丁酸盐与炎症性肠病的研究进展

艾 静 王承党

福建医科大学附属第一医院消化内科 福建医科大学消化疾病研究室(350005)

炎症性肠病(IBD)包括克罗恩病(CD)和溃疡性结肠炎(UC)，目前认为肠道菌群紊乱、细菌代谢产物改变、肠道免疫功能异常等因素在IBD的发病机制中发挥重要作用。丁酸盐是肠道细菌的代谢产物，其在IBD中的作用备受关注。本文就丁酸盐与IBD的研究进展作一综述。

一、肠腔内丁酸盐的来源与功能

丁酸盐是含四个碳原子的短链脂肪酸(short chain fatty acid, SCFA)，肠腔内的丁酸盐主要来自肠道细菌分解膳食纤维，如低聚果糖、大麦、淀粉、燕麦糠等[1-3]。Cummings等[4]通过尸检发现SCFA在盲肠、升结肠、降结肠、乙状结肠中的含量分别为(131±9) mmol/kg、(123±12) mmol/kg、(80±17) mmol/kg、(100±30) mmol/kg，其中乙酸盐、丙酸盐、丁酸盐的含量比约为57∶22∶21，SCFA含量从右半结肠至左半结肠逐渐降低，可能与右半结肠pH值低于左半结肠有关。鉴于活体测定肠腔中丁酸盐含量较困难，Hallert等[3]利用气相色谱法测定粪便中丁酸盐，以评估其在肠腔内含量，结果显示每克粪便含丁酸盐约11 mmol，乙酸盐、丙酸盐、丁酸盐比例约为47∶11∶12。丁酸盐在结肠内主要通过非离子扩散和载体介导(如单羧酸转运体蛋白1)进入细胞，载体介导转运具有pH值、时间、浓度依赖性[5-6]。丁酸盐在肠腔中的作用主要有：①提供结肠黏膜细胞70%以上的能量；②促进肠腔内钠、钾、水吸收；③抑制结肠癌细胞生长；④增加抗氧化物质谷胱甘肽表达，降低过氧化物酶、环氧合酶(COX)表达，减轻炎症反应；⑤调节肠道神经，降低内脏敏感性[7]；⑥抑制组蛋白去乙酰化和核因子(NF)-κB活化，保护肠黏膜屏障[1]。此外，丁酸盐还可改善肥胖、抑制胰岛素抵抗、降低胆固醇合成、预防心脑血管疾病、改善脑缺血性疾病预后、提高记忆力等[8]。

二、丁酸盐与IBD的关系

Paturi等[9]采用气相色谱法分析显示，IBD小鼠肠腔中丁酸盐含量较正常小鼠显著降低，口服蓝莓和西兰花可增加丁酸盐含量，改善肠道炎症。研究[10-11]显示，丁酸盐与美沙拉秦联合应用治疗轻中度UC，可提高美沙拉秦疗效。丁酸盐与5-氨基水杨酸联合治疗对激素、5-氨基水杨酸耐药的远端UC，可诱导UC症状缓解，患者排便次数、临床评分、对治疗效果满意程度均优于单用5-氨基水杨酸。IBD不仅表现为肠腔内丁酸盐含量下降，亦有研究[12]认为，IBD患者氧化丁酸盐的能力下降，丁酸盐的生理作用在体内未充分发挥。

三、丁酸盐改善IBD的机制

1. 丁酸盐与肠道黏膜屏障：肠道黏液层主要由黏蛋白2(MUC2)、三叶因子3(TFF3)、分泌型IgA等物质组成，是保护肠道上皮细胞的重要防线。在三硝基苯磺酸(TNBS)诱导结肠炎模型小鼠体内，给予丁酸盐可上调TFF3的表达，促进肠黏膜修复，减轻炎症程度[13]。在葡聚糖硫酸钠(DSS)诱导BALB/c小鼠结肠炎模型和重症联合免疫缺陷(SCID)结肠炎模型小鼠体内，MUC2表达抑制，而给予酪丁酸梭菌产生丁酸盐可促进MUC2表达[14]。然而，另一项研究[15]显示，对UC缓解期患者进行丁酸盐灌肠治疗，并不能改变肠黏膜中MUC2、TFF3、分泌型IgA的表达水平。相关结论有待进一步研究。

