肠道菌群与代谢在慢性荨麻疹发病机制中的研究进展

Research progress in gut microbiota and metabolism in the pathogenesis of chronic urticaria

摘要

慢性荨麻疹(chronic urticaria，CU)是一种病程迁延的免疫性皮肤病，其发病机制尚未完全阐明。肠道菌群作为人体最大的微生态系统，参与复杂的代谢活动，并衍生大量代谢产物。肠道菌群-代谢在CU发生和发展中具有重要作用。CU患者普遍存在肠道菌群失调，主要表现为有益菌减少和机会致病菌增多，并伴随关键代谢产物的改变。这些改变可通过破坏肠道屏障、调节肥大细胞及T细胞等免疫细胞的功能等作用，驱动或加剧远端的皮肤炎症反应，参与CU的病理过程。特定的菌群与代谢物可作为CU临床诊断、疗效预测以及预后评估的潜在生物标志物，靶向肠道菌群的干预措施也展现出改善CU症状的治疗潜力。探究CU患者肠道菌群与代谢的特征和其在发病机制中的作用及临床意义，有望为寻找CU个体化的诊疗新靶点提供理论依据。

Abstract

Chronic urticaria (CU) is a persistent immune-mediated skin disease with an incompletely understood pathogenesis. As the largest micro-ecosystem in the human body, the gut microbiota participates in complex metabolic processes and produces a wide range of metabolites. The gut microbiota-metabolism axis plays a crucial role in the onset and progression of CU. Patients with CU commonly exhibit gut dysbiosis, characterized by a reduction in beneficial bacteria and an increase in opportunistic pathogens, accompanied by alterations in key metabolites. These changes may disrupt the intestinal barrier and modulate the function of immune cells such as mast cells and T cells, thereby triggering or aggravating distal cutaneous inflammation and contributing to CU pathophysiology. Certain bacterial taxa and metabolites hold promise as potential biomarkers for CU diagnosis, therapeutic response, and prognosis, while interventions targeting gut microbiota have demonstrated potential in ameliorating CU symptoms. Elucidating the characteristics and mechanistic roles of gut microbiota and metabolism in CU could provide a theoretical basis for developing novel individualized diagnostic and therapeutic strategies.

关键词

慢性荨麻疹 / 发病机制 / 肠道菌群 / 代谢组学 / 代谢生物标志物 / 微生物疗法

Key words

chronic urticaria / pathogenesis / gut microbiota / metabolomics / metabolite biomarkers / microbiota therapy

慢性荨麻疹(chronic urticaria，CU)是一种以伴有不同程度瘙痒的风团和/或血管性水肿为特征、持续时间大于6周的免疫相关性皮肤病^[1]。CU根据症状的发生有无明确的诱发因素分为慢性自发性荨麻疹(chronic spontaneous urticaria，CSU)和慢性诱导性荨麻疹(chronic inducible urticaria，CIndU)^[2]。临床上，CSU比CIndU更为常见，且二者可以在同一患者身上同时存在^[3]。CIndU中最常见的临床类型是症状性皮肤划痕症(symptomatic dermographism，SD)。中国成人CU的患病率为2.6%^[4]，其危险因素包括遗传^[5]、女性、环境^[6]、糖尿病和高血脂等代谢异常^[7]及精神心理因素^[8]等。CU发病机制涉及自身免疫、凝血级联反应和补体途径异常、肥大细胞(mast cells，MCs)活化及与多种免疫细胞(如嗜碱性粒细胞、嗜酸性粒细胞和T细胞)相互作用、神经免疫、肠道菌群-代谢等^[9-13]。其中MCs的活化和脱颗粒及随后释放的炎症介质是CU的主要驱动因素^[14]。

肠道菌群-代谢研究近年来逐渐受到关注。肠道微生物组，包括肠道菌群、其基因组及代谢产物^[15]，是肠道-皮肤轴的主要调节因子^[16]。研究^[17]表明肠道菌群失衡与包括CU在内的某些皮肤疾病的发生和发展有关。肠道菌群可以产生多种代谢物，在宿主体内作为代谢反应的信号分子和底物发挥作用^[18]。由于代谢物的特征非常接近个体表型的维度，其对于疾病诊断、预后及治疗有较大的预测作用^[19]。通过代谢组学对小分子代谢物(50~1 500 D，1 D=1 u)^[20]进行高通量研究，可以为疾病机制研究和治疗靶点发掘提供新思路。

1 肠道菌群研究现状与技术应用

当前肠道菌群-代谢研究主要分析疾病患者与健康人群的肠道菌群组成及代谢产物差异，以探索其在疾病发生和发展中的作用，并挖掘潜在生物标志物和治疗靶点，为免疫性、炎症性和代谢性疾病的机制探索、诊断和治疗提供新思路。高通量测序技术，包括16S核糖体RNA(ribosomal RNA，rRNA)测序、宏基因组测序、宏转录组测序和宏病毒组测序，推动了肠道菌群研究的快速发展，标志着肠道菌群研究进入一个新时代^[21]。单细胞测序技术通过分析单个细胞的基因组或转录组信息，克服了传统群体测序的均值限制，可更精准地解析细胞异质性和功能差异。此外，生物信息学分析整合了16S rRNA测序、宏基因组、转录组、蛋白质组和代谢组等多组学数据，有助于更全面地揭示微生物群落功能及其与宿主的互作机制^[22]。粪便微生物移植(fecal microbiota transplantation，FMT)将健康供体的功能菌群移植至受体消化道，可重塑受体失衡的肠道微生态，恢复肠道菌群多样性和稳态^[23]。目前，16S rRNA测序、宏基因组学、代谢组学和FMT等技术已广泛应用于CU患者肠道菌群及代谢特征的研究，以探索其潜在致病机制和治疗策略。

