曹明為，劉玉蘭，馬靜靜，董衛(wèi)國

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·新進(jìn)展·

緩解期炎性腸病伴腸易激綜合征樣癥狀機(jī)制的研究進(jìn)展

曹明為，劉玉蘭，馬靜靜，董衛(wèi)國

炎性腸病(IBD)是一種病因不十分清楚的慢性非特異性腸道炎性疾病，緩解期IBD(IBDR)患者常伴有腸易激綜合征(IBS)樣癥狀。IBS樣癥狀的存在導(dǎo)致患者的生活質(zhì)量降低，影響醫(yī)生對病情的評估及治療策略的選擇。因此，本文對IBDR患者伴有IBS樣癥狀的機(jī)制進(jìn)行綜述，得出IBDR伴IBS樣癥狀與腸道低度炎癥和神經(jīng)重塑均有關(guān)聯(lián)，也可能為IBD合并了IBS。

炎性腸疾?。荒c易激綜合征；炎癥；神經(jīng)重塑

曹明為，劉玉蘭，馬靜靜，等.緩解期炎性腸病伴腸易激綜合征樣癥狀機(jī)制的研究進(jìn)展[J].中國全科醫(yī)學(xué)，2016，19(28)：3506-3509.[www.chinagp.net]

CAO M W,LIU Y L,MA J J,et al.Research progress of mechanism of inflammatory bowel disease patients with irritable bowel syndrome-like symptoms during remission[J].Chinese General Practice，2016，19(28)：3506-3509.

腸易激綜合征(irritable bowel disease,IBS)是一種功能性腸病，臨床癥狀主要表現(xiàn)為腹痛、排便習(xí)慣改變和糞便性狀改變。炎性腸病(inflammatory bowel diseases,IBD)包括潰瘍性結(jié)腸炎(ulcerative colitis,UC)和克羅恩病(crohn′s disease,CD)，病程分為活動期和緩解期。緩解期IBD(IBDR)患者存在IBS樣癥狀已被廣泛報(bào)道[1-3]。MINDERHOUD等[1]調(diào)查了107例IBDR成人患者，其中31%UC患者和41%CD患者存在IBS樣癥狀。2010年KEOHANE等[2]研究發(fā)現(xiàn)38.6%UC患者和59.7%CD患者存在IBS樣癥狀。研究發(fā)現(xiàn)IBDR伴有IBS樣癥狀比不伴有IBS樣癥狀患者，更容易發(fā)生抑郁，生活質(zhì)量降低[2-4]。而且IBDR伴有IBS樣癥狀患者使得醫(yī)生在評估疾病活動程度時(shí)更為困難，在診斷及治療策略上難以抉擇，對疼痛的評估可導(dǎo)致不必要的花費(fèi)、過度的檢查及治療。因此，本文對IBDR患者伴有IBS樣癥狀的機(jī)制進(jìn)行綜述，現(xiàn)報(bào)道如下。

1　IBDR伴IBS樣癥狀與腸道黏膜存在低度炎癥有關(guān)

2010年KEOHANE等[2]研究發(fā)現(xiàn)IBDR伴有IBS樣癥狀與不伴有IBS樣癥狀患者相比，糞鈣衛(wèi)蛋白水平更高，認(rèn)為IBDR患者IBS樣癥狀是由于低度炎癥導(dǎo)致，而不是合并功能性腸病。2014年VIVINUS-NEBOT等[3]研究證實(shí)IBDR伴IBS樣癥狀與低度炎癥的相關(guān)性，研究者收集IBDR患者腸道活檢組織，發(fā)現(xiàn)IBDR伴有IBS樣癥狀與不伴有IBS樣癥狀患者相比，組織細(xì)胞通透性增加，緊密連接蛋白、α-連環(huán)素及閉合蛋白的表達(dá)降低，活檢組織細(xì)胞中上皮內(nèi)淋巴細(xì)胞(IELs)、嗜酸粒細(xì)胞、肥大細(xì)胞及腫瘤壞死因子α(TNF-α)表達(dá)增加，因此，認(rèn)為在IBDR中，IBS樣癥狀出現(xiàn)與滲透性增加導(dǎo)致的持續(xù)低度炎癥有關(guān)。

