Sex-dependent Lupus Blautia (Ruminococcus) gnavus strain induction of zonulin-mediated intestinal permeability and autoimmunity.
Sex-dependent Lupus Blautia (Ruminococcus) gnavus strain induction of zonulin-mediated intestinal permeability and autoimmunity.
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DOI：
10.3389/fimmu.2022.897971
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发表时间：
2022
影响因子：
7.3
通讯作者：
Azzouz, Doua F.
中科院分区：
文献类型：
--
作者：
Silverman, Gregg J.;Deng, Jing;Azzouz, Doua F.
肠道微生物群的失衡被怀疑是系统性红斑狼疮发病机制的一个因素，我们的研究和其他研究已经证明，活动性狼疮肾炎患者存在专性厌氧菌 Blautia（瘤胃球菌） gnavus (RG) 的扩张。为了研究狼疮患者的 RG 菌株在限菌系统中是否具有体内致病特性，我们用来自健康成人或狼疮患者的单独 RG 菌株定植 C57BL/6 小鼠。这些菌株在抗生素预处理的无特定病原体、无菌成体及其新生儿定植窝鼠肠道定植的能力相似。狼疮衍生的 RG 菌株诱导高水平的肠道通透性，雌性小鼠显着高于雄性小鼠，而来自健康供体的 RG 物种型菌株 (ATCC29149/VPI C7-1) 几乎没有影响或没有影响。这些狼疮 RG 菌株诱导的功能改变与 RG 易位至肠系膜淋巴结有关，并提高了连蛋白的血清水平，连蛋白是形成肠道屏障的细胞之间紧密连接形成的调节剂。值得注意的是，狼疮 RG 诱导的肠道通透性水平与血清 IgG 抗 RG 细胞壁脂聚糖抗体以及作为 SLE 生物标志物的抗天然 DNA 自身抗体显着相关。引人注目的是，通过口服醋酸拉佐肽（一种八肽，连蛋白的特异性分子拮抗剂）治疗，肠道通透性完全逆转。总而言之，这些研究记录了狼疮患者的 RG 菌株导致肠漏的途径，以及与临床狼疮疾病发作发病机制有关的自身免疫特征。
Imbalances in the gut microbiome are suspected contributors to the pathogenesis of Systemic Lupus Erythematosus, and our studies and others have documented that patients with active Lupus nephritis have expansions of the obligate anaerobe, Blautia (Ruminococcus) gnavus (RG). To investigate whether the RG strains in Lupus patients have in vivo pathogenic properties in a gnotobiotic system, we colonized C57BL/6 mice with individual RG strains from healthy adults or those from Lupus patients. These strains were similar in their capacity for murine intestinal colonization of antibiotic-preconditioned specific-pathogen-free, as well as of germ-free adults and of their neonatally colonized litters. Lupus-derived RG strains induced high levels of intestinal permeability that was significantly greater in female than male mice, whereas the RG species-type strain (ATCC29149/VPI C7-1) from a healthy donor had little or no effects. These Lupus RG strain-induced functional alterations were associated with RG translocation to mesenteric lymph nodes, and raised serum levels of zonulin, a regulator of tight junction formation between cells that form the gut barrier. Notably, the level of Lupus RG-induced intestinal permeability was significantly correlated with serum IgG anti RG cell-wall lipoglycan antibodies, and with anti-native DNA autoantibodies that are a biomarker for SLE. Strikingly, gut permeability was completely reversed by oral treatment with larazotide acetate, an octapeptide that is a specific molecular antagonist of zonulin. Taken together, these studies document a pathway by which RG strains from Lupus patients contribute to a leaky gut and features of autoimmunity implicated in the pathogenesis of flares of clinical Lupus disease.
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DOI：
10.1038/nrmicro3552
发表时间：
2016-01
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
Donaldson GP;Lee SM;Mazmanian SK
通讯作者：
Mazmanian SK
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
9.8
作者：
Png, Chin Wen;Linden, Sara K.;Florin, Timothy H. J.
通讯作者：
Florin, Timothy H. J.
影响因子：
7.3
作者：
Ma, Longhuan;Morel, Laurence
通讯作者：
Morel, Laurence
影响因子：
7.3
作者：
Bagavant H;Araszkiewicz AM;Ingram JK;Cizio K;Merrill JT;Arriens C;Guthridge JM;James JA;Deshmukh US
通讯作者：
Deshmukh US