2 <bold>CU</bold>患者肠道菌群的特点

在健康成人中，肠道菌群或肠道微生物群[包括细菌(占99%以上)、真菌、病毒、古菌和寄生虫]在人体发挥多重生理作用^[24]，如形成重要的生物屏障进而保护肠黏膜^[25]、参与代谢活动以及免疫系统的发育和调节等^[26]。肠道菌群的组成和功能受年龄、遗传、饮食、药物、污染、运动和疾病等影响^[27]。在健康成人^[28]和CSU患者^[29-30]的肠道菌群组成中，拟杆菌门(Bacteroidetes)和厚壁菌门(Firmicutes)通常占主导地位，其次是放线菌门(Actinobacteria)、变形菌门(Proteobacteria)和疣微菌门(Verrucomicrobia)。与健康人群相比，CSU患者的肠道菌群α多样性在不同研究中变化不同，可为增高^[29]、降低^[30-32]或差异无统计学意义^[33-34]，这可能与不同研究人群的遗传背景、临床特征、饮食生活习惯、居住环境、样本量和研究方法等因素有关^[29]。CSU患者的β多样性则存在显著差异^{[29, 32-33, 35]}，表明CSU患者的微生物群落结构发生了变化，且不同CSU患者之间微生物群落差异更大。在CSU患者中，机会致病菌如变形菌门(Proteobacteria)^[36][包括未鉴定的肠杆菌科(Enterobacteriaceae)^[30]、肺炎克雷伯菌(Klebsiella pneumoniae)及大肠杆菌(Escherichia coli)^[31]]和霍尔德曼菌属(Holdemania)^{[31, 34]}的丰度增加，而产生短链脂肪酸(short-chain fatty acids，SCFAs)的细菌如拟杆菌属(Bacteroides)^[30]、乳杆菌属(Lactobacillus)^[37]、双歧杆菌属(Bifidobacterium)^{[30, 37]}、瘤胃球菌属(Ruminococcus)^[33]、罗斯拜瑞氏菌属(Roseburia)^[31]和毛螺菌科(Lachnospiraceae)^[32]的丰度则减少。一项病例对照研究^[38]发现：SD患者的肠道菌群多样性显著降低，与健康对照(healthy controls，HCs)相比，SD患者的肠道菌群α多样性显著降低，β多样性也显示出显著差异；SD患者的疣微菌门(Verrucomicrobia)丰度和有益的瘤胃菌科(Ruminococcaceae)丰度减少，而与炎症相关的肠杆菌目(Enterobacteriales)丰度则显著升高。Liu等^[39]采用16S核糖体DNA(ribosomal DNA，rDNA)基因测序发现慢性自发性荨麻疹合并皮肤划痕症(chronic spontaneous urticaria and symptomatic dermographism，CSD)患者肠道菌群的α多样性降低，且肠道菌群结构显著变化，CSD患者中罕见小球菌(Subdoligranulum)和布氏瘤胃球菌(Ruminococcus bromii)等产生SCFAs的细菌相对丰度降低，而肠杆菌科(Enterobacteriaceae)和克雷伯氏菌属(Klebsiella)等机会性病原体的相对丰度增加。Wang等^[33]对39例CSU患者和40例HCs的粪便样本进行16S rRNA基因测序，发现苏黎世杆菌属(Turicibacter)丰度增加。有研究^[40]表明血苏黎世杆菌种(Turicibacter sanguinis)表达一种与5-羟色胺具有序列和结构同源性的Na⁺-神经递质同向转运体相关蛋白质，而5-羟色胺可能参与了CSU的发病^[41]。CU患者的幽门螺杆菌(Helicobacter pylori，HP)感染率高于HCs^[42]，且有荟萃分析^[43]表明HP感染与CU的发生有关。这可能由于HP 21~35 kD的混合蛋白质成分可有效刺激CSU中MCs脱颗粒^[44]。肠道菌群可能参与了CU的发生和发展。

值得注意的是，肠道菌群的改变与CU之间的关系可能是双向的。一项孟德尔随机化研究^[45]发现不同CU亚型可能导致特定菌群的丰度发生因果性改变。遗传预测的SD与α-变形菌纲(Alphaproteobacteria)和粪球菌属1(Coprococcus1)等菌群的丰度降低存在因果关联；而温度触发性荨麻疹(由寒冷和炎热共同引起的荨麻疹)则可能因果性地导致有益的瘤胃菌科(Ruminococcaceae)丰度下降，并促进与炎症相关的脱硫弧菌属(Desulfovibrio)丰度增加。这些发现支持了肠-皮肤轴的双向互作模型，提示疾病状态本身可能重塑肠道微生态，形成一种维持或加剧疾病的恶性循环。

3 <bold>CU</bold>患者肠道菌群代谢产物的特点

近年来多项研究表明，CU患者肠道菌群的代谢产物与健康人存在显著差异。Luo等^[29]对CSU患者和HCs进行非靶向代谢组学分析显示：CSU组不饱和脂肪酸[如(±)8-HETE、γ-亚麻酸、花生四烯酸]表达水平下降，不饱和脂肪酸的代谢通路下调。Wang等^[30]采用类似方法比较了CSU患者和HCs肠道菌群及其代谢产物的差异，发现CSU患者血清二十二碳六烯酸(docosahexaenoic acid，DHA)、花生四烯酸(arachidonic Acid，AA)、谷氨酸和琥珀酸水平降低，提示不饱和脂肪酸和丁酸盐代谢途径发生变化。笔者团队^[31]的既往研究表明CSU患者血清中的SCFAs水平降低和脂多糖(lipopolysaccharide，LPS)水平升高，且血清中己酸盐水平与SCFAs产生菌水平呈正相关，与肺炎克雷伯菌(Klebsiella pneumoniae)和大肠杆菌(Escherichia coli)等机会致病菌水平呈负相关；而血LPS水平与SCFAs产生菌呈负相关，与机会致病菌呈正相关。另有研究^[33]通过非靶向代谢组学分析显示：CSU患者的异丁酸、3-吲哚丙酸 (3-indolepropionic acid，IPA)和黄嘌呤减少，且黄嘌呤与患者确诊为CSU的时长呈负相关。