1.1腸道微生物、腸道黏膜上皮與腸道黏膜炎癥腸道柔嫩梭類菌群總量在IBD中減少已被廣泛報(bào)道[5-6]，LOPEZ-SILES等[7]利用PCR-變性梯度凝膠電泳技術(shù)(PCR-denaturing gradient gel electtrophoresis，PCR-DGGE)研究認(rèn)為IBD患者腸道柔嫩梭類菌群種類也減少。腸道柔嫩梭類菌是健康人腸道最豐富的細(xì)菌，約占總量5%。在研究2，4，6-三硝基苯黃氨酸誘導(dǎo)結(jié)腸的小鼠模型中發(fā)現(xiàn)口飼柔嫩梭菌群或其培養(yǎng)上清液均可以減弱其炎性反應(yīng)[8]。認(rèn)為柔嫩梭菌群的代謝產(chǎn)物可以抑制核內(nèi)轉(zhuǎn)錄因子(NF-KB)活化和產(chǎn)生白介素8(IL-8)。QUEVRAIN等[9]認(rèn)為這種代謝產(chǎn)物是一種15 kd的蛋白質(zhì)，通過抑制腸道上皮細(xì)胞NF-KB途徑而減輕動物模型的炎癥。腸道上皮以往被認(rèn)為只是腸道的機(jī)械屏障，現(xiàn)在認(rèn)為腸道上皮可感應(yīng)抗原，并釋放抗炎因子、增加黏蛋白、分泌細(xì)胞因子來參與免疫反應(yīng)[10]。近期有研究認(rèn)為微生物介導(dǎo)的腸道上皮細(xì)胞凋亡可以增加腸道上皮滲透性[11]。

腸道氣體對結(jié)腸內(nèi)環(huán)境穩(wěn)態(tài)起著重要作用，腸道氣體總量及成分的平衡即腸道利用氣體的還原產(chǎn)乙酸菌、產(chǎn)甲烷古菌和硫酸鹽還原菌(sulphate-reducing bacteria，SRB)與產(chǎn)氣發(fā)酵菌之間的平衡，其副產(chǎn)品為氫氣、甲烷、硫化氫、二氧化碳。有研究描述結(jié)腸氣體體積和成分的變化與腸道疾病的相關(guān)性，如便秘及IBS患者呼氣中甲烷增高[12]。硫化氫是氫氣在廣泛存在于腸道黏膜上皮的SRB作用下的產(chǎn)物，在IBD患者中發(fā)現(xiàn)硫化氫和SRB增高[12]。氫氣是一種抗氧化劑，在健康人中腸道氫氣能夠保護(hù)腸道黏膜不受氧化應(yīng)激侵襲[12]，氧化應(yīng)激被認(rèn)為是IBD患者腸道損傷的機(jī)制之一[13]，對于IBD患者，腸道氣體與腸道微生物之間的關(guān)聯(lián)仍需進(jìn)一步研究。

1.2心理障礙與腸道黏膜炎癥臨床研究表明，心理壓力可以影響腸道的上皮屏障功能，導(dǎo)致腸道滲透性增加[14]，其是IBD和IBS發(fā)病的一個(gè)重要機(jī)制[15]。如前所述，腸道滲透性的增加可以導(dǎo)致腸道的低度炎癥。動物實(shí)驗(yàn)認(rèn)為心理壓力通過促進(jìn)促腎上腺皮質(zhì)激素釋放激素(corticotropin-releasing hormone，CRH)分泌激活肥大細(xì)胞，增加腸道滲透性。VANUYTSEL等[16]招募志愿者證明在人體也如此。OVERMAN等[17]研究認(rèn)為CRH激活肥大細(xì)胞，肥大細(xì)胞分泌TNF-α和蛋白酶，導(dǎo)致腸道滲透性增加。同時(shí)，MORRISON等[18]研究認(rèn)為對疾病持有消極態(tài)度也是導(dǎo)致IBS樣癥狀的獨(dú)立因素之一。

