营养敏感激素，也可以由胆汁酸诱导生成。FGF21可通过多种机制改善胰岛素敏感性。在肝脏中，FGF21抑制哺乳动物雷帕霉素靶蛋白复合物1(mammalian target of rapamycin complex 1，mTORC1)信号通路，激活肝脏胰岛素敏感性[69]；而在脂肪组织中，FGF21通过激活PPARγ促进脂肪酸氧化，进而改善胰岛素敏感性[83-84]。FGF21还可以刺激脂肪组织中脂联素分泌，从而降低ob/ob小鼠和饮食诱导肥胖小鼠的神经酰胺和血糖，并增强胰岛素敏感性[85]。
3 胆汁酸与肠道微生物肠道微生物在胆汁酸代谢过程中具有极其重要的调控作用，原因在于肠道微生物合成的酶可改变次级胆汁酸的组成模式，从而进一步影响各种次级胆汁酸介导的糖脂代谢调控过程[86]。胆汁酸与微生物相互作用，胆汁酸的组成差异可以解释37%的肠道微生物分布差异[19]。胆汁酸发挥生理作用离不开肠道微生物的介导，肠道微生物通过胆汁盐水解酶将结合型胆汁酸解偶联生成游离型胆汁酸，再经过脱氢或脱羟基作用将游离型胆汁酸生成次级胆汁酸，如将胆酸转化为脱氧胆酸，鹅脱氧胆酸转化为石胆酸。参与初级胆汁酸向次级胆汁酸转化的细菌主要为拟杆菌属(Bacteroides)、梭菌属(Clostridium)、优杆菌属(Eubacterium)、乳杆菌属(Lactobacillus)和埃希氏杆菌属(Escherichia)[4]。生物信息学分析结果显示，胆盐水解酶分布于117个属的591株肠道细菌中，其中27.52%菌株含不止1个胆盐水解酶基因，而胆盐水解酶基因的相对丰度与代谢类疾病，如糖尿病和动脉粥样硬化等，存在多效相关性[87]。消除肠道细菌的胆盐水解酶能力，会减少高脂饮食对小鼠带来的体重增加[87-88]。游离型胆汁酸和次级胆汁酸可通过被动吸收的方式由肠上皮细胞重新吸收。一旦经循坏系统回到肝脏，游离型胆汁酸和次级胆汁酸又会重新与甘氨酸或牛磺酸结合，生成结合型胆汁酸。肠道菌群紊乱会导致产胆汁盐水解酶菌群减少，导致胆汁酸代谢失调而无法维持体内葡萄糖平衡及正常的胆固醇分解和排泄，造成糖脂代谢疾病。通过质谱及组学技术，研究者发现除脱羟基化、脱水、异构化以及解偶联外，微生物组还存在第5种胆汁酸代谢机制，即由菌群合成的氨基酸结合型胆酸，其中氨基酸通过酰胺键连接至胆盐主链，这些新发现的结合型胆汁酸也可以激活FXR受体[89]。
改变肠道微生物的组成会改变肠道胆汁酸谱。连续使用7 d的万古霉素(只针对革兰氏阳性菌，如溶血性链球菌、肺炎球菌等)后，研究者发现参试者血浆和粪便中次级胆汁酸的含量显著降低，而这与抗生素显著改变肠道微生物的结构有关[90]。而不同的抗生素对血浆和粪便胆汁酸谱的改变也有区别，如使用阿莫西林时并未发现胆汁酸谱发生了显著的改变[91]。同样，胆汁酸反过来也会影响肠道微生物，如某些12α羟基化胆汁酸会促使艰难梭菌(Clostridioides difficile)孢子的萌发[92]。胆汁酸-肠道微生物轴的平衡失调会增加出现糖脂代谢紊乱进而发生肥胖的几率。在高脂饮食下不易发胖的小鼠与更易发胖的小鼠相比，肝脏中非12羟基化胆汁酸，包括UDCA、CDCA和LCA的含量显著提高，这一改变与肠道菌群中梭状芽胞杆菌(Clostridium scindens)丰度的改变有关[93]。小鼠饲喂梭状芽胞杆菌会显著提高其肝脏中非12羟基化胆汁酸的含量。高脂饮食下更容易出现肥胖症状的小鼠，可能是由于其胆汁酸组成的改变导致回肠中GLP-1含量以及棕色脂肪组织中PPARγ协同激活因子-1α(PPARγ coactivator 1α，PGC1α)-解耦联蛋白-1(uncoupling protein-1，UCP-1)信号通路的显著下调。此外，饲粮中添加UDCA也可以通过提高非12羟基化胆汁酸的含量，维持高脂饮食下小鼠的代谢稳态[93]。
