Akkermansia muciniphila restrains type 1 diabetes onset by eliciting cDC2 and Treg cell differentiation in NOD and STZ-induced experimental models

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-04-07 DOI:10.1016/j.lfs.2025.123624

Vanessa Fernandes Rodrigues , Jefferson Elias-Oliveira , Ítalo Sousa Pereira , Jéssica Assis Pereira , Sara Cândida Barbosa , Melissa Santana Gonsalez Machado , Jhefferson Barbosa Guimarães , Thaílla Cristina Faria Pacheco , Jonatã Bortolucci , Lívia Soares Zaramela , Vânia Luiza Deperon Bonato , João Santana Silva , Flaviano Santos Martins , José Carlos Alves-Filho , Luiz Gustavo Gardinassi , Valeria Reginatto , Daniela Carlos

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引用次数: 0

Abstract

Aims

Akkermansia muciniphila (A. muciniphila), a Gram-negative anaerobic mucus-layer-degrading bacterium found in the intestinal mucosa, exhibits potential as a probiotic, showing promise in mitigating autoimmune and chronic inflammatory diseases. This study aims to investigate whether A. muciniphila supplementation might confer protection against type 1 diabetes (T1D) and to elucidate the immunological pathways through which it exerts its beneficial effects.

Materials and methods

Non-obese diabetic (NOD) mice and streptozotocin (STZ)-induced type 1 diabetes (T1D) models were used to evaluate the protective effects of A. muciniphila during T1D course. Body weight, blood glucose levels, and T1D incidence were monitored. Immune responses in the pancreas, pancreatic (PLN) and cecal lymph nodes (CLN) and bone marrow-derived dendritic cells (BMDC) were evaluated by flow cytometry and ELISA.

Key findings

Viable A. muciniphila supplementation conferred protection against T1D onset in STZ-induced T1D and NOD mouse models. T1D modulation by A. muciniphila in the STZ model was independent of the gut microbiota, and it was associated with increased tolerogenic type-2 dendritic cells (SIRP-α⁺CD11b⁺CD103⁺) and regulatory T (Treg) cells in PLN and pancreas. BMDC differentiated in the presence of A. muciniphila exhibited a tolerogenic profile and induced Treg cell generation in vitro. A. muciniphila-induced protection in T1D outcome was abrogated in FOXP3-DTR mice depleted of Treg cells, indicating that its mechanism of action is dependent on the CD4⁺Foxp3⁺ Treg cells.

Significance

A. muciniphila supplementation attenuates T1D development in mice by modulating the tolerogenic immune response and is a promising new therapeutic tool for this autoimmune disease.

Abstract Image

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在NOD和stz诱导的实验模型中，嗜粘杆菌通过诱导cDC2和Treg细胞分化抑制1型糖尿病的发病

AimsAkkermansia muciniphila （a . muciniphila）是一种在肠粘膜中发现的革兰氏阴性厌氧黏液层降解细菌，具有作为益生菌的潜力，在减轻自身免疫性和慢性炎症性疾病方面表现出希望。本研究旨在探讨嗜粘液芽胞杆菌补充剂是否可能对1型糖尿病（T1D）具有保护作用，并阐明其发挥有益作用的免疫途径。材料与方法采用非肥胖型糖尿病（NOD）小鼠和链脲佐菌素（STZ）诱导的1型糖尿病（T1D）模型，评价嗜粘杆菌在T1D过程中的保护作用。监测体重、血糖水平和T1D发病率。采用流式细胞术和ELISA检测胰腺、胰腺（PLN）、盲肠淋巴结（CLN）和骨髓源性树突状细胞（BMDC）的免疫应答。在stz诱导的T1D和NOD小鼠模型中，补充活的嗜粘液芽胞杆菌对T1D发作具有保护作用。在STZ模型中，嗜粘杆菌对T1D的调节与肠道菌群无关，与PLN和胰腺中耐受原2型树突状细胞（SIRP-α+CD11b+CD103+）和调节性T细胞（Treg）的增加有关。在嗜粘杆菌存在下分化的BMDC表现出耐受性，并在体外诱导Treg细胞生成。在Treg细胞缺失的Foxp3 - dtr小鼠中，A. muciniphila诱导的T1D结局保护作用被取消，表明其作用机制依赖于CD4+Foxp3+ Treg细胞。嗜粘菌补充通过调节耐受性免疫反应减轻小鼠T1D的发展，是一种有前途的自身免疫性疾病的新治疗工具。

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.