4 肠道菌群代谢产物在<bold>CU</bold>发生和发展中的作用

多种肠道菌群相关代谢产物(如SCFAs、LPS等)，通过作用于MCs、T细胞等免疫细胞或通过影响肠道黏膜屏障功能，参与肠道炎症过程及CU的发生和发展(表1)。

4.1 SCFAs

SCFAs是碳原子数为1~6的有机羧酸，是特定肠道微生物群发酵抗性淀粉和膳食纤维的最终产物，主要包括乙酸盐、丙酸盐、丁酸盐、异丁酸酯、戊酸酯和异戊酸酯等^[46]。SCFAs具有多种生物学效应，通过促进上皮细胞增殖、更新和修复^[47]，增强肠上皮细胞的耗氧量以稳定缺氧诱导因子的表达^[48]，增加紧密连接蛋白[如ZO-1和occludin-1^{[31, 49]}、claudin-2^[50]和黏蛋白2(mucin 2，MUC-2)^{[31, 51]}]的表达，以及诱导抗菌肽的产生^[52]，从而防止病原菌和有害物质(如内毒素)进入血液，促进上皮屏障功能。SCFAs可以调节肠道病原体[如大肠杆菌(Escherichia coli)和克雷伯氏菌属(Klebsiella)及白色念珠菌(Candida albicans)]的生长和毒力^[53-54]。上皮屏障功能障碍、组织重塑、微生物组改变和免疫失调等病理生理学特征，共同推动包括CU在内的Ⅱ型慢性炎症性疾病的进程，使病情持续恶化并影响治疗反应^[55]。丁酸盐还可以通过促进角质形成细胞的代谢和分化来调节皮肤屏障的完整性^[56]。有研究^[57]表明皮肤屏障功能受损可能易导致包括荨麻疹在内的幼儿皮肤病。皮肤屏障受损时，空气过敏原更容易进入体内，触发神经元释放P物质，通过G蛋白偶联受体Mas相关基因PRB2导致MCs脱颗粒释放组胺和前列腺素D2，引发CU^[58]。SCFAs是肠-皮肤轴的信号因子，有助于缓解皮肤炎症^[59]。SCFAs具有调节多种免疫细胞的活化和细胞因子的作用。SCFAs通过与MCs上表达的受体，如G蛋白偶联受体43^[60]、G蛋白偶联受体109A^[61]和过氧化物酶体增殖物激活受体γ^[62]结合，来抑制炎症反应。丙酸盐和丁酸盐可以通过抑制组蛋白去乙酰化酶来抑制免疫球蛋白E(immunoglobulin E，IgE)和非IgE介导的人或小鼠MCs脱颗粒，mmol水平的丙酸盐和丁酸盐对IgE/抗原诱导的小鼠和人MCs脱颗粒的抑制高达90%^[63]。丁酸盐和丙酸盐还可以诱导调节性T细胞(regulatory T cells，Tregs)的分化和细胞数量的增加^[64-65]，进而调节参与CSU发病的Ⅱ型炎症细胞CD4⁺辅助性T细胞2(T helper 2 cell，Th2)的分化及其相关细胞因子如白细胞介素(interleukin，IL)-4和IL-13的产生^[66-67]。丁酸盐还可以抑制Th17细胞的分化^[68]并减少促炎因子IL-17的分泌^[69]。CSU患者外周血Th17细胞百分比增加及IL-17、IL-21和转化生长因子-β1水平升高，且与瘙痒水平、生活质量和疾病严重程度呈正相关；相反，外周血Tregs细胞的比例与这些临床参数之间则呈负相关^[55]。

4.2 LPS

LPS作为革兰氏阴性菌细胞壁的一种成分，本身可以下调特定的紧密连接蛋白(如occludin和claudin-1^[70])，损害上皮屏障的完整性。从肠腔渗透到血液循环^[71]后，可通过Toll样受体4(Toll-like receptor 4，TLR4)促进IgE诱导的MCs脱颗粒^[72]以及激活MCs产生各种炎症介质，如肿瘤坏死因子-α(tumor necrosis factor-α，TNF-α)和IL-13^{[31, 73]}。此外，LPS还可通过TLR4直接激活巨噬细胞，诱导炎症介质(如TNF-α和IL-6)的释放^[74]。

4.3 不饱和脂肪酸

肠道菌群参与多不饱和脂肪酸(polyunsaturated fatty acids，PUFAs)，尤其是亚油酸的代谢过程(将亚油酸转化为共轭亚油酸)，控制宿主肠道上皮内免疫稳态^[75]。ω-3 PUFAs通过改变肠道菌群的组成对肠黏膜屏障具有保护作用^[76]。亚油酸作为神经酰胺的基本成分对于保持皮肤屏障完整性至关重要^[77]。不饱和脂肪酸如AA、二十碳五烯酸(eicosapentaenoic acid，EPA)和DHA还存在于免疫系统细胞的细胞膜中，促进免疫系统发育成熟^[78]。PUFAs具有抗炎特性^[79]和促进炎症消退的作用^[79-80]。PUFAs可能通过促炎与抗炎的类花生酸比例的改变来缓解炎症性皮肤病(如特应性皮炎、银屑病等)相关的症状^[81]。也有研究^[82]发现CU患者中ω-6和ω-3系列的PUFAs水平较高，ω-6和ω-3系列的PUFAs及脂质过氧化可能参与了CU的发病机制。在炎症背景下，ω-3和ω-6 PUFAs及其脂质介质之间的相互作用复杂且尚未被充分理解^[83]。

4.4 IPA

IPA是一种膳食色氨酸代谢物，完全由肠道生孢梭菌(Clostridium sporogenes)产生^[84]，并从肠道吸收入血^[85]。IPA具有减轻肠道炎症和调节肠道微生物群的能力^[86]。IPA可以通过与孕烷X受体^[87]、热激蛋白70^[88]相互作用，缓解肠道炎症、保护肠道黏膜。CSU患者体内IPA的降低可能与其持续的炎症状态有关^[33]。

