丁酸鹽與炎癥性腸病的研究進(jìn)展

艾 靜 王承黨

福建醫(yī)科大學(xué)附屬第一醫(yī)院消化內(nèi)科 福建醫(yī)科大學(xué)消化疾病研究室(350005)

炎癥性腸病(IBD)包括克羅恩病(CD)和潰瘍性結(jié)腸炎(UC)，目前認(rèn)為腸道菌群紊亂、細(xì)菌代謝產(chǎn)物改變、腸道免疫功能異常等因素在IBD的發(fā)病機(jī)制中發(fā)揮重要作用。丁酸鹽是腸道細(xì)菌的代謝產(chǎn)物，其在IBD中的作用備受關(guān)注。本文就丁酸鹽與IBD的研究進(jìn)展作一綜述。

一、腸腔內(nèi)丁酸鹽的來(lái)源與功能

丁酸鹽是含四個(gè)碳原子的短鏈脂肪酸(short chain fatty acid, SCFA)，腸腔內(nèi)的丁酸鹽主要來(lái)自腸道細(xì)菌分解膳食纖維，如低聚果糖、大麥、淀粉、燕麥糠等[1-3]。Cummings等[4]通過(guò)尸檢發(fā)現(xiàn)SCFA在盲腸、升結(jié)腸、降結(jié)腸、乙狀結(jié)腸中的含量分別為(131±9) mmol/kg、(123±12) mmol/kg、(80±17) mmol/kg、(100±30) mmol/kg，其中乙酸鹽、丙酸鹽、丁酸鹽的含量比約為57∶22∶21，SCFA含量從右半結(jié)腸至左半結(jié)腸逐漸降低，可能與右半結(jié)腸pH值低于左半結(jié)腸有關(guān)。鑒于活體測(cè)定腸腔中丁酸鹽含量較困難，Hallert等[3]利用氣相色譜法測(cè)定糞便中丁酸鹽，以評(píng)估其在腸腔內(nèi)含量，結(jié)果顯示每克糞便含丁酸鹽約11 mmol，乙酸鹽、丙酸鹽、丁酸鹽比例約為47∶11∶12。丁酸鹽在結(jié)腸內(nèi)主要通過(guò)非離子擴(kuò)散和載體介導(dǎo)(如單羧酸轉(zhuǎn)運(yùn)體蛋白1)進(jìn)入細(xì)胞，載體介導(dǎo)轉(zhuǎn)運(yùn)具有pH值、時(shí)間、濃度依賴性[5-6]。丁酸鹽在腸腔中的作用主要有：①提供結(jié)腸黏膜細(xì)胞70%以上的能量；②促進(jìn)腸腔內(nèi)鈉、鉀、水吸收；③抑制結(jié)腸癌細(xì)胞生長(zhǎng)；④增加抗氧化物質(zhì)谷胱甘肽表達(dá)，降低過(guò)氧化物酶、環(huán)氧合酶(COX)表達(dá)，減輕炎癥反應(yīng)；⑤調(diào)節(jié)腸道神經(jīng)，降低內(nèi)臟敏感性[7]；⑥抑制組蛋白去乙酰化和核因子(NF)-κB活化，保護(hù)腸黏膜屏障[1]。此外，丁酸鹽還可改善肥胖、抑制胰島素抵抗、降低膽固醇合成、預(yù)防心腦血管疾病、改善腦缺血性疾病預(yù)后、提高記憶力等[8]。