上文中提到的肠道中FXR的激活或者抑制可以影响机体糖脂代谢，虽然这看似矛盾的结果的相关机制仍不明确，但近来的发现其可能与肠道微生物有关[12]。白色脂肪主要以甘油三酯的形式存储热量，而棕色脂肪具有生热功能，可促进能量的消耗，从而增加体热并降低体重。使用FXR激动剂Fexaramine处理小鼠，可刺激FGF15和FGF21的分泌，改善胰岛素耐受和糖耐量反应，并且促进白色脂肪组织褐变。而这一效应主要是通过LCA生成菌Acetatifactor和Bacteroides介导，抗生素处理则会减弱Fexaramine的代谢调控改善功能[12]。肠道微生物介导的胆汁酸组成改变会通过受体FXR影响宿主代谢。然而，对于FXR信号激活到底是促进还是预防胰岛素抵抗以及糖脂代谢紊乱，似乎存在相反的发现。之前有研究发现，肠道微生物引起的FXR拮抗会改善宿主代谢[43, 94]。肠道中减少的Lactobacillus会导致FXR拮抗剂T-β-MCA含量的增加，从而使高脂饮食条件下的小鼠避免出现代谢紊乱[88]。并且注射T-β-MCA也会改善代谢疾病小鼠的症状，而这一功能与厚壁菌门(Firmicutes)和拟杆菌门(Bacteroidetes)比例的降低有关[95]。FXR敲除小鼠即使饲喂高脂饲粮也未出现肥胖症状，并且移植FXR敲除小鼠的肠道菌群到无菌野生小鼠中，会减轻野生小鼠的肥胖症状并改善葡萄糖耐量[96]。在仓鼠中使用抗生素治疗会引起胆汁酸谱重塑，肠道FXR信号通路受到抑制，对改善葡萄糖耐受不良和肝脂肪变性有有益作用[97]。而2型糖尿病患者肠道中脆弱拟杆菌(Bacteroides fragilis)相对丰度较高，其分泌的胆盐水解酶降低肠道中FXR拮抗剂甘氨熊脱氧胆酸(GUDCA)和TUDCA这2种胆汁酸的含量。而二甲双胍的摄入通过抑制脆弱拟杆菌的丰度，降低低该菌的胆盐水解酶活性，使GUDCA含量升高，以不依赖于肠道腺苷酸活化蛋白激酶(AMP-activated protein kinase，AMPK)信号通路的方式，抑制肠道FXR信号，促使血液GLP-1含量上升，发挥改善代谢的作用[98]。
胆汁酸诱导的TGR5激活会导致细胞内cAMP累积，从而激活蛋白激酶A(protein kinase A，PKA)。PKA促使cAMP反应元件结合蛋白(cAMP responsive element binding protein, CREB)磷酸化，该蛋白可以诱导热调节组织棕色脂肪组织和白色脂肪组织DIO2基因的转录。DIO2基因转录翻译的产物是DIO2，该酶可以催化四碘甲状腺原氨酸(T4)转化为活化形式三碘甲状腺原氨酸(T3)，从而促进机体产热，维持机体的代谢稳态[99]。富含多酚的卡姆果提取物会引起小鼠肠道中Akkermansia muciniphila数量的增加和Lactobacillus数量的减少，进而引起血浆胆汁酸谱的改变，而这一改变会促进棕色脂肪组织中TGR5表达量升高，从而增加产热，使小鼠在高脂高果糖饮食摄入情况下依然维持代谢稳态。此外，胆汁酸还会通过肠道微生物的介导促进脂肪组织褐变，增加其产热[100]。
4 小结与展望胆汁酸在肠道和肝脏的吸收和代谢中起着关键作用，并且它们参与调节糖脂代谢和能量代谢的稳态。糖脂代谢紊乱不仅会影响饲料转化效率、胃肠营养吸收，也会给畜禽带来相关疾病，造成经济损失。未来有关胆汁酸的研究应进一步：1)发掘不同生理状态下(疾病、应激、健康、亚健康等)胆汁酸谱的变化及其通过相应受体参与宿主生理代谢的机制；2)利用高速发展的组学方法和系统生物学思维阐释胆汁酸与肠道微生物之间互作关系及其维持代谢稳态中的作用。并以此为基点，利用外源干预手段(如添加益生元、益生菌、复生元、外源胆汁酸或菌群移植等)或饲养方式(如改良饲喂频率、转换饲料类型等)调节肠道微生物和胆汁酸谱以促进畜禽自身代谢健康将会是未来动物营养学研究的一个重要方向。
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