潰瘍性結(jié)腸炎與小腸細(xì)菌過度生長(zhǎng)關(guān)系探討

劉治宏，崔立紅

1.陸軍軍醫(yī)大學(xué)研究生院，重慶 400038；2.海軍總醫(yī)院消化內(nèi)科

潰瘍性結(jié)腸炎(ulcerative colitis, UC)表現(xiàn)為腸道慢性非特異性炎癥，具有復(fù)發(fā)、緩解的病程特點(diǎn)。UC發(fā)病率較高[1]，整體發(fā)病率為1.2～20.3例每年每100 000人，患病率為7.6～245例每年每100 000人[2]。患者通常出現(xiàn)血性腹瀉和腹部絞痛等癥狀[3]。流行病學(xué)表明,UC發(fā)病率的升高伴隨著社會(huì)西方化和工業(yè)化的進(jìn)程，正如自1990年以來，UC在西方國(guó)家的發(fā)生率基本穩(wěn)定，但在新興工業(yè)化國(guó)家呈上升的趨勢(shì)[4]。盡管有許多遺傳和環(huán)境因素已被發(fā)現(xiàn)增加了該病的發(fā)病率[5]，但UC的確切發(fā)病機(jī)制目前仍不明確。

小腸細(xì)菌過度生長(zhǎng)(small intestinal bacterial overgrowth, SIBO)是外來細(xì)菌或腸道內(nèi)常駐細(xì)菌數(shù)量增加導(dǎo)致的食物過度發(fā)酵、黏膜炎癥、小腸通透性破壞、吸收不良、絨毛損傷[6]。SIBO與很多疾病密切相關(guān)，如非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)[7]、腸易激綜合征[8]、深靜脈血栓(deep vein thrombosis, DVT)[9-10]、糖尿病[11-12]、胃腸道腫瘤[13]、帕金森[14-15]、炎癥性腸病[16]等。呼氣試驗(yàn)有廉價(jià)、簡(jiǎn)便、非侵入性等優(yōu)點(diǎn)，本試驗(yàn)采用此方法檢測(cè)SIBO[17]。

目前，關(guān)于UC與SIBO的關(guān)系報(bào)道甚少。本文通過檢測(cè)輕-中度UC患者的甲烷-氫氣呼氣試驗(yàn)，探討UC患者與SIBO之間的關(guān)系。

1 資料與方法

1.1一般資料選取2016年6月至2017年12月海軍總醫(yī)院就診，并同時(shí)完善甲烷-氫氣呼氣試驗(yàn)的輕-中度UC患者，共120例，男64例，女56例，男女比例1.14∶1,年齡(38.6±9.5)歲。對(duì)照組選取同期來院體檢健康者60名，男31名，女29名，男女比例1.07∶1，年齡(39.0±9.0)歲。兩組性別、年齡比較，差異均無統(tǒng)計(jì)學(xué)意義(P>0.05)，具有可比性。

1.2排除標(biāo)準(zhǔn)(1)肝臟病變、急性感染、其他慢性炎性疾病及妊娠患者；(2)行結(jié)腸切除術(shù)的UC患者，因其可能會(huì)導(dǎo)致口盲傳輸時(shí)間(orocecal transit time，OCTT)(OCTT為小腸傳遞時(shí)間，主要反映小腸傳輸功能[18])延長(zhǎng)，從而導(dǎo)致SIBO陽性；(3)在試驗(yàn)開始前1個(gè)月內(nèi)使用抗生素和益生菌的患者；(4)糖尿病患者，因糖尿病擾亂了自主神經(jīng)功能，可能導(dǎo)致胃腸功能紊亂、菌群失調(diào)等[19]；(5)長(zhǎng)期應(yīng)用PPI、萎縮性胃炎患者，因其胃酸減少可能導(dǎo)致SIBO。研究[20-21]認(rèn)為，PPI和胃大部切除術(shù)等可能引起胃酸分泌減少的情況會(huì)引起SIBO；(6)肥胖患者。

1.3甲烷-氫氣呼氣試驗(yàn)受檢者口服底物前需漱口，而后向采氣袋內(nèi)吹入氣體，之后30 min服用乳果糖10 ml，自此每隔30 min重復(fù)上述步驟采氣，直至收集8個(gè)采氣袋。最后由甲烷-氫氣呼出氣體分析儀 (BreathTracker)(美國(guó)Quintron公司)檢測(cè)呼出氣體。

