探討腸心軸於蠕蟲感染促動脈粥狀硬化消退之作用

Abstract

動脈粥樣硬化的進展和退行性變化與1 型和2 型免疫反應密切相關。先前研究表明，蠕蟲感染，如鞭蟲（Trichuris muris）和多角螺旋蟲（Heligmosomoides polygyrus），可誘導2型免疫反應和調節性T細胞（Tregs）的擴展，影響腸道微生物組。本研究探討蠕蟲誘導的2 型免疫對動脈粥樣硬化的緩解作用，著重研究C57BL/6小鼠（包括WT和Nod2-/-基因型）中腸道微生物群與免疫細胞亞群在主動脈弓和腸固有層的相互作用。通過16S rRNA 測序和光譜流式細胞術及CITE-seq，我們發現與疾病狀態相關的顯著微生物群變化。動脈粥樣硬化的進展與Blautia和Faecalibaculum的增加相關，而退行性變化則與產生丁酸鹽的菌屬如Butyricicoccus和Eubacterium Nodaum Group相關。免疫反應的變化包括某些巨噬細胞亞群的減少和主動脈弓中Th2細胞的增加，以及退行性變化期間腸固有層中Tregs細胞的增加。我們應用CITE-Seq分析了主動脈弓和腸固有層中免疫細胞群 的變化，探討了這些特定細胞群如何影響動脈粥樣硬化及其逆轉途徑。研究結果表明，微生物群與免疫的相互作用在動脈粥樣硬化的進展和退行中起關鍵作用，突顯了微生物群作為疾病階段生物標誌物的潛力，並提供了新療法的見解。

Atherosclerosis progression and regression have been previously linked to type 1and type 2 immune responses. Prior studies have demonstrated that helminth infections,specifically with Trichuris muris (T. muris) and Heligmosomoides polygyrus (H. poly), can induce strong type 2 immune responses and the expansion of regulatory T cells (Tregs),further influencing the composition of the gut microbiome. Our study explored the effectsof helminth-induced type 2 immunity in atherosclerosis, focusing on the interplay between gut microbiota and immune cell subsets in the aortic arch and gut lamina propria lymphocytesof C57BL/6 mice, including both WT and Nod2-/- genotypes. Through longitudinal microbiome survey via 16S rRNA sequencing and immune profiling with spectral flow cytometry and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), we identified significant microbiota alterations associated with disease states. Atherosclerosis progression correlated with genus increases in Blautia and Dubosiella, whereas regression was associated with butyrate-producing genera such as Butyricicoccus. Changes in immune response included a reduction in certain macrophage subsets and an increase in Th2 cells in the aortic arch, alongside an increase in Treg cells in the lamina propria during helminth-indued aortic plaque regression. We applied CITE-seq to map immune population shifts in the aortic arch and lamina propria to further acquire transcriptomic changes in atherosclerosis. We explored how these specific clusters affect atherosclerosis and their pathways to disease reversing. Our findings suggest a pivotal role of microbiome-immune interactions in atherosclerosis progression and helminth-induced aortic plaque regression, highlighting the microbiome’s potential as a biomarker for disease stages and providing insights into novel therapeutic strategies.