5 <bold>CU</bold>中潜在肠道菌群<bold>-</bold>代谢的生物标志物

一项横断面病例对照研究^[90]发现CSU患者的厚壁菌门(Firmicutes)/拟杆菌门(Bacteroidetes)(F/B)比值较高，且作为炎症标志物与疾病活动度和控制不佳有关。毛螺菌属(Lachnospira)在地氯雷他定应答者中比无应答者更丰富，是预测CSU患者抗组胺药疗效的标志物^[91]。另有研究^[92]发现罕见小球菌(Subdoligranulum)和罗氏菌属的布氏瘤胃球菌(Ruminococcus bromii)在健康人群中富集，其受试者操作特征(receiver operating characteristic，ROC)曲线的曲线下面积分别高达0.914和0.921，可作为诊断SD的潜在生物标志物，而粪便普氏菌(Prevotella stercorea)的丰度则与SD的病程呈负相关，提示其可能与疾病的慢性化过程有关。Liu等^[39]的研究发现罕见小球菌(Subdoligranulum)和布氏瘤胃球菌(Ruminococcus bromii)还对CSD具有潜在的诊断价值；肠杆菌科(Enterobacteriaceae)和克雷伯氏菌属(Klebsiella)对CSD病程具有潜在预测价值，而双孢梭菌(Clostridium disporicum)对CSD患者皮肤病生活质量指数(dermatology quality of life index，DLQI)具有潜在预测价值。

Kocak等^[93]首次使用液相色谱-四极杆飞行时间质谱探讨CU的代谢改变，结果表明：与HCs相比，CU患者的尿囊酸、尿黑酸、吲哚乙酸、脯氨酸和苯丙氨酸减少，而色氨酸、亚精胺、赖氨酸、缬氨酸、鸟氨酸、组氨酸、谷氨酸、亮氨酸和酪氨酸等增加，通过分析个体的代谢谱可以诊断CU。笔者团队^[7]采用非靶向脂质组学研究CU患者和HCs之间的脂质代谢差异，结果发现：与HCs相比，CU患者的血浆甘油磷脂中的磷脂酰丝氨酸、磷脂酰乙醇胺和磷脂酰甘油增加，而磷脂酰胆碱减少，磷脂酰胆碱对CU疾病活动具有潜在的预测价值，磷脂酰丝氨酸则可为评估CU患者生活质量的潜在预测指标。此研究^[7]还根据脂质特征发现CU的不同代谢亚型，其中磷脂酰乙醇胺(36꞉3)是CSU特异性的分型标志物，而甘油二酯(diacylglycerol，DG)代谢物，如DG(18꞉0/18꞉1)、DG(18꞉1/18꞉1)和DG(20꞉1/18꞉1)，是CSD的分型特征标志物。通过高效液相色谱比较CSU患者和HC血浆中的腺苷(adenosine，ADO)水平，发现CSU患者的ADO水平升高，重度CSU患者ADO水平高于中度和轻度CSU患者，且高ADO水平与7日荨麻疹活动度评分和第2代H1抗组胺药的疗效显著相关，表明ADO可能是预测CSU患者疾病活动和治疗结局的新候选生物标志物^[94]。进一步对CU患者和HCs的血浆样本进行靶向和非靶代谢组学分析发现，与HCs相比，CU患者的血浆L-天冬氨酸增加而N6-乙酰基-L-赖氨酸、马来酸和丙酮酸降低，4种小分子物质具有作为CU诊断生物标志物的潜力；其中血浆丙酮酸和马来酸可能是预测CU患者疾病活动度、第2代H1抗组胺药疗效和预后的有效生物标志物^[95]。目前CU中潜在肠道菌群-代谢的生物标志物总结见表2。

6 肠道菌群在<bold>CU</bold>中的潜在治疗应用

CU与肠道菌群失调在发病机制层面的密切关联，为开发靶向肠道微生态的干预新策略提供了理论依据。重塑CU患者失衡的肠道菌群，可以恢复其有益的代谢和免疫调节功能，进而阻断肠-皮肤轴的病理级联反应，最终改善远端皮肤的炎症症状。目前，以益生菌和FMT为代表的干预措施，已在临床研究中展现出治疗CU的潜力。

6.1 益生菌

益生菌干预是目前研究最深入、证据最丰富的调节策略。一项包含了多项随机对照试验(randomized controlled trial，RCT)的系统评价和荟萃分析^[96]指出，与安慰剂相比，益生菌作为CU的辅助治疗，能够显著提高临床总有效率[危险比(risk ratio，RR)=1.30]和完全缓解率(RR=1.60)，并有效降低患者的症状评分。具体的临床研究亦提供了有力的例证，且在不同年龄段患者中均观察到积极效果。一项针对206例CU患儿的大样本RCT^[97]证实：在常规疗法基础上联用包含乳杆菌属(Lactobacillus)和双歧杆菌属(Bifidobacteria)的益生菌制剂，可有效降低患儿的临床症状评分、风团大小和发作频率。益生菌对CU成年患者同样具有治疗潜力。一项针对难治性CSU患者的研究^[98]发现，补充唾液乳杆菌(Lactobacillus salivarius)LS01和短双歧杆菌(Bifidobacterium breve)BR03后，患者的荨麻疹活动度评分及生活质量均得到改善。而另一项针对成年CU患者的RCT^[99]则发现，尽管益生菌干预组的主要症状评分与安慰剂组差异无统计学意义，但其DLQI得到了显著改善。这些研究共同支持了益生菌对CU的潜在治疗作用。

6.2 FMT

FMT通过将健康供体的功能性菌群移植给患者，对患者失调的肠道微生态进行系统性的重塑。Zhu等^[31]的动物研究为FMT对CSU的潜在治疗作用提供了证据。研究者将CSU患者的粪便菌群移植给无菌小鼠，成功在小鼠体内复现了CSU的核心症状(如皮肤肥大细胞活化、血管通透性增加等)。CSU模型鼠接受来自健康人的FMT后，其“荨麻疹样”症状得到了显著缓解。FMT对CSU患者的潜在治疗作用在临床实践中也得到了初步印证^[92]。1例伴有阵发性胃部不适的难治性荨麻疹女性患者在接受了多供体、多疗程的FMT治疗后，其临床症状获得了完全且持续的缓解，在随访1年后成功停药，并恢复了正常饮食和社交生活。治疗后的16S rRNA测序分析证实了其肠道菌群发生了显著的改变：普氏菌属(Prevotella)的相对丰度显著增加，且患者的F/B比值也从治疗前的极高水平(1.68)恢复至正常范围(0.30)。未来FMT对CU的治疗需要更大规模的RCT来验证其临床疗效和安全性。

