Träger Constantin, Kaiser Maria, Freudenstein David, Heckscher Simon, Dettmer Katja, Oefner Peter J, Liebisch Gerhard, Hiergeist Andreas, Gessner André, Lee De-Hyung, Angstwurm Klemens, Linker Ralf A, Haase Stefanie
Department of Neurology, University Hospital Regensburg, Regensburg, Germany.
Institute of Functional Genomics, University of Regensburg, Regensburg, Germany.
EBioMedicine. 2025 Jun;116:105743. doi: 10.1016/j.ebiom.2025.105743. Epub 2025 May 12.
Modulation of the gut microbiota composition has been suggested as a potential disease modifying therapy in immune-mediated diseases such as multiple sclerosis (MS). However, a conclusive mechanism linking gut microbiota modulation to peripheral immune responses has remained elusive so far.
In this exploratory cohort study, people with MS (pwMS) and healthy controls (HC) supplemented a lactobacilli-rich probiotic for two or six weeks and were additionally investigated six weeks after the last intake. Immune cell phenotyping was performed in blood samples, complemented by mRNA expression analysis, serum cytokine measurements, and Treg suppression assays. Besides gut microbiota composition analysis, metabolite production was investigated in stool and serum. Links between metabolites and peripheral immune system were investigated in in vitro T cell differentiation assays.
In peripheral blood, Treg cells increased in both groups, while Th1 cells were significantly reduced in pwMS. This promotion of a regulatory immunophenotype was complemented by increased concentrations of IL-10 in serum and higher expression of IL10 and CTLA4. Functional assays revealed an enhanced suppressive capacity of Treg cells due to the probiotic intervention. The tryptophan metabolite indole-3-acetate (IAA) increased in stool and serum samples of pwMS during the probiotic intake. In vitro, IAA specifically enhanced the formation of IL-10 secreting T cells together with CYP1a1 expression. This effect was blocked by addition of an aryl hydrocarbon receptor (AHR) inhibitor.
A lactobacilli-enriched probiotic promotes a regulatory immunophenotype in pwMS, probably by enhancing AHR agonists in the gut. It may be of interest as add-on therapy in immune-mediated diseases such as MS.
This study has in part been funded by Novartis Pharma GmbH and BMBF grant no. 01EJ2202B.
肠道微生物群组成的调节已被认为是免疫介导疾病（如多发性硬化症，MS）中一种潜在的疾病修饰疗法。然而，迄今为止，将肠道微生物群调节与外周免疫反应联系起来的确切机制仍不清楚。
在这项探索性队列研究中，MS患者（pwMS）和健康对照者（HC）补充富含乳酸杆菌的益生菌两周或六周，并在最后一次摄入后六周进行额外调查。对血样进行免疫细胞表型分析，并辅以mRNA表达分析、血清细胞因子测量和调节性T细胞（Treg）抑制试验。除了肠道微生物群组成分析外，还对粪便和血清中的代谢产物生成进行了研究。在体外T细胞分化试验中研究了代谢产物与外周免疫系统之间的联系。
在外周血中，两组的Treg细胞均增加，而pwMS患者的Th1细胞显著减少。血清中IL-10浓度升高以及IL10和CTLA4表达增加，进一步促进了调节性免疫表型。功能试验显示，益生菌干预使Treg细胞的抑制能力增强。在摄入益生菌期间，pwMS患者的粪便和血清样本中色氨酸代谢产物吲哚-3-乙酸（IAA）增加。在体外，IAA与CYP1a1表达一起特异性增强了分泌IL-10的T细胞的形成。添加芳烃受体（AHR）抑制剂可阻断这种效应。
富含乳酸杆菌的益生菌可能通过增强肠道中的AHR激动剂，促进pwMS患者的调节性免疫表型。作为MS等免疫介导疾病的辅助治疗可能具有一定意义。
本研究部分由诺华制药有限公司和德国联邦教育与研究部（BMBF）资助，资助编号为01EJ2202B。