二、丁酸鹽與IBD的關(guān)系

Paturi等[9]采用氣相色譜法分析顯示，IBD小鼠腸腔中丁酸鹽含量較正常小鼠顯著降低，口服藍(lán)莓和西蘭花可增加丁酸鹽含量，改善腸道炎癥。研究[10-11]顯示，丁酸鹽與美沙拉秦聯(lián)合應(yīng)用治療輕中度UC，可提高美沙拉秦療效。丁酸鹽與5-氨基水楊酸聯(lián)合治療對(duì)激素、5-氨基水楊酸耐藥的遠(yuǎn)端UC，可誘導(dǎo)UC癥狀緩解，患者排便次數(shù)、臨床評(píng)分、對(duì)治療效果滿意程度均優(yōu)于單用5-氨基水楊酸。IBD不僅表現(xiàn)為腸腔內(nèi)丁酸鹽含量下降，亦有研究[12]認(rèn)為，IBD患者氧化丁酸鹽的能力下降，丁酸鹽的生理作用在體內(nèi)未充分發(fā)揮。

三、丁酸鹽改善IBD的機(jī)制

1. 丁酸鹽與腸道黏膜屏障：腸道黏液層主要由黏蛋白2(MUC2)、三葉因子3(TFF3)、分泌型IgA等物質(zhì)組成，是保護(hù)腸道上皮細(xì)胞的重要防線。在三硝基苯磺酸(TNBS)誘導(dǎo)結(jié)腸炎模型小鼠體內(nèi)，給予丁酸鹽可上調(diào)TFF3的表達(dá)，促進(jìn)腸黏膜修復(fù)，減輕炎癥程度[13]。在葡聚糖硫酸鈉(DSS)誘導(dǎo)BALB/c小鼠結(jié)腸炎模型和重癥聯(lián)合免疫缺陷(SCID)結(jié)腸炎模型小鼠體內(nèi)，MUC2表達(dá)抑制，而給予酪丁酸梭菌產(chǎn)生丁酸鹽可促進(jìn)MUC2表達(dá)[14]。然而，另一項(xiàng)研究[15]顯示，對(duì)UC緩解期患者進(jìn)行丁酸鹽灌腸治療，并不能改變腸黏膜中MUC2、TFF3、分泌型IgA的表達(dá)水平。相關(guān)結(jié)論有待進(jìn)一步研究。

腸上皮細(xì)胞間存在穿膜蛋白和胞質(zhì)外周蛋白維持細(xì)胞間緊密連接，穿膜蛋白包括閉合蛋白、封閉蛋白等，胞質(zhì)外周蛋白包括ZO家族、PDZ蛋白等。Peng等[16]的研究顯示，丁酸鹽可通過(guò)活化結(jié)腸癌Caco-2細(xì)胞中的腺苷酸活化蛋白激酶，增加閉合蛋白、封閉蛋白1、封閉蛋白4、ZO-1蛋白在細(xì)胞膜的合成。Wang等[17]的研究發(fā)現(xiàn)，丁酸鹽可通過(guò)活化轉(zhuǎn)錄因子SP1，促進(jìn)封閉蛋白1表達(dá)。Peng等[18]的研究顯示，丁酸鹽對(duì)腸黏膜屏障的作用呈劑量依賴性，低濃度丁酸鹽對(duì)腸黏膜屏障具有保護(hù)作用，而高濃度丁酸鹽促進(jìn)上皮細(xì)胞凋亡、抑制細(xì)胞增殖，破壞腸黏膜屏障。

