01
Li Zhang, et al.
Cell Metab. 2024
The pathogenesis of irritable bowel syndrome (IBS) with diarrhea (IBS-D) is related to many factors including psychological stress, abnormal muscle contraction, inflammation and intestinal flora disturbance. However, a comprehensive analysis of the logical regulatory correlation between these factors is lacking. In this study, researchers found that stress induced excessive production of xanthine in the serum of IBS-D patients and mice, and demonstrated in vivo that xanthine could directly induce the production of symptoms associated with IBS. Through metagenomic sequencing on mice stool, they found that stress and xanthine treatment directly altered the abundance and metabolic profile of Lactobacillus murinus in mice's gut. Further investigation showed that the amplified Lactobacillus murinus produced large amounts of spermidine, which directly induced the occurrence of IBS-D. Researchers unraveled that spermidine can inhibit the k63 polyubiquitination of TRAF3 and inhibit the basal expression of type I interferon (IFN)-α in plasmacytoid dendritic cells (pDC). The reduction of type 1 interferon can directly promote the contraction of colon smooth muscle cells, resulting in increased defecation. These results elucidated the detailed molecular mechanisms of stress-induced IBS-D, revealing the intrinsic links between immune metabolism disorders, mental stress, microbiome disturbance and colon smooth muscle contraction dysfunction.
DOI: 10.1016/j.cmet.2024.09.002
02
Teplizumab is the first drug approved by the U.S. Food and Drug Administration (FDA) for delaying the onset of type 1 diabetes (T1D) in high-risk patients. Previous literature described the immediate effects of the 14-day treatment, but longer-term effects of the drug remain unknown. In this study, the authors analyzed peripheral blood cells from participants in the clinical trial with stage 2 T1D who were at high risk for progression to clinical stage 3 T1D. Through flow cytometry, single-cell RNA sequencing (scRNA-Seq) and bulk RNA-Seq, they analyzed the transcriptome and phenotypes of cells in circulating peripheral blood mononuclear cells (PBMCs) before and up to 18 months after treatment with teplizumab or placebo. Results showed that there was initially an increase in transcriptomic signatures of cell activation of CD8+ T cells followed by a decline and differentiation of cells into effector cells with features of exhaustion and regulation at 18 months. They further confirmed that Teplizumab treatment reduced expression of IL7R in CD8+ T cells, which is needed for their growth and expansion. In consistence, expansion of autoantigen-reactive CD8+ T cells in teplizumab-treated patients was also reduced. Their observations suggested that anti-CD3 monoclonal antibodies affected multiple immune cell subsets, including differentiation into CD8+ cells with regulatory and exhaustion features and prevention of expansion of autoantigen-specific CD8+ T cells in T1D.
DOI: 10.1172/JCI177492
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