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Intestinal Fungal Dysbiosis Is Associated With Visceral Hypersensitivity in Patients With Irritable Bowel Syndrome and Rats
Gastroenterology ( IF 25.7 ) Pub Date : 2017-06-15 , DOI: 10.1053/j.gastro.2017.06.004
Sara Botschuijver , Guus Roeselers , Evgeni Levin , Daisy M. Jonkers , Olaf Welting , Sigrid E.M. Heinsbroek , Heleen H. de Weerd , Teun Boekhout , Matteo Fornai , Ad A. Masclee , Frank H.J. Schuren , Wouter J. de Jonge , Jurgen Seppen , René M. van den Wijngaard

Background & Aims

Visceral hypersensitivity is one feature of irritable bowel syndrome (IBS). Bacterial dysbiosis might be involved in the activation of nociceptive sensory pathways, but there have been few studies of the role of the mycobiome (the fungal microbiome) in the development of IBS. We analyzed intestinal mycobiomes of patients with IBS and a rat model of visceral hypersensitivity.

Methods

We used internal transcribed spacer 1-based metabarcoding to compare fecal mycobiomes of 18 healthy volunteers with those of 39 patients with IBS (with visceral hypersensitivity or normal levels of sensitivity). We also compared the mycobiomes of Long-Evans rats separated from their mothers (hypersensitive) with non-handled (normally sensitive) rats. We investigated whether fungi can cause visceral hypersensitivity using rats exposed to fungicide (fluconazole and nystatin). The functional relevance of the gut mycobiome was confirmed in fecal transplantation experiments: adult maternally separated rats were subjected to water avoidance stress (to induce visceral hypersensitivity), then given fungicide and donor cecum content via oral gavage. Other rats subjected to water avoidance stress were given soluble β-glucans, which antagonize C-type lectin domain family 7 member A (CLEC7A or DECTIN1) signaling via spleen-associated tyrosine kinase (SYK), a SYK inhibitor to reduce visceral hypersensitivity, or vehicle (control). The sensitivity of mast cells to fungi was tested with mesenteric windows (ex vivo) and the human mast cell line HMC-1.

Results

α diversity (Shannon index) and mycobiome signature (stability selection) of both groups of IBS patients differed from healthy volunteers, and the mycobiome signature of hypersensitive patients differed from that of normally sensitive patients. We observed mycobiome dysbiosis in rats that had been separated from their mothers compared with non-handled rats. Administration of fungicide to hypersensitive rats reduced their visceral hypersensitivity to normal levels of sensitivity. Administration of cecal mycobiomes from rats that had been separated from their mothers (but not non-handled mycobiome) restored hypersensitivity to distension. Administration of soluble β-glucans or a SYK inhibitor reduced visceral hypersensitivity, compared with controls. Particulate β-glucan (a DECTIN-1 agonist) induced mast cell degranulation in mesenteric windows and HMC-1 cells responded to fungal antigens by release of histamine.

Conclusions

In an analysis of patients with IBS and controls, we associated fungal dysbiosis with IBS. In studies of rats, we found fungi to promote visceral hypersensitivity, which could be reduced by administration of fungicides, soluble β-glucans, or a SYK inhibitor. The intestinal fungi might therefore be manipulated for treatment of IBS-related visceral hypersensitivity.



中文翻译:

肠易激综合征和大鼠肠道真菌性营养不良与内脏超敏反应有关。

背景与目标

内脏超敏反应是肠易激综合症(IBS)的特征之一。细菌性营养不良可能参与了伤害性感觉通路的激活,但是关于真菌基因组(真菌微生物组)在IBS发生中的作用的研究很少。我们分析了IBS患者和内脏超敏性大鼠模型的肠道菌群。

方法

我们使用基于内部转录间隔基1的元条形码来比较18名健康志愿者与39名IBS患者(内脏超敏或正常水平的敏感性)的粪便中的真菌生物素。我们还比较了与母亲分开的长伊文思大鼠(超敏)和未处理的鼠(正常敏感)的菌群。我们使用暴露于杀真菌剂(氟康唑和制霉菌素)的大鼠调查了真菌是否会引起内脏超敏反应。粪便移植实验证实了肠道菌群的功能相关性:成年母体分离的大鼠受到避水胁迫(诱发内脏超敏反应),然后通过管饲法给予杀真菌剂和施主盲肠含量。其他遭受避水胁迫的大鼠也服用了可溶性β-葡聚糖,它们通过脾脏相关酪氨酸激酶(SYK)(一种降低内脏超敏性的SYK抑制剂)或赋形剂(对照)拮抗C型凝集素结构域家族7成员A(CLEC7A或DECTIN1)的信号传导。用肠系膜窗(离体)和人类肥大细胞系HMC-1测试了肥大细胞对真菌的敏感性。

结果

两组IBS患者的α多样性(Shannon指数)和真菌组特征(稳定性选择)与健康志愿者不同,超敏患者的真菌组特征与正常敏感性患者不同。与未处理的大鼠相比,我们观察到了与母亲分离的大鼠中的真菌组生物代谢异常。向高敏大鼠施用杀真菌剂可将其内脏超敏降至正常水平。从与母亲分离的大鼠(但非未处理的真菌生物组)中施用盲肠真菌生物素可恢复对扩张的超敏反应。与对照组相比,可溶性β-葡聚糖或SYK抑制剂的给药降低了内脏超敏性。

结论

在对IBS和对照患者的分析中,我们将真菌性营养不良与IBS相关联。在对大鼠的研究中,我们发现真菌可促进内脏超敏反应,可通过施用杀菌剂,可溶性β-葡聚糖或SYK抑制剂来减轻这种过敏。因此,可以对肠道真菌进行处理,以治疗IBS相关的内脏超敏反应。

更新日期:2017-06-15
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