7 结 语

CU的肠道菌群与健康人群相比，存在多样性差异，其部分关键代谢产物可通过影响肠道上皮屏障功能、皮肤屏障功能、免疫细胞的活化及炎症介质的释放等，在CU的发生和发展中发挥作用。目前肠道菌群代谢产物中SCFAs在CSU中的相关研究较多，但其他较少涉及的代谢产物^[26]如低聚半乳糖、低聚果糖、γ-氨基丁酸和芳香烃受体的配体如色氨酸等也可能参与CU的发病，有待进一步探索。借助肠道菌群-代谢-免疫轴寻找CU的代谢分型、潜在生物标志物及干预新靶点，并开展更大规模、设计更严谨的多中心RCT，以验证潜在生物标志物的临床应用价值、评估不同菌群干预方案(如特定益生菌组合和FMT)的长期疗效与安全性，进一步探索个体化精准医学防治手段，或将成为未来CU研究的重要方向。总之，系统解析CU患者的肠道菌群动态及其多维度代谢特征谱，不仅可为临床分型、诊断和预后提供新型生物标志物，还将为个体化靶向干预策略的制订奠定理论依据。

参考文献

[1] 中华医学会皮肤性病学分会荨麻疹研究中心. 中国荨麻疹诊疗指南(2022版)[J]. 中华皮肤科杂志, 2022, 55(12): 1041-1049.

[2] Centre for Urticaria Research, Chinese Society of Dermatology. Guideline for diagnosis and treatment of urticaria in China(2022)[J]. Chinese Journal of Dermatology, 2022, 55(12): 1041-1049.

[3] Zuberbier T, Latiff AHA, Abuzakouk M, et al. The international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria[J]. Allergy, 2022, 77(3): 734-766.

[4] Kolkhir P, Giménez-Arnau AM, Kulthanan K, et al. Urticaria[J]. Nat Rev Dis Primers, 2022, 8: 61.

[5] Zhang X, Song X, Zhang M, et al. Prevalence and risk factors of chronic urticaria in China: a nationwide cross-sectional study[J]. Allergy, 2022, 77(7): 2233-2236.

[6] Li J, Guo A, Chen W, et al. Association of ORAI1 gene polymorphisms with chronic spontaneous urticaria and the efficacy of the nonsedating H1 antihistamine desloratadine[J]. J Allergy Clin Immunol, 2017, 139(4): 1386-1388.

[7] Wang Y, Tang N, Mao M, et al. Fine particulate matter (PM_2.5) promotes IgE-mediated mast cell activation through ROS/Gadd45b/JNK axis[J]. J Dermatol Sci, 2021, 102(1): 47-57.

[8] Li J, Li L, Liu R, et al. Integrative lipidomic features identify plasma lipid signatures in chronic urticaria[J]. Front Immunol, 2022, 13: 933312.

[9] Huang Y, Xiao Y, Jing D, et al. Association of chronic spontaneous urticaria with anxiety and depression in adolescents: A mediation analysis[J]. Front Psychiatry, 2021, 12: 655802.

[10] 梁云生, 黎展宏, 伍奕蓓. 从发病机制认知变化看慢性自发性荨麻疹治疗进展[J]. 中华皮肤科杂志, 2023, 56(6): 552-558.

[11] LIANG Yunsheng, LI Zhanhong, WU Yibei. Progress in the treatment of chronic spontaneous urticaria: insights from the changes in the understandingofitspathogenesis[J]. Chinese Journal of Dermatology, 2023, 56(6): 552-558.

[12] Kolkhir P, Bonnekoh H, Metz M, et al. Chronic spontaneous urticaria: a review[J]. JAMA, 2024, 332(17): 1464-1477.

[13] 王佳怡, 李捷. 慢性荨麻疹发病机制的研究进展[J]. 中南大学学报(医学版), 2023, 48(10): 1602-1610.

[14] WANG Jiayi, LI Jie. Research progress in the pathogenesis of chronic urticaria[J]. Journal of Central South University. Medical Science, 2023, 48(10): 1602-1610.

[15] Kolkhir P, Muñoz M, Asero R, et al. Autoimmune chronic spontaneous urticaria[J]. J Allergy Clin Immunol, 2022, 149(6): 1819-1831.

[16] Zhou B, Li J, Liu R, et al. The role of crosstalk of immune cells in pathogenesis of chronic spontaneous urticaria[J]. Front Immunol, 2022, 13: 879754.

[17] Zuberbier T, Ensina LF, Giménez-Arnau A, et al. Chronic urticaria: unmet needs, emerging drugs, and new perspectives on personalised treatment[J]. Lancet, 2024, 404(10450): 393-404.

[18] Marchesi JR, Ravel J. The vocabulary of microbiome research: a proposal[J]. Microbiome, 2015, 3: 31.

[19] Salem I, Ramser A, Isham N, et al. The gut microbiome as a major regulator of the gut-skin axis[J]. Front Microbiol, 2018, 9: 1459.

[20] Cai R, Zhou C, Tang R, et al. Current insights on gut microbiome and chronic urticaria: progress in the pathogenesis and opportunities for novel therapeutic approaches[J]. Gut Microbes, 2024, 16(1): 2382774.

[21] Krautkramer KA, Fan J, Bäckhed F. Gut microbial metabolites as multi-Kingdom intermediates[J]. Nat Rev Microbiol, 2021, 19(2): 77-94.

[22] Qiu S, Cai Y, Yao H, et al. Small molecule metabolites: discovery of biomarkers and therapeutic targets[J]. Signal Transduct Target Ther, 2023, 8(1): 132.

[23] Wishart DS. Metabolomics for investigating physiological and pathophysiological processes[J]. Physiol Rev, 2019, 99(4): 1819-1875.

[24] 罗菀蓉, 高杨, 张文婕, 等. 肠道微生态研究技术和研究策略[J]. 中华炎性肠病杂志(中英文), 2024, 8(5): 329-334.

