Multi 'Omics Analysis of Intestinal Tissue in Ankylosing Spondylitis Identifies Alterations in the Tryptophan Metabolism Pathway.
Multi 'Omics Analysis of Intestinal Tissue in Ankylosing Spondylitis Identifies Alterations in the Tryptophan Metabolism Pathway.
复制标题
强直性脊柱炎肠组织色氨酸代谢途径的多组学分析
DOI：
10.3389/fimmu.2021.587119
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发表时间：
2021
影响因子：
7.3
通讯作者：
Kuhn KA
中科院分区：
文献类型：
--
作者：
Berlinberg AJ;Regner EH;Stahly A;Brar A;Reisz JA;Gerich ME;Fennimore BP;Scott FI;Freeman AE;Kuhn KA
肠道微生物生态失调、肠道炎症和Th17免疫都与脊椎关节炎（SpA）的病理生理有关；然而，连接它们的机制仍然未知。一种潜在的假设认为，肠道菌群失调作为一个整体会产生影响人体免疫细胞的代谢物。为了确定潜在的与疾病相关的微生物产生的代谢物，我们分别对来自轴性SpA （axSpA， N=21）、克罗恩病（CD， N=27）和克罗恩-axSpA重叠（CD-axSpA， N=12）以及对照组（HC， N=24）的配对结肠活检和粪便样本进行了代谢组学筛选和shotgun宏基因组学。使用基于LC-MS的代谢组学对受试者远端结肠的4个非炎症活检进行分析，我们发现色氨酸途径代谢物发生了显著变化，包括与HC和CD相比，axSpA和CD-axSpA中的吲哚-3-乙酸（IAA）增加，axSpA和CD-axSpA中的吲哚-3-乙醛（I3Ald）增加，但与HC相比，CD没有增加，这表明axSpA的发展可能具有特异性。然后，我们对粪便样本进行鸟枪宏基因组学分析，以表征这些疾病状态下肠道微生物生态失调的特征。尽管4组之间α -多样性没有显著差异，但我们的结果证实了参与色氨酸代谢的许多酶的基因丰度存在差异。具体来说，产生IAA和I3Ald的吲哚丙酮酸脱羧酶的基因丰度在axSpA个体中显著升高，而HC的基因丰度显示出色氨酸合成的倾向。在CD中未观察到这种遗传变化，再次提示axSpA具有疾病特异性。鉴于色氨酸及其代谢物在免疫功能中的新作用，这些数据表明，色氨酸代谢为I3Ald和IAA是肠道微生物群可能影响axSpA发育的一种机制。
Intestinal microbial dysbiosis, intestinal inflammation, and Th17 immunity are all linked to the pathophysiology of spondyloarthritis (SpA); however, the mechanisms linking them remain unknown. One potential hypothesis suggests that the dysbiotic gut microbiome as a whole produces metabolites that influence human immune cells. To identify potential disease-relevant, microbiome-produced metabolites, we performed metabolomics screening and shotgun metagenomics on paired colon biopsies and fecal samples, respectively, from subjects with axial SpA (axSpA, N=21), Crohn’s disease (CD, N=27), and Crohn’s-axSpA overlap (CD-axSpA, N=12), as well as controls (HC, N=24). Using LC-MS based metabolomics of 4 non-inflamed pinch biopsies of the distal colon from subjects, we identified significant alterations in tryptophan pathway metabolites, including an expansion of indole-3-acetate (IAA) in axSpA and CD-axSpA compared to HC and CD and indole-3-acetaldehyde (I3Ald) in axSpA and CD-axSpA but not CD compared to HC, suggesting possible specificity to the development of axSpA. We then performed shotgun metagenomics of fecal samples to characterize gut microbial dysbiosis across these disease states. In spite of no significant differences in alpha-diversity among the 4 groups, our results confirmed differences in gene abundances of numerous enzymes involved in tryptophan metabolism. Specifically, gene abundance of indolepyruvate decarboxylase, which generates IAA and I3Ald, was significantly elevated in individuals with axSpA while gene abundances in HC demonstrated a propensity towards tryptophan synthesis. Such genetic changes were not observed in CD, again suggesting disease specificity for axSpA. Given the emerging role of tryptophan and its metabolites in immune function, altogether these data indicate that tryptophan metabolism into I3Ald and then IAA is one mechanism by which the gut microbiome potentially influences the development of axSpA.