肠上皮细胞间存在穿膜蛋白和胞质外周蛋白维持细胞间紧密连接，穿膜蛋白包括闭合蛋白、封闭蛋白等，胞质外周蛋白包括ZO家族、PDZ蛋白等。Peng等[16]的研究显示，丁酸盐可通过活化结肠癌Caco-2细胞中的腺苷酸活化蛋白激酶，增加闭合蛋白、封闭蛋白1、封闭蛋白4、ZO-1蛋白在细胞膜的合成。Wang等[17]的研究发现，丁酸盐可通过活化转录因子SP1，促进封闭蛋白1表达。Peng等[18]的研究显示，丁酸盐对肠黏膜屏障的作用呈剂量依赖性，低浓度丁酸盐对肠黏膜屏障具有保护作用，而高浓度丁酸盐促进上皮细胞凋亡、抑制细胞增殖，破坏肠黏膜屏障。

2. 丁酸盐与炎性因子：Segain等[19]和Tedelind等[20]对IBD患者的肠黏膜、外周血单核细胞、中性粒细胞研究发现，丁酸盐可通过抑制NF-κB的抑制蛋白Iκβα降解，从而使COX-2、细胞间黏附分子-1(ICAM)-1、肿瘤坏死因子(TNF)-α、白细胞介素(IL)-1β、IL-6等炎性因子表达下降。Weng等[21]的研究发现，丁酸盐抑制促炎因子IL-8分泌与Iκβα无关，而与锌指蛋白A20表达相关。Klampfer等[22]的研究显示，丁酸盐可抑制干扰素(IFN)-γ对转录激活因子STAT1酪氨酸/丝氨酸磷酸化，从而对肠道黏膜炎症起负向调节作用。Malago等[23]的研究发现，低剂量丁酸盐通过抑制组蛋白去乙酰化而抑制Caco-2 细胞分泌IL-8，而高剂量丁酸盐通过抑制热休克蛋白Hsp70促进IL-8分泌。Di Sabatino等[24]对轻中度CD患者的研究显示，给予患者丁酸盐(4 g/d)治疗8周后，内镜和组织学炎症评分、红细胞沉降率、外周血白细胞计数、黏膜IL-1β和NF-κB表达水平均较治疗前显著下降。上述研究证实丁酸盐可抑制炎性因子分泌，缓解IBD相关症状，作用效应可能与其剂量相关。

3. 丁酸盐与IBD相关结直肠癌：结直肠癌变是IBD的并发症，与患者发病年龄、病程长短、炎症程度有关。Peyrin-Biroulet等[25]的研究显示，IBD相关结直肠癌与散发性结直肠癌相比，发病年龄提早(56.9岁对70.9岁)、5年生存率降低(41.3%对51.9%)。IBD癌变机制可能与遗传信息、炎性因子、氧化应激、肠黏膜屏障破坏等因素有关[26]。Daroqui等[27]的研究显示，丁酸盐可通过改变染色体结构、修饰组蛋白，抑制人结肠癌细胞中原癌基因c-myc、细胞周期蛋白D1转录和表达，促进癌细胞凋亡。COX-2/前列腺素E2(PGE2)通路在肿瘤的发生、发展过程中发挥重要作用，参与肿瘤细胞增殖、凋亡逃逸、血管再生等过程[28-29]。Jahns等[30]的研究发现，丁酸盐可抑制结直肠癌组织COX-2基因表达及其蛋白活性。Wang等[31]的研究显示，将人结肠癌细胞株HT-29培养于含丁酸盐的培养基24 h后，细胞凋亡数量增加，丁酸盐通过激活caspase-9、caspase-3诱导细胞凋亡。此外，Ruemmele等[32]的研究发现，丁酸盐可上调促凋亡基因BAK表达，激活线粒体途径诱导细胞凋亡。Yu等[33]对结直肠癌细胞研究发现，丁酸盐可抑制血管内皮生长因子及其受体神经纤毛蛋白-1表达，从而抑制肿瘤细胞增殖和迁移。

四、结语

丁酸盐作为细菌代谢产物，可抑制肠道炎症、预防癌变、改善IBD病情。然而，丁酸盐具有双重效应，高浓度可破坏肠道黏膜、促进炎症反应。因此，未来需对丁酸盐治疗IBD的剂量以及如何确保病变部位丁酸盐浓度等问题进一步探索，以期为临床治疗IBD提供一种新方法。

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