Therapeutic helminth infection of macaques with idiopathic chronic diarrhea alters the inflammatory signature and mucosal microbiota of the colon.
Therapeutic helminth infection of macaques with idiopathic chronic diarrhea alters the inflammatory signature and mucosal microbiota of the colon.
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特发性慢性腹泻的猕猴的治疗性蠕虫感染改变了结肠的炎症特征和粘膜微生物群。
DOI：
10.1371/journal.ppat.1003000
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Loke P
中科院分区：
文献类型：
--
作者：
Broadhurst MJ;Ardeshir A;Kanwar B;Mirpuri J;Gundra UM;Leung JM;Wiens KE;Vujkovic-Cvijin I;Kim CC;Yarovinsky F;Lerche NW;McCune JM;Loke P
特发性慢性腹泻（ICD）是圈养恒河猴发病的主要原因。在这里，我们发现，将受影响的动物暴露于鞭虫鞭虫后，五只接受治疗的猴子中，有四只猴子的粪便稠度得到了临床改善，并伴随着体重增加。通过对治疗前后结肠镜检查期间收集的捏取活检进行流式细胞术分析，我们发现蠕虫治疗后粘膜 TH2 反应的诱导，与活化的 CD4+ Ki67+ 细胞的减少有关。与此同时，寡核苷酸微阵列和实时 PCR 分析的表达谱显示，TH1 型炎症基因表达减少，而与 IgE 信号传导、肥大细胞激活、嗜酸性粒细胞募集、巨噬细胞替代激活和蠕虫排出相关的基因表达增加。通过使用实时 PCR 分析对捏取活检中的细菌 16S rRNA 进行定量，我们发现治疗后细菌对肠粘膜的附着减少。最后，细菌 16S rRNA 的深度测序揭示了蠕虫治疗后附着在肠粘膜上的微生物群落组成的变化。因此，与健康对照相比，五分之三的 ICD 猴子中蓝藻门的链球菌属丰度大大增加，但在治疗后降低至对照水平；相比之下，特内里古特门在治疗后得到了扩大。这些发现表明，灵长类动物的蠕虫治疗可以通过恢复粘膜屏障功能和减少整体细菌附着以及改变附着细菌群落来改善结肠炎。这些结果还将猴子 ICD 定义为易于处理的溃疡性结肠炎临床前模型，可以在其中进一步研究这些影响。灵长类动物研究中心圈养的幼年猕猴经常出现慢性腹泻，这种疾病很难治疗，因为人们对此知之甚少。这种疾病与溃疡性结肠炎有许多特征，溃疡性结肠炎是一种影响人类肠道的自身免疫性疾病。最近，寄生虫已被用于治疗人类炎症性肠病的临床试验，并取得了积极的结果，但人们对寄生虫如何改善症状知之甚少。我们进行了一项试验，用人类鞭虫治疗患有慢性腹泻的猕猴，并在治疗前后收集肠道活检。我们发现，经过治疗的 5 只猕猴中有 4 只改善了症状，并研究了随着病情好转，它们肠道免疫反应的变化。我们发现，用蠕虫治疗后，猴子肠壁上附着的细菌减少了，肠道细菌的炎症反应也减少了。此外，患病猕猴的肠道细菌组成发生了改变，并在用鞭虫治疗后恢复到接近正常水平。这些结果提供了一种潜在机制，寄生虫可以通过减少针对肠道细菌的免疫反应来改善肠道炎症的症状。
Idiopathic chronic diarrhea (ICD) is a leading cause of morbidity amongst rhesus monkeys kept in captivity. Here, we show that exposure of affected animals to the whipworm Trichuris trichiura led to clinical improvement in fecal consistency, accompanied by weight gain, in four out of the five treated monkeys. By flow cytometry analysis of pinch biopsies collected during colonoscopies before and after treatment, we found an induction of a mucosal TH2 response following helminth treatment that was associated with a decrease in activated CD4+ Ki67+ cells. In parallel, expression profiling with oligonucleotide microarrays and real-time PCR analysis revealed reductions in TH1-type inflammatory gene expression and increased expression of genes associated with IgE signaling, mast cell activation, eosinophil recruitment, alternative activation of macrophages, and worm expulsion. By quantifying bacterial 16S rRNA in pinch biopsies using real-time PCR analysis, we found reduced bacterial attachment to the intestinal mucosa post-treatment. Finally, deep sequencing of bacterial 16S rRNA revealed changes to the composition of microbial communities attached to the intestinal mucosa following helminth treatment. Thus, the genus Streptophyta of the phylum Cyanobacteria was vastly increased in abundance in three out of five ICD monkeys relative to healthy controls, but was reduced to control levels post-treatment; by contrast, the phylum Tenericutes was expanded post-treatment. These findings suggest that helminth treatment in primates can ameliorate colitis by restoring mucosal barrier functions and reducing overall bacterial attachment, and also by altering the communities of attached bacteria. These results also define ICD in monkeys as a tractable preclinical model for ulcerative colitis in which these effects can be further investigated. Young macaques kept in captivity at Primate Research Centers often develop chronic diarrhea, which is difficult to treat because it is poorly understood. This disease shares many features with ulcerative colitis, which is an autoimmune disease affecting the intestinal tract of humans. Recently, parasitic worms have been used in clinical trials to treat inflammatory bowel diseases in humans with positive results, but very little is known about how worms can improve symptoms. We performed a trial where we treated macaques suffering from chronic diarrhea with human whipworms, collecting gut biopsies before and after treatment. We found that 4 out of the 5 treated macaques improved their symptoms and studied the changes in their gut immune responses, as they got better. We found that after treatment with worms, the monkeys had less bacteria attached to their intestinal wall and a reduced inflammatory response to the gut bacteria. Additionally, the composition of gut bacteria was altered in the sick macaques and was restored close to normal after treatment with whipworms. These results provide a potential mechanism by which parasitic worms may improve the symptoms of intestinal inflammation, by reducing the immune response against intestinal bacteria.
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DOI：
10.1038/ismej.2012.8
发表时间：
2012-08
期刊：
The ISME journal
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.4
作者：
Elliott, DE;Setiawan, T;Weinstock, JV
通讯作者：
Weinstock, JV
影响因子：
64.8
作者：
Bouskra, Djahida;Brezillon, Christophe;Eberl, Gerard
通讯作者：
Eberl, Gerard
DOI：
10.1073/pnas.1000080107
发表时间：
2011-03-15
影响因子：
11.1
作者：
Caporaso, J. Gregory;Lauber, Christian L.;Knight, Rob
通讯作者：
Knight, Rob
影响因子：
3.1
作者：
Khan, WI;Blennerhasset, PA;Collins, SM
通讯作者：
Collins, SM