2. 丁酸鹽與炎性因子：Segain等[19]和Tedelind等[20]對(duì)IBD患者的腸黏膜、外周血單核細(xì)胞、中性粒細(xì)胞研究發(fā)現(xiàn)，丁酸鹽可通過(guò)抑制NF-κB的抑制蛋白Iκβα降解，從而使COX-2、細(xì)胞間黏附分子-1(ICAM)-1、腫瘤壞死因子(TNF)-α、白細(xì)胞介素(IL)-1β、IL-6等炎性因子表達(dá)下降。Weng等[21]的研究發(fā)現(xiàn)，丁酸鹽抑制促炎因子IL-8分泌與Iκβα無(wú)關(guān)，而與鋅指蛋白A20表達(dá)相關(guān)。Klampfer等[22]的研究顯示，丁酸鹽可抑制干擾素(IFN)-γ對(duì)轉(zhuǎn)錄激活因子STAT1酪氨酸/絲氨酸磷酸化，從而對(duì)腸道黏膜炎癥起負(fù)向調(diào)節(jié)作用。Malago等[23]的研究發(fā)現(xiàn)，低劑量丁酸鹽通過(guò)抑制組蛋白去乙?；种艭aco-2 細(xì)胞分泌IL-8，而高劑量丁酸鹽通過(guò)抑制熱休克蛋白Hsp70促進(jìn)IL-8分泌。Di Sabatino等[24]對(duì)輕中度CD患者的研究顯示，給予患者丁酸鹽(4 g/d)治療8周后，內(nèi)鏡和組織學(xué)炎癥評(píng)分、紅細(xì)胞沉降率、外周血白細(xì)胞計(jì)數(shù)、黏膜IL-1β和NF-κB表達(dá)水平均較治療前顯著下降。上述研究證實(shí)丁酸鹽可抑制炎性因子分泌，緩解IBD相關(guān)癥狀，作用效應(yīng)可能與其劑量相關(guān)。

3. 丁酸鹽與IBD相關(guān)結(jié)直腸癌：結(jié)直腸癌變是IBD的并發(fā)癥，與患者發(fā)病年齡、病程長(zhǎng)短、炎癥程度有關(guān)。Peyrin-Biroulet等[25]的研究顯示，IBD相關(guān)結(jié)直腸癌與散發(fā)性結(jié)直腸癌相比，發(fā)病年齡提早(56.9歲對(duì)70.9歲)、5年生存率降低(41.3%對(duì)51.9%)。IBD癌變機(jī)制可能與遺傳信息、炎性因子、氧化應(yīng)激、腸黏膜屏障破壞等因素有關(guān)[26]。Daroqui等[27]的研究顯示，丁酸鹽可通過(guò)改變?nèi)旧w結(jié)構(gòu)、修飾組蛋白，抑制人結(jié)腸癌細(xì)胞中原癌基因c-myc、細(xì)胞周期蛋白D1轉(zhuǎn)錄和表達(dá)，促進(jìn)癌細(xì)胞凋亡。COX-2/前列腺素E2(PGE2)通路在腫瘤的發(fā)生、發(fā)展過(guò)程中發(fā)揮重要作用，參與腫瘤細(xì)胞增殖、凋亡逃逸、血管再生等過(guò)程[28-29]。Jahns等[30]的研究發(fā)現(xiàn)，丁酸鹽可抑制結(jié)直腸癌組織COX-2基因表達(dá)及其蛋白活性。Wang等[31]的研究顯示，將人結(jié)腸癌細(xì)胞株HT-29培養(yǎng)于含丁酸鹽的培養(yǎng)基24 h后，細(xì)胞凋亡數(shù)量增加，丁酸鹽通過(guò)激活caspase-9、caspase-3誘導(dǎo)細(xì)胞凋亡。此外，Ruemmele等[32]的研究發(fā)現(xiàn)，丁酸鹽可上調(diào)促凋亡基因BAK表達(dá)，激活線粒體途徑誘導(dǎo)細(xì)胞凋亡。Yu等[33]對(duì)結(jié)直腸癌細(xì)胞研究發(fā)現(xiàn)，丁酸鹽可抑制血管內(nèi)皮生長(zhǎng)因子及其受體神經(jīng)纖毛蛋白-1表達(dá)，從而抑制腫瘤細(xì)胞增殖和遷移。

四、結(jié)語(yǔ)

丁酸鹽作為細(xì)菌代謝產(chǎn)物，可抑制腸道炎癥、預(yù)防癌變、改善IBD病情。然而，丁酸鹽具有雙重效應(yīng)，高濃度可破壞腸道黏膜、促進(jìn)炎癥反應(yīng)。因此，未來(lái)需對(duì)丁酸鹽治療IBD的劑量以及如何確保病變部位丁酸鹽濃度等問(wèn)題進(jìn)一步探索，以期為臨床治療IBD提供一種新方法。

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