1.3飲食與腸道黏膜炎癥流行病學(xué)研究顯示IBD的發(fā)生率在亞洲逐年上升，尤其是工業(yè)化地區(qū)，并認(rèn)為與亞洲飲食習(xí)慣逐漸趨向西方化有關(guān)[19]。很多日常飲食比如維生素、氨基酸、多不飽和脂肪酸被認(rèn)為可以通過微生物調(diào)節(jié)腸道黏膜免疫[20]。飲食可以治療IBD，這在動物實(shí)驗(yàn)中已得到證實(shí)[21]。DEVKOTA等[22]認(rèn)為食物可以改變腸道微生物的構(gòu)成來促進(jìn)炎癥和其他免疫性疾病。維生素D有抗炎作用，在人白細(xì)胞抗原(HLA)-27轉(zhuǎn)基因老鼠中，高鈣飲食可以減少腸道黏膜滲透性，緩解腹瀉，其被證明可以增加腸道上皮細(xì)胞對損傷的耐受性及減少對腸道病原的免疫反應(yīng)性[23]。小樣本對照試驗(yàn)研究認(rèn)為補(bǔ)充維生素D可以減少緩解期IBD的復(fù)發(fā)[24]。N-3多不飽和脂肪酸有抗炎作用，盡管1項(xiàng)對照試驗(yàn)發(fā)現(xiàn)對恢復(fù)期CD患者的復(fù)發(fā)率沒有影響[25]。一項(xiàng)Meta分析得出低含量發(fā)酵性/寡糖/雙糖/單糖及糖醇(FODMAP)的飲食可改善胃腸功能紊亂[26]。飲食可以通過改變腸道微生物構(gòu)成，發(fā)揮抗炎作用，這可能為緩解期患者腹痛提供一種無不良反應(yīng)且經(jīng)濟(jì)的新治療方向。

2　IBDR伴IBS樣癥狀與神經(jīng)重塑有關(guān)

支配消化道的神經(jīng)分布于消化道壁內(nèi)的內(nèi)在神經(jīng)系統(tǒng)和外在神經(jīng)系統(tǒng)，其中內(nèi)在神經(jīng)系統(tǒng)，又有“腸腦”之稱，是由分布在消化壁內(nèi)的神經(jīng)元和神經(jīng)纖維所組成的神經(jīng)網(wǎng)絡(luò)，具有調(diào)節(jié)腸道的運(yùn)動、感覺、分泌等生理功能。感染可引起腸道神經(jīng)系統(tǒng)重塑。研究發(fā)現(xiàn)，患者在腸道病毒、細(xì)菌或寄生蟲感染時(shí)，或病原體被清除及黏膜炎癥消退后，可發(fā)生IBS樣癥狀，稱之為感染后IBS(PI-IBS)[27]。PI-IBS患者的結(jié)腸組織呈現(xiàn)低度炎癥，炎癥使內(nèi)臟敏感性增加，且炎癥后神經(jīng)重塑影響腸道的運(yùn)動、感覺、分泌功能[28]。

瞬時(shí)電壓感受器陽離子通道(transient receptor potential cation channel subfamily V member 1,TRPV-1)在內(nèi)臟神經(jīng)敏感性中起著重要作用。AKBAR等[29]研究了TRPV-1與腹痛敏感性的相關(guān)性，研究者收集IBDR伴有IBS樣癥狀患者及其腸道活檢組織，用免疫組織化學(xué)法測得前者TRPV-1陽性神經(jīng)元高于后者，認(rèn)為TRPV-1可能在IBDR患者內(nèi)臟敏感性增高和持續(xù)腹痛中起著重要作用。這為IBD伴有IBS樣癥狀患者提供了一種治療方向。在腸道，5-羥色胺是一種重要的神經(jīng)遞質(zhì)和旁分泌信號分子，在內(nèi)臟功能扮演重要角色。研究發(fā)現(xiàn)CD臨床緩解期伴有IBS癥狀患者有更高的色氨酸羥化酶-1(TPH-1)，認(rèn)為5-羥色氨酸對CD患者產(chǎn)生IBS樣癥狀起著重要作用[30]。不僅外周神經(jīng)重塑導(dǎo)致的神經(jīng)內(nèi)分泌功能與IBS樣癥狀有關(guān)，中樞神經(jīng)亦參與IBS的形成，SCHMID等[31]進(jìn)行了一項(xiàng)功能磁共振研究認(rèn)為安慰劑可以通過減少中樞疼痛區(qū)域的激活來減少UC緩解期患者腹脹不適。

3　IBDR伴IBS樣癥狀與并發(fā)IBS有關(guān)

目前研究認(rèn)為IBD與IBS存在一定相關(guān)性，IBS是否是IBD的一個(gè)亞型[32]？腹痛是二者常見的癥狀之一，但結(jié)腸黏膜上皮細(xì)胞持續(xù)分泌的干擾素α(IFN-α)導(dǎo)致上皮屏障的破壞，可能與IBD的腹痛相關(guān)，而與IBS的腹痛無關(guān)[3]。腸道微生物的紊亂是IBD和IBS的共同病因，但研究發(fā)現(xiàn)柔嫩梭類菌在IBS與IBD疾病中總量均較少，但種間仍存在差異[7]。且臨床上發(fā)現(xiàn)益生菌對IBD和IBS患者的療效差異很大。IBD與IBS的相關(guān)性仍需進(jìn)一步研究。