[25] LUO Wanrong, GAO Yang, ZHANG Wenjie, et al. Research technologies and strategies of gut microecology[J]. Chinese Journal of Inflammatory Bowel Diseases, 2024, 8(5): 329-334.

[26] Lloyd-Price J, Arze C, Ananthakrishnan AN, et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases[J]. Nature, 2019, 569(7758): 655-662.

[27] Hou S, Yu J, Li Y, et al. Advances in fecal microbiota transplantation for gut dysbiosis-related diseases[J/OL]. Adv Sci (Weinh), 2025, 12(13): e2413197[2025-04-02].

[28] Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? revisiting the ratio of bacterial to host cells in humans[J]. Cell, 2016, 164(3): 337-340.

[29] Citi S. Intestinal barriers protect against disease[J]. Science, 2018, 359(6380): 1097-1098.

[30] Mahmud MR, Akter S, Tamanna SK, et al. Impact of gut microbiome on skin health: gut-skin axis observed through the lenses of therapeutics and skin diseases[J]. Gut Microbes, 2022, 14(1): 2096995.

[31] Zuo WF, Pang Q, Yao LP, et al. Gut microbiota: a magical multifunctional target regulated by medicine food homology species[J]. J Adv Res, 2023, 52: 151-170.

[32] Lozupone CA, Stombaugh JI, Gordon JI, et al. Diversity, stability and resilience of the human gut microbiota[J]. Nature, 2012, 489(7415): 220-230.

[33] Luo Z, Jin Z, Tao X, et al. Combined microbiome and metabolome analysis of gut microbiota and metabolite interactions in chronic spontaneous urticaria[J]. Front Cell Infect Microbiol, 2023, 12: 1094737.

[34] Wang D, Guo S, He H, et al. Gut microbiome and serum metabolome analyses identify unsaturated fatty acids and butanoate metabolism induced by gut microbiota in patients with chronic spontaneous urticaria[J]. Front Cell Infect Microbiol, 2020, 10: 24.

[35] Zhu L, Jian X, Zhou B, et al. Gut microbiota facilitate chronic spontaneous urticaria[J]. Nat Commun, 2024, 15(1): 112.

[36] Ćesić D, Lugović Mihić L, Ozretić P, et al. Association of gut Lachnospiraceae and chronic spontaneous urticaria[J]. Life (Basel), 2023, 13(6): 1280.

[37] Wang X, Yi W, He L, et al. Abnormalities in gut microbiota and metabolism in patients with chronic spontaneous urticaria[J]. Front Immunol, 2021, 12: 691304.

[38] 闫慧敏, 杜笑, 孟令贺, 等. 基于16S rRNA基因测序的慢性自发性荨麻疹患者肠道菌群差异研究[J]. 中华皮肤科杂志, 2021, 54(12): 1071-1076.

[39] YAN Huimin, DU Xiao, MENG Linghe, et al. Analysis of differences in gut microbiota in patients with chronic spontaneous urticaria by 16S rRNA high-throughput sequencing[J]. Chinese Journal of Dermatology, 2021, 54(12): 1071-1076.

[40] Yüksekal G, Sevimli Dikicier B, Koku Aydın B, et al. Investigation of intestinal microbiome in chronic spontaneous urticaria patients[J]. Int J Dermatol, 2022, 61(8): 988-994.

[41] Zhang X, Zhang J, Chu Z, et al. Gut microbiome alterations and functional prediction in chronic spontaneous urticaria patients[J]. J Microbiol Biotechnol, 2021, 31(5): 747-755.

[42] Rezazadeh A, Shahabi S, Bagheri M, et al. The protective effect of Lactobacillus and Bifidobacterium as the gut microbiota members against chronic urticaria[J]. Int Immunopharmacol, 2018, 59: 168-173.

[43] Liu R, Peng C, Jing D, et al. Identification of gut microbiota signatures in symptomatic dermographism[J]. Exp Dermatol, 2021, 30(12): 1794-1799.

[44] Liu R, Peng C, Jing D, et al. Biomarkers of gut microbiota in chronic spontaneous urticaria and symptomatic dermographism[J]. Front Cell Infect Microbiol, 2021, 11: 703126.

[45] Fung TC, Vuong HE, Luna CDG, et al. Intestinal serotonin and fluoxetine exposure modulate bacterial colonization in the gut[J]. Nat Microbiol, 2019, 4(12): 2064-2073.

[46] Zabolinejad N, Molkara S, Bakhshodeh B, et al. The expression of serotonin transporter protein in the skin of patients with chronic spontaneous urticaria and its relation with depression and anxiety[J]. Arch Dermatol Res, 2019, 311(10): 825-831.

[47] 王鲁梅, 卢婉娇, 莫瑞玲, 等. 幽门螺杆菌感染对慢性荨麻疹患者外周血γ-干扰素和白细胞介素-4的调控机制[J]. 中华实验和临床感染病杂志(电子版), 2017, 11(5): 504-507.

[48] WANG Lumei, LU Wanjiao, MO Ruiling, et al. Regulatory mechanism of Helicobacter pylori infection on peripheral interferon gamma and interleukin-4 in peripheral blood of patients with chronic urticaria[J]. Chinese Journal of Experimental and Clinical Infectious Diseases. Electronic Edition, 2017, 11(5): 504-507.

[49] Cui YL, Zhou BY, Gao GC. A systematic review and meta-analysis of the correlation between Helicobacter pylori infection and chronic urticaria[J]. Ann Palliat Med, 2021, 10(10): 10584-10590.

[50] Tan RJ, Sun HQ, Zhang W, et al. A 21-35 kDa mixed protein component from Helicobacter pylori activates mast cells effectively in chronic spontaneous urticaria[J]. Helicobacter, 2016, 21(6): 565-574.

[51] Xiao X, Xue P, Yan X, et al. Exploring the bidirectional effects of gut microbiota and short-chain fatty acids on urticaria subtypes through mendelian randomization and mediation analysis[J]. Clin Cosmet Investig Dermatol, 2024, 17: 1827-1839.

