溃疡性结肠炎与小肠细菌过度生长关系探讨

刘治宏，崔立红

1.陆军军医大学研究生院，重庆 400038；2.海军总医院消化内科

溃疡性结肠炎(ulcerative colitis, UC)表现为肠道慢性非特异性炎症，具有复发、缓解的病程特点。UC发病率较高[1]，整体发病率为1.2～20.3例每年每100 000人，患病率为7.6～245例每年每100 000人[2]。患者通常出现血性腹泻和腹部绞痛等症状[3]。流行病学表明,UC发病率的升高伴随着社会西方化和工业化的进程，正如自1990年以来，UC在西方国家的发生率基本稳定，但在新兴工业化国家呈上升的趋势[4]。尽管有许多遗传和环境因素已被发现增加了该病的发病率[5]，但UC的确切发病机制目前仍不明确。

小肠细菌过度生长(small intestinal bacterial overgrowth, SIBO)是外来细菌或肠道内常驻细菌数量增加导致的食物过度发酵、黏膜炎症、小肠通透性破坏、吸收不良、绒毛损伤[6]。SIBO与很多疾病密切相关，如非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)[7]、肠易激综合征[8]、深静脉血栓(deep vein thrombosis, DVT)[9-10]、糖尿病[11-12]、胃肠道肿瘤[13]、帕金森[14-15]、炎症性肠病[16]等。呼气试验有廉价、简便、非侵入性等优点，本试验采用此方法检测SIBO[17]。

目前，关于UC与SIBO的关系报道甚少。本文通过检测轻-中度UC患者的甲烷-氢气呼气试验，探讨UC患者与SIBO之间的关系。

1 资料与方法

1.1一般资料选取2016年6月至2017年12月海军总医院就诊，并同时完善甲烷-氢气呼气试验的轻-中度UC患者，共120例，男64例，女56例，男女比例1.14∶1,年龄(38.6±9.5)岁。对照组选取同期来院体检健康者60名，男31名，女29名，男女比例1.07∶1，年龄(39.0±9.0)岁。两组性别、年龄比较，差异均无统计学意义(P>0.05)，具有可比性。

1.2排除标准(1)肝脏病变、急性感染、其他慢性炎性疾病及妊娠患者；(2)行结肠切除术的UC患者，因其可能会导致口盲传输时间(orocecal transit time，OCTT)(OCTT为小肠传递时间，主要反映小肠传输功能[18])延长，从而导致SIBO阳性；(3)在试验开始前1个月内使用抗生素和益生菌的患者；(4)糖尿病患者，因糖尿病扰乱了自主神经功能，可能导致胃肠功能紊乱、菌群失调等[19]；(5)长期应用PPI、萎缩性胃炎患者，因其胃酸减少可能导致SIBO。研究[20-21]认为，PPI和胃大部切除术等可能引起胃酸分泌减少的情况会引起SIBO；(6)肥胖患者。

1.3甲烷-氢气呼气试验受检者口服底物前需漱口，而后向采气袋内吹入气体，之后30 min服用乳果糖10 ml，自此每隔30 min重复上述步骤采气，直至收集8个采气袋。最后由甲烷-氢气呼出气体分析仪 (BreathTracker)(美国Quintron公司)检测呼出气体。

注意事项：空腹8 h以上接受检查，整个过程禁食，可饮水；晨起后禁止吸烟；检测过程中不做剧烈运动。

SIBO的诊断标准(口服乳果糖120 min内存在以下任意一种情况即可)：

(1)氢气浓度>基础值20 ppm；

(2)甲烷浓度升高>基础值12 ppm；

(3)甲烷和氢气浓度之和升高>基础值15 ppm；

(4)整个检查过程中出现双峰曲线。

1.4治疗及分组采用随机数字法，对UC患者中存在SIBO的，分成A、B两组，A组给予美沙拉嗪(0.5 g，上海爱的发制药有限公司)治疗(1 g，4次/d，6周)；B组给予美沙拉嗪(1 g，4次/d，6周)和利福昔明(0.2 g，ALFA WASSERMANN制药公司)(0.2 g，4次/d，14 d)治疗，再比较两组的临床疗效、ESR和CRP。两组均进行健康的饮食、生活教育。

1.5临床疗效临床疗效评价参照既往文献共识[22-23]标准。总有效率=完全缓解+显效+有效(见表1)。

表1 临床疗效评价标准Tab 1 Clinical efficacy evaluation standard

注：相应诊断符合①+②或③，即可诊断。

1.6ESR、CRP检测分别于治疗前、后采集患者清晨空腹静脉血，检测ESR、CRP。

2 结果

2.1试验组、对照组SIBO阳性率结果比较试验组120例患者中，SIBO(+)53例，阳性率44.2%；对照组60名健康体检者，SIBO(+)13名，阳性率21.7%。试验组SIBO阳性率明显高于对照组，差异有统计学意义(χ2=8.720，P<0.001)。