注意事項(xiàng)：空腹8 h以上接受檢查，整個(gè)過程禁食，可飲水；晨起后禁止吸煙；檢測(cè)過程中不做劇烈運(yùn)動(dòng)。

SIBO的診斷標(biāo)準(zhǔn)(口服乳果糖120 min內(nèi)存在以下任意一種情況即可)：

(1)氫氣濃度>基礎(chǔ)值20 ppm；

(2)甲烷濃度升高>基礎(chǔ)值12 ppm；

(3)甲烷和氫氣濃度之和升高>基礎(chǔ)值15 ppm；

(4)整個(gè)檢查過程中出現(xiàn)雙峰曲線。

1.4治療及分組采用隨機(jī)數(shù)字法，對(duì)UC患者中存在SIBO的，分成A、B兩組，A組給予美沙拉嗪(0.5 g，上海愛的發(fā)制藥有限公司)治療(1 g，4次/d，6周)；B組給予美沙拉嗪(1 g，4次/d，6周)和利福昔明(0.2 g，ALFA WASSERMANN制藥公司)(0.2 g，4次/d，14 d)治療，再比較兩組的臨床療效、ESR和CRP。兩組均進(jìn)行健康的飲食、生活教育。

1.5臨床療效臨床療效評(píng)價(jià)參照既往文獻(xiàn)共識(shí)[22-23]標(biāo)準(zhǔn)?？傆行?完全緩解+顯效+有效(見表1)。

表1 臨床療效評(píng)價(jià)標(biāo)準(zhǔn)Tab 1 Clinical efficacy evaluation standard

注：相應(yīng)診斷符合①+②或③，即可診斷。

1.6ESR、CRP檢測(cè)分別于治療前、后采集患者清晨空腹靜脈血，檢測(cè)ESR、CRP。

2 結(jié)果

2.1試驗(yàn)組、對(duì)照組SIBO陽性率結(jié)果比較試驗(yàn)組120例患者中，SIBO(+)53例，陽性率44.2%；對(duì)照組60名健康體檢者，SIBO(+)13名，陽性率21.7%。試驗(yàn)組SIBO陽性率明顯高于對(duì)照組，差異有統(tǒng)計(jì)學(xué)意義(χ2=8.720，P<0.001)。

2.2A、B組臨床療效比較利福昔明根除SIBO后可提高美沙拉嗪對(duì)UC的臨床療效。A組的總有效率是80.77%，B組是92.59%，B組的療效明顯優(yōu)于A組(P<0.05，見表2)。

表2 A、B組間療效比較Tab 2 Comparison of efficacy between group A and group B

2.3ESR、CRP比較利福昔明根除SIBO后，ESR、CRP較根除治療前明顯降低，治療后B組ESR、CRP明顯低于A組(P<0.01，見表3)，提示根除SIBO有助于UC病情緩解。

表3 各組治療前后ESR、CRP變化Tab 3 Changes of ESR, CRP before and after treatment in each group