[52] Rauf A, Khalil AA, Rahman UU, et al. Recent advances in the therapeutic application of short-chain fatty acids (SCFAs): an updated review[J]. Crit Rev Food Sci Nutr, 2022, 62(22): 6034-6054.

[53] Bilotta AJ, Ma C, Yang W, et al. Propionate enhances cell speed and persistence to promote intestinal epithelial turnover and repair[J]. Cell Mol Gastroenterol Hepatol, 2021, 11(4): 1023-1044.

[54] Kelly CJ, Zheng L, Campbell EL, et al. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function[J]. Cell Host Microbe, 2015, 17(5): 662-671.

[55] Wang J, Ren C, Jin L, et al. Seabuckthorn Wuwei Pulvis attenuates chronic obstructive pulmonary disease in rat through gut microbiota-short chain fatty acids axis[J]. J Ethnopharmacol, 2023, 314: 116591.

[56] Huang X, Oshima T, Tomita T, et al. Butyrate alleviates cytokine-induced barrier dysfunction by modifying claudin-2 levels[J]. Biology (Basel), 2021, 10(3): 205.

[57] Willemsen LM, Koetsier MA, van Deventer SH, et al. Short chain fatty acids stimulate epithelial mucin 2 expression through differential effects on prostaglandin E(1) and E(2) production by intestinal myofibroblasts[J]. Gut, 2003, 52(10): 1442-1447.

[58] Beisner J, Filipe Rosa L, Kaden-Volynets V, et al. Prebiotic inulin and sodium butyrate attenuate obesity-induced intestinal barrier dysfunction by induction of antimicrobial peptides[J]. Front Immunol, 2021, 12: 678360.

[59] Zhang S, Dogan B, Guo C, et al. Short chain fatty acids modulate the growth and virulence of pathosymbiont Escherichia coli and host response[J]. Antibiotics (Basel), 2020, 9(8): 462.

[60] McCrory C, Lenardon M, Traven A. Bacteria-derived short-chain fatty acids as potential regulators of fungal commensalism and pathogenesis[J]. Trends Microbiol, 2024, 32(11): 1106-1118.

[61] Kolkhir P, Akdis CA, Akdis M, et al. Type 2 chronic inflammatory diseases: targets, therapies and unmet needs[J]. Nat Rev Drug Discov, 2023, 22(9): 743-767.

[62] Trompette A, Pernot J, Perdijk O, et al. Gut-derived short-chain fatty acids modulate skin barrier integrity by promoting keratinocyte metabolism and differentiation[J]. Mucosal Immunol, 2022, 15(5): 908-926.

[63] Bager P, Wohlfahrt J, Thyssen JP, et al. Filaggrin genotype and skin diseases independent of atopic dermatitis in childhood[J]. Pediatr Allergy Immunol, 2016, 27(2): 162-168.

[64] Serhan N, Basso L, Sibilano R, et al. House dust mites activate nociceptor-mast cell clusters to drive type 2 skin inflammation[J]. Nat Immunol, 2019, 20(11): 1435-1443.

[65] Xiao X, Hu X, Yao J,et al. The role of short-chain fatty acids in inflammatory skin diseases[J]. Front Microbiol, 2022, 13: 1083432.

[66] Karaki SI, Mitsui R, Hayashi H, et al. Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine[J]. Cell Tissue Res, 2006, 324(3): 353-360.

[67] Nagata K, Ando D, Ashikari T, et al. Butyrate, valerate, and niacin ameliorate anaphylaxis by suppressing IgE-dependent mast cell activation: roles of GPR109A, PGE2, and epigenetic regulation[J]. J Immunol, 2024, 212(5): 771-784.

[68] Sugiyama H, Nonaka T, Kishimoto T, et al. Peroxisome proliferator-activated receptors are expressed in mouse bone marrow-derived mast cells[J]. FEBS Lett, 2000, 467(2/3): 259-262.

[69] Folkerts J, Redegeld F, Folkerts G, et al. Butyrate inhibits human mast cell activation via epigenetic regulation of FcεRI-mediated signaling[J]. Allergy, 2020, 75(8): 1966-1978.

[70] Furusawa Y, Obata Y, Fukuda S, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells[J]. Nature, 2013, 504(7480): 446-450.

[71] Arpaia N, Campbell C, Fan X, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation[J]. Nature, 2013, 504(7480): 451-455.

[72] Kay AB, Clark P, Maurer M, et al. Elevations in T-helper-2-initiating cytokines (interleukin-33, interleukin-25 and thymic stromal lymphopoietin) in lesional skin from chronic spontaneous (‘idiopathic’) urticaria[J]. Br J Dermatol, 2015, 172(5): 1294-1302.

[73] Chen Q, Zhong H, Chen WC, et al. Different expression patterns of plasma Th1-, Th2-, Th17- and Th22-related cytokines correlate with serum autoreactivity and allergen sensitivity in chronic spontaneous urticaria[J]. J Eur Acad Dermatol Venereol, 2018, 32(3): 441-448.

[74] Chen L, Sun M, Wu W, et al. Microbiota metabolite butyrate differentially regulates Th1 and Th17 cells’ differentiation and function in induction of colitis[J]. Inflamm Bowel Dis, 2019, 25(9): 1450-1461.

[75] Zhang M, Zhou Q, Dorfman RG, et al. Butyrate inhibits interleukin-17 and generates Tregs to ameliorate colorectal colitis in rats[J]. BMC Gastroenterol, 2016, 16(1): 84.

[76] Wu J, He C, Bu J, et al. Betaine attenuates LPS-induced downregulation of Occludin and Claudin-1 and restores intestinal barrier function[J]. BMC Vet Res, 2020, 16(1): 75.

[77] Wang R, Yang X, Liu J, et al. Gut microbiota regulates acute myeloid leukaemia via alteration of intestinal barrier function mediated by butyrate[J]. Nat Commun, 2022, 13(1): 2522.

[78] Medina-Tamayo J, Ibarra-Sánchez A, Padilla-Trejo A, et al. IgE-dependent sensitization increases responsiveness to LPS but does not modify development of endotoxin tolerance in mast cells[J]. Inflamm Res, 2011, 60(1): 19-27.

