Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Computer Science, Aalto University, 02150, Espoo, Finland.
Genome Med. 2021 Feb 28;13(1):35. doi: 10.1186/s13073-021-00853-7.
Immunoglobulin G4-related disease (IgG4-RD) and systemic sclerosis (SSc) are rare autoimmune diseases characterized by the presence of CD4+ cytotoxic T cells in the blood as well as inflammation and fibrosis in various organs, but they have no established etiologies. Similar to other autoimmune diseases, the gut microbiome might encode disease-triggering or disease-sustaining factors.
The gut microbiomes from IgG4-RD and SSc patients as well as healthy individuals with no recent antibiotic treatment were studied by metagenomic sequencing of stool DNA. De novo assembly-based taxonomic and functional characterization, followed by association and accessory gene set enrichment analysis, were applied to describe microbiome changes associated with both diseases.
Microbiomes of IgG4-RD and SSc patients distinctly separated from those of healthy controls: numerous opportunistic pathogenic Clostridium and typically oral Streptococcus species were significantly overabundant, while Alistipes, Bacteroides, and butyrate-producing species were depleted in the two diseases compared to healthy controls. Accessory gene content analysis in these species revealed an enrichment of Th17-activating Eggerthella lenta strains in IgG4-RD and SSc and a preferential colonization of a homocysteine-producing strain of Clostridium bolteae in SSc. Overabundance of the classical mevalonate pathway, hydroxyproline dehydratase, and fibronectin-binding protein in disease microbiomes reflects potential functional differences in host immune recognition and extracellular matrix utilization associated with fibrosis. Strikingly, the majority of species that were differentially abundant in IgG4-RD and SSc compared to controls showed the same directionality in both diseases. Compared with multiple sclerosis and rheumatoid arthritis, the gut microbiomes of IgG4-RD and SSc showed similar signatures; in contrast, the most differentially abundant taxa were not the facultative anaerobes consistently identified in inflammatory bowel diseases, suggesting the microbial signatures of IgG4-RD and SSc do not result from mucosal inflammation and decreased anaerobism.
These results provide an initial characterization of gut microbiome ecology in fibrosis-prone IgG4-RD and SSc and reveal microbial functions that offer insights into the pathophysiology of these rare diseases.
免疫球蛋白 G4 相关疾病（IgG4-RD）和系统性硬化症（SSc）是两种罕见的自身免疫性疾病，其特征为血液中存在 CD4+细胞毒性 T 细胞，以及各种器官的炎症和纤维化，但它们的病因尚未确定。与其他自身免疫性疾病类似，肠道微生物组可能编码疾病触发或维持因素。
通过对粪便 DNA 进行宏基因组测序，研究 IgG4-RD 和 SSc 患者以及近期未接受抗生素治疗的健康个体的肠道微生物组。应用从头组装的分类和功能特征描述、关联和辅助基因集富集分析，来描述与这两种疾病相关的微生物组变化。
IgG4-RD 和 SSc 患者的微生物组与健康对照组明显分离：大量机会性致病梭菌和典型的口腔链球菌明显过度丰富，而在这两种疾病中，与健康对照组相比，Alistipes、Bacteroides 和丁酸盐产生菌被消耗。对这些物种的辅助基因含量分析表明，Th17 激活的 Eggerthella lenta 菌株在 IgG4-RD 和 SSc 中富集，同型半胱氨酸产生的 Clostridium bolteae 菌株优先定植于 SSc。疾病微生物组中经典的甲羟戊酸途径、羟脯氨酸脱水酶和纤维连接蛋白结合蛋白的过度表达反映了宿主免疫识别和细胞外基质利用与纤维化相关的潜在功能差异。引人注目的是，与对照组相比，在 IgG4-RD 和 SSc 中差异丰度较高的大多数物种在这两种疾病中表现出相同的方向性。与多发性硬化症和类风湿关节炎相比，IgG4-RD 和 SSc 的肠道微生物组具有相似的特征；相比之下，差异最大的分类群并不是在炎症性肠病中始终存在的兼性厌氧菌，这表明 IgG4-RD 和 SSc 的微生物特征并非源于黏膜炎症和厌氧菌减少。
这些结果初步描述了易纤维化的 IgG4-RD 和 SSc 中肠道微生物组生态，并揭示了微生物功能，为这些罕见疾病的病理生理学提供了新的见解。
