Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Rappaport Technion Integrated Cancer Center (RTICC), Haifa 32000, Israel.
Department of Gastroenterology, Rambam Health Care Campus, Haifa 3109601, Israel; Clinical Research Institute, Rambam Health Care Campus, Haifa 3109601, Israel.
Cell Host Microbe. 2024 Mar 13;32(3):322-334.e9. doi: 10.1016/j.chom.2024.02.003. Epub 2024 Feb 28.
Reversible genomic DNA inversions control the expression of numerous gut bacterial molecules, but how this impacts disease remains uncertain. By analyzing metagenomic samples from inflammatory bowel disease (IBD) cohorts, we identified multiple invertible regions where a particular orientation correlated with disease. These include the promoter of polysaccharide A (PSA) of Bacteroides fragilis, which induces regulatory T cells (Tregs) and ameliorates experimental colitis. The PSA promoter was mostly oriented "OFF" in IBD patients, which correlated with increased B. fragilis-associated bacteriophages. Similarly, in mice colonized with a healthy human microbiota and B. fragilis, induction of colitis caused a decline of PSA in the "ON" orientation that reversed as inflammation resolved. Monocolonization of mice with B. fragilis revealed that bacteriophage infection increased the frequency of PSA in the "OFF" orientation, causing reduced PSA expression and decreased Treg cells. Altogether, we reveal dynamic bacterial phase variations driven by bacteriophages and host inflammation, signifying bacterial functional plasticity during disease.
可反转的基因组 DNA 倒位控制着众多肠道细菌分子的表达，但这如何影响疾病尚不清楚。通过分析炎症性肠病 (IBD) 队列的宏基因组样本，我们确定了多个可反转的区域，其中特定的取向与疾病相关。这些区域包括脆弱拟杆菌多糖 A (PSA) 的启动子，它能诱导调节性 T 细胞 (Treg) 并改善实验性结肠炎。PSA 启动子在 IBD 患者中主要呈“关闭”状态，这与增加的脆弱拟杆菌相关噬菌体有关。同样，在定植有健康人类微生物组和脆弱拟杆菌的小鼠中，结肠炎的诱导导致 PSA 在“开启”状态下的表达下降，而随着炎症的缓解，这种下降又得到逆转。用脆弱拟杆菌单定植小鼠表明，噬菌体感染增加了 PSA 在“关闭”状态下的频率，导致 PSA 表达减少和 Treg 细胞减少。总之，我们揭示了由噬菌体和宿主炎症驱动的细菌动态相位变化，这表明了细菌在疾病过程中的功能可塑性。