2.2A、B组临床疗效比较利福昔明根除SIBO后可提高美沙拉嗪对UC的临床疗效。A组的总有效率是80.77%，B组是92.59%，B组的疗效明显优于A组(P<0.05，见表2)。

表2 A、B组间疗效比较Tab 2 Comparison of efficacy between group A and group B

2.3ESR、CRP比较利福昔明根除SIBO后，ESR、CRP较根除治疗前明显降低，治疗后B组ESR、CRP明显低于A组(P<0.01，见表3)，提示根除SIBO有助于UC病情缓解。

表3 各组治疗前后ESR、CRP变化Tab 3 Changes of ESR, CRP before and after treatment in each group

3 讨论

3.1UC对SIBO的影响UC一般局限于结肠，偶尔延伸到回肠末端。但通过试验，我们发现，UC患者的SIBO阳性率高于健康人群。国外也有研究[24]发现，UC患者及动物模型存在小肠功能异常，可以表现为肠液减少，D-木糖、氨基酸和脂肪的吸收减少等方面。可能的机制有：(1)营养吸收不良：使用灌注研究发现，UC患者的肠液、电解质的吸收显著减少。GUSTAFSSON等[25]发现，即使是在缓解期，UC患者和正常人的肠道分泌能力也不同，即近端结肠黏膜对cAMP依赖的分泌更敏感，对Ca2+依赖的分泌不敏感。(2)通透性的变化：BÜNING等[26]发现，遗传因素导致UC患者的肠道通透性增加，也证实了UC患者即使是在缓解期，小肠通透性依然是增加的。(3)动力紊乱：RANA等[27]认为，UC患者还原性谷胱甘肽、IL-6、IL-8、TNF-α、IL-10失衡，脂质过氧化等导致肠道蠕动能力改变，进而增加UC患者的SIBO发生率。ROLAND等[28]通过对37例或同时进行乳果糖氢呼气试验(lactulose breath testing，LBT)和无线动力胶囊(wireless motility capsule, WMC, 又叫SmartPill)(一种全胃肠动力检测系统，可检测压力、pH和温度[29]) 证明了口盲传输时间的延长容易导致SIBO。另在UC患者中，结肠环肌中IL-1β增加，并可能通过过氧化氢的生成导致UC患者结肠运动功能障碍[30]。以上改变可能由于细胞因子和肠神经系统的改变而引起。

3.2SIBO对UC的影响肠道菌群的改变目前被认为是UC发生的重要机制之一[31]。肠道正常菌群(500～1 000种，总细胞数为1014)有很多功能：抑制病原菌生长；加强上皮屏障作用；通过Toll样受体通路，调节炎症反应[32]。临床研究[33]表明，UC患者中厚壁菌门和拟杆菌减少，变形菌和放线菌增加。孙勇等[34]通过对比缓解期与活动期UC患者的肠黏膜病理与肠道菌群，证明了菌群失调与肠道病理损伤有密切关系。UYGUN等[35]通过对30例UC患者进行粪菌移植，发现30%患者无效，70%患者出现临床症状减轻(其中另有总体30%的患者达到临床和内镜下缓解)。多种益生菌被发现可以通过阻断致病菌的有害作用维持肠道稳态，增加上皮屏障完整性，促进固有免疫，平衡炎性因子等多种机制维持UC的缓解，防止复发[36]。UC患者的菌群改变也许如被破坏的原始森林，很难完全恢复。

3.3利福昔明治疗对UC的影响文献[37]报道，利福昔明可以帮助UC患者达到临床缓解。本试验中部分UC患者在应用利福昔明后临床症状也有明显缓解。具体机制可能包括以下几点：(1)利福昔明的直接杀菌活性。利福昔明为利福霉素衍生物，抗菌谱包括大部分革兰氏阳性菌和革兰氏阴性菌[38]。而且其不改变肠道菌群的构成，还会增加部分益生菌数量[39]；(2)减少细菌黏附和内化[40]；(3)激活孕烷受体X[41]。在动物模型的炎症性肠病，利福昔明产生治疗效果通过激活孕烷X受体，从而减少NF-κB水平；(4)抑制细菌移位[42]。需要指出的是，利福昔明对SIBO的清除率可达70%[43-44]。B组根除SIBO后，理论上仍有约30%阳性患者，由于时间限制，本试验未进一步研究。考虑到B组可能仍有30%SIBO阳性患者，所有患者根除SIBO后，B组的症状、炎性因子可能会有进一步的改善。

综上，本研究发现，UC患者的SIBO阳性率明显高于健康人，利福昔明根除SIBO后，部分UC患者症状、炎性指标明显缓解。阐释了SIBO在UC中的作用，并提出了利福昔明的治疗方案。

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