[79] Huang Z, Kraus VB. Does lipopolysaccharide-mediated inflammation have a role in OA?[J]. Nat Rev Rheumatol, 2016, 12(2): 123-129.

[80] Poplutz M, Levikova M, Lüscher-Firzlaff J, et al. Endotoxin tolerance in mast cells, its consequences for IgE-mediated signalling, and the effects of BCL3 deficiency[J]. Sci Rep, 2017, 7(1): 4534.

[81] Song X, Zhang H, Zhang Y, et al. Gut microbial fatty acid isomerization modulates intraepithelial T cells[J]. Nature, 2023, 619(7971): 837-843.

[82] Bourragat A, Escoula Q, Bellenger S, et al. The transplantation of the gut microbiome of fat-1 mice protects against colonic mucus layer disruption and endoplasmic reticulum stress induced by high fat diet[J]. Gut Microbes, 2024, 16(1): 2356270.

[83] Rabionet M, Gorgas K, Sandhoff R. Ceramide synthesis in the epidermis[J]. Biochim Biophys Acta, 2014, 1841(3): 422-434.

[84] Miles EA, Childs CE, Calder PC. Long-chain polyunsaturated fatty acids (LCPUFAs) and the developing immune system: a narrative review[J]. Nutrients, 2021, 13(1): 247.

[85] Pereira M, Liang J, Edwards-Hicks J, et al. Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting[J]. Cell Rep, 2024, 43(2): 113700.

[86] Serhan CN, Bäck M, Chiurchiù V, et al. Expert consensus report on lipid mediators: Role in resolution of inflammation and muscle preservation[J/OL]. FASEB J, 2024, 38(10): e23699[2025-02-02].

[87] Djuricic I, Calder PC. Beneficial outcomes of omega-6 and omega-3 polyunsaturated fatty acids on human health: an update for 2021[J]. Nutrients, 2021, 13(7): 2421.

[88] Kobayashi S. Investigation of the roles of the substances in serum lipids and their constitutive fatty acids in chronic urticaria[J]. J Dermatol, 1989, 16(3): 196-206.

[89] Innes JK, Calder PC. Omega-6 fatty acids and inflammation[J]. Prostaglandins Leukot Essent Fatty Acids, 2018, 132: 41-48.

[90] Rosas HD, Doros G, Bhasin S, et al. A systems-level “misunderstanding”: the plasma metabolome in Huntington’s disease[J]. Ann Clin Transl Neurol, 2015, 2(7): 756-768.

[91] Wikoff WR, Anfora AT, Liu J, et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites[J]. Proc Natl Acad Sci USA, 2009, 106(10): 3698-3703.

[92] Wang G, Fan Y, Zhang G, et al. Microbiota-derived indoles alleviate intestinal inflammation and modulate microbiome by microbial cross-feeding[J]. Microbiome, 2024, 12(1): 59.

[93] Flannigan KL, Nieves KM, Szczepanski HE, et al. The pregnane X receptor and indole-3-propionic acid shape the intestinal mesenchyme to restrain inflammation and fibrosis[J]. Cell Mol Gastroenterol Hepatol, 2023, 15(3): 765-795.

[94] Gao H, Sun M, Li A, et al. Microbiota-derived IPA alleviates intestinal mucosal inflammation through upregulating Th1/Th17 cell apoptosis in inflammatory bowel disease[J]. Gut Microbes, 2025, 17(1): 2467235.

[95] Fusco W, Lorenzo MB, Cintoni M, et al. Short-chain fatty-acid-producing bacteria: key components of the human gut microbiota[J]. Nutrients, 2023, 15(9): 2211.

[96] Podder I, Pesqué D, Carrón N, et al. Gut microbial alteration in chronic spontaneous urticaria unresponsive to second generation antihistamines and its correlation with disease characteristics- a cross-sectional case-control study[J/OL]. Clin Transl Allergy, 2025, 15(1): e70027[2025-04-02].

[97] Liu R, Peng C, Jing D, et al. Lachnospira is a signature of antihistamine efficacy in chronic spontaneous urticaria[J]. Exp Dermatol, 2022, 31(2): 242-247.

[98] Wu LQ, Yuan QF, Qin ZC, et al. Faecal microbiota transplantation for treatment of chronic urticaria with recurrent abdominal pain and food allergy[J]. Singapore Med J, 2023.

[99] Kocak OF, Atakay M, Yaman ME, et al. Chemometrics assisted untargeted metabolomic analysis to explore metabolic alterations in chronic urticaria via LC/Q-TOF/MS/MS[J]. Scand J Clin Lab Invest, 2022, 82(7/8): 533-540.

[100] Mao M, Liu H, Yan S, et al. Plasma adenosine is linked to disease activity and response to treatment in patients with chronic spontaneous urticaria[J]. Allergy, 2021, 76(2): 571-573.

[101] Jian X, Hou G, Li L, et al. Identification of pyruvic and maleic acid as potential markers for disease activity and prognosis in chronic urticaria[J]. J Allergy Clin Immunol, 2024, 154(2): 412-423.

[102] Liu CW, Cheng YC, Yu YT, et al. Roles of gut-microbiota and probiotics in chronic urticaria: a systematic review and meta-analysis[J/OL]. Australas J Dermatol, 2022, 63(2): e166-e170[2025-04-02].

[103] Bi XD, Lu BZ, Pan XX, et al. Adjunct therapy with probiotics for chronic urticaria in children: randomised placebo-controlled trial[J]. Allergy Asthma Clin Immunol, 2021, 17(1): 39.

[104] Nettis E, Di Leo E, Pastore A, et al. Probiotics and refractory chronic spontaneous urticaria[J]. Eur Ann Allergy Clin Immunol, 2016, 48(5): 182-187.

[105] Atefi N, Fallahpour M, Sharifi S, et al. Probiotic as an adjuvant therapy in chronic urticaria: a blinded randomized controlled clinical trial[J]. Eur Ann Allergy Clin Immunol, 2022, 54(3): 123-130.

基金资助

国家自然科学基金(82173424)

国家自然科学基金(82473532)

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