3 討論

3.1UC對(duì)SIBO的影響UC一般局限于結(jié)腸，偶爾延伸到回腸末端。但通過試驗(yàn)，我們發(fā)現(xiàn)，UC患者的SIBO陽性率高于健康人群。國(guó)外也有研究[24]發(fā)現(xiàn)，UC患者及動(dòng)物模型存在小腸功能異常，可以表現(xiàn)為腸液減少，D-木糖、氨基酸和脂肪的吸收減少等方面?？赡艿臋C(jī)制有：(1)營(yíng)養(yǎng)吸收不良：使用灌注研究發(fā)現(xiàn)，UC患者的腸液、電解質(zhì)的吸收顯著減少。GUSTAFSSON等[25]發(fā)現(xiàn)，即使是在緩解期，UC患者和正常人的腸道分泌能力也不同，即近端結(jié)腸黏膜對(duì)cAMP依賴的分泌更敏感，對(duì)Ca2+依賴的分泌不敏感。(2)通透性的變化：BüNING等[26]發(fā)現(xiàn)，遺傳因素導(dǎo)致UC患者的腸道通透性增加，也證實(shí)了UC患者即使是在緩解期，小腸通透性依然是增加的。(3)動(dòng)力紊亂：RANA等[27]認(rèn)為，UC患者還原性谷胱甘肽、IL-6、IL-8、TNF-α、IL-10失衡，脂質(zhì)過氧化等導(dǎo)致腸道蠕動(dòng)能力改變，進(jìn)而增加UC患者的SIBO發(fā)生率。ROLAND等[28]通過對(duì)37例或同時(shí)進(jìn)行乳果糖氫呼氣試驗(yàn)(lactulose breath testing，LBT)和無線動(dòng)力膠囊(wireless motility capsule, WMC, 又叫SmartPill)(一種全胃腸動(dòng)力檢測(cè)系統(tǒng)，可檢測(cè)壓力、pH和溫度[29]) 證明了口盲傳輸時(shí)間的延長(zhǎng)容易導(dǎo)致SIBO。另在UC患者中，結(jié)腸環(huán)肌中IL-1β增加，并可能通過過氧化氫的生成導(dǎo)致UC患者結(jié)腸運(yùn)動(dòng)功能障礙[30]。以上改變可能由于細(xì)胞因子和腸神經(jīng)系統(tǒng)的改變而引起。

3.2SIBO對(duì)UC的影響腸道菌群的改變目前被認(rèn)為是UC發(fā)生的重要機(jī)制之一[31]。腸道正常菌群(500～1 000種，總細(xì)胞數(shù)為1014)有很多功能：抑制病原菌生長(zhǎng)；加強(qiáng)上皮屏障作用；通過Toll樣受體通路，調(diào)節(jié)炎癥反應(yīng)[32]。臨床研究[33]表明，UC患者中厚壁菌門和擬桿菌減少，變形菌和放線菌增加。孫勇等[34]通過對(duì)比緩解期與活動(dòng)期UC患者的腸黏膜病理與腸道菌群，證明了菌群失調(diào)與腸道病理損傷有密切關(guān)系。UYGUN等[35]通過對(duì)30例UC患者進(jìn)行糞菌移植，發(fā)現(xiàn)30%患者無效，70%患者出現(xiàn)臨床癥狀減輕(其中另有總體30%的患者達(dá)到臨床和內(nèi)鏡下緩解)。多種益生菌被發(fā)現(xiàn)可以通過阻斷致病菌的有害作用維持腸道穩(wěn)態(tài)，增加上皮屏障完整性，促進(jìn)固有免疫，平衡炎性因子等多種機(jī)制維持UC的緩解，防止復(fù)發(fā)[36]。UC患者的菌群改變也許如被破壞的原始森林，很難完全恢復(fù)。

3.3利福昔明治療對(duì)UC的影響文獻(xiàn)[37]報(bào)道，利福昔明可以幫助UC患者達(dá)到臨床緩解。本試驗(yàn)中部分UC患者在應(yīng)用利福昔明后臨床癥狀也有明顯緩解。具體機(jī)制可能包括以下幾點(diǎn)：(1)利福昔明的直接殺菌活性。利福昔明為利福霉素衍生物，抗菌譜包括大部分革蘭氏陽性菌和革蘭氏陰性菌[38]。而且其不改變腸道菌群的構(gòu)成，還會(huì)增加部分益生菌數(shù)量[39]；(2)減少細(xì)菌黏附和內(nèi)化[40]；(3)激活孕烷受體X[41]。在動(dòng)物模型的炎癥性腸病，利福昔明產(chǎn)生治療效果通過激活孕烷X受體，從而減少NF-κB水平；(4)抑制細(xì)菌移位[42]。需要指出的是，利福昔明對(duì)SIBO的清除率可達(dá)70%[43-44]。B組根除SIBO后，理論上仍有約30%陽性患者，由于時(shí)間限制，本試驗(yàn)未進(jìn)一步研究?？紤]到B組可能仍有30%SIBO陽性患者，所有患者根除SIBO后，B組的癥狀、炎性因子可能會(huì)有進(jìn)一步的改善。

綜上，本研究發(fā)現(xiàn)，UC患者的SIBO陽性率明顯高于健康人，利福昔明根除SIBO后，部分UC患者癥狀、炎性指標(biāo)明顯緩解。闡釋了SIBO在UC中的作用，并提出了利福昔明的治療方案。

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