KEOHANE等[2]研究認(rèn)為IBDR患者存在IBS樣癥狀是因?yàn)槟c道存在神秘的低度炎癥，但JONEFJALL等[33]研究發(fā)現(xiàn)UC緩解期合并IBS患者的糞鈣衛(wèi)蛋白并沒有增加，這似乎說明UC緩解期伴IBS樣癥狀的發(fā)生與腸道神秘炎癥活動無關(guān)。同時(shí)，對于KEOHANE等[2]的研究，SPRAKES等[34]持懷疑態(tài)度，認(rèn)為糞鈣衛(wèi)蛋白并不能區(qū)分IBDR出現(xiàn)IBS樣癥狀是來自于疾病輕度活動還是合并了IBS。ZIMMERMAN等[4]研究發(fā)現(xiàn)部分兒童克羅恩疾病緩解期合并功能性腹痛(functional abdominal pain,FAP)。認(rèn)為IBD-FAP患者且更容易合并抑郁。KEOHANE等[2]研究發(fā)現(xiàn)IBD伴IBS樣癥狀患者的焦慮抑郁量表得分更高。但均未揭示是抑郁導(dǎo)致了腹痛，還是腹痛的癥狀讓患者處于抑郁狀態(tài)。抑郁是IBS的重要危險(xiǎn)因素之一，因此IBD伴IBS樣癥狀患者可能是IBS的高危人群。

4　小結(jié)

IBDR患者存在IBS樣癥狀已被廣泛報(bào)道，IBS樣癥狀不僅增加患者心理障礙、也使得醫(yī)生在評估病情時(shí)更加困難，增加了醫(yī)療負(fù)擔(dān)。醫(yī)生對IBDR患者伴有IBS樣癥狀的評估，直接影響了治療方案的選擇，若醫(yī)生將IBS樣癥狀歸咎于合并IBS，而非炎癥，則有可能忽略抗炎治療而引起并發(fā)癥等的發(fā)生。IBDR伴有IBS樣癥狀與腸道低度炎癥和神經(jīng)重塑均有關(guān)聯(lián)，也可能為IBD合并了IBS。

作者貢獻(xiàn)：曹明為負(fù)責(zé)研究設(shè)計(jì)與實(shí)施，撰寫論文；劉玉蘭、馬靜靜負(fù)責(zé)論文修改；董衛(wèi)國負(fù)責(zé)論文質(zhì)量控制與審校。

本文無利益沖突。

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(本文編輯：崔沙沙)

Research Progress of Mechanism of Inflammatory Bowel Disease Patients with Irritable Bowel Syndrome-like Symptoms during Remission

CAOMing-wei,LIUYu-lan,MAJing-jing,DONGWei-guo.

DepartmentofGastroenterology,RenminHospitalofWuhanUniversity,Wuhan430060,China

Correspondingauthor:DONGWei-guo,DepartmentofGastroenterology,RenminHospitalofWuhanUniversity,Wuhan430060,China;E-mail:dwg@whu.edu.cn

Inflammatory bowel disease(IBD) is a chronic nonspecific inflammatory bowel disease with not very clear causes,IBD during remission(IBDR) patients often have irritable bowel syndrome(IBS)-like symptoms.The presence of IBS-like symptoms leads to reduced quality of life of patients,and influences assessment of disease and choice of treatment strategies of doctors.Therefore,the paper reviews the mechanism of IBDR patients with IBS-like symptoms,and concludes that IBDR with IBS-like symptoms was related to intestinal low-grade inflammation and nerve remodeling,and may also have combined IBS for IBD.

Inflammatory bowel diseases;Irritable bowel syndrome;Inflammation;Nerve remodeling

430060湖北省武漢市，武漢大學(xué)人民醫(yī)院消化內(nèi)科

董衛(wèi)國，430060湖北省武漢市，武漢大學(xué)人民醫(yī)院消化內(nèi)科；E-mail：dwg@whu.edu.cn

R 574

ADOI：10.3969/j.issn.1007-9572.2016.28.025

2016-04-07；

2016-08-22)