Rheumatoid arthritis (RA) is a chronic autoimmune disease with a complex and diverse etiology. The onset of RA is closely associated with intestinal flora, which is essential for immune regulation.
Fecal samples of 22 healthy controls and 38 patients with newly diagnosed RA were used for performing 16S rRNA sequencing, microbiota diversity assessment, and functional enrichment analysis. Through integrative analysis of random forest feature selection and bidirectional Mendelian randomization (MR), Eubacterium rectale was prioritized as a key bacterial candidate associated with RA. Furthermore, E. rectale was used to treat the arthritis model mice by gavage treatment, and we evaluated joint inflammation and immune cell profile in mice. Finally, untargeted metabolomics was used to evaluate the changes in serum and fecal metabolites in the arthritis mouse model before and after E. rectale intervention.
The beta diversity of the intestinal flora exhibited significant differences between RA patients and healthy controls (HC). Functional enrichment analysis revealed that RA patients' intestinal microbiota functions were enriched in pathways like genetic information processing and material metabolism. Further random forest model revealed E. rectale, Bacteroides, etc., and twelve genera with characteristic significance in RA patients. According to further MR analysis, Anaerostipes and E. rectale had a protective effect on RA, and reverse MR analysis showed no evidence of a causal relationship between these groups and RA. In vivo experiments showed that after the administration of E. rectale, the joint inflammation of the mice was relatively slight, the bone destruction and bone density of the joints improved, the proportion of Treg and follicular regulatory T cells (Tfr) cells increased, and the proportion of follicular helper T cells (Tfh) cells decreased. Metabolomic analysis revealed significant changes in both serum and fecal metabolites in mice with collagen-induced arthritis (CIA) compared with healthy controls. The changes in metabolites such as butyric acid were reversed after treatment with E. rectal.
The study demonstrates that E. rectale has a protective effect on RA. E. rectale significantly attenuates joint inflammation in mouse models by may regulating the expression level of butyrate, ameliorating the Treg and Tfr/Tfh immune imbalance status, and re-establishing the immune tolerance. These findings serve as valuable references for future studies on the pathogenesis of RA and the development of new therapeutic approaches.
Copyright © 2025 Liu, Wu, Fan, Qin, Li, Li, Gao and Wang.

Reprogramming tryptophan metabolism (TRP) may be able to overcome immunosuppression and restore the immune checkpoint blockade (ICB) response in patients with epithelial ovarian cancer (EOC) resistant to ICB therapy because TRP metabolism is involved in the kynurenine/indole and serotonin pathways of tryptophan metabolism. Herein, employing amitriptyline (AMI), an antagonist of TLR4 and serotonin transporter (SERT), we revealed that AMI remodels the immunological landscape of EOC. In particular, AMI lowered the expression of IDO1, IL-4I1, and PD-L1, the quantity of KYN and indoles, and the level of immunosuppressive immune cells MDSC, Tregs, and CD8+CD39+/PD-1+ T cell. AMI boosted the killing potential of anti-PD-1-directed CD8+T cells and worked in concert with PD-1 inhibitors to suppress tumor growth and to prolong the survival of EOC-bearing mice. This work highlights AMI as an effective regulator of ICB response by manipulating EOC cell TRP metabolism, indicating it could be a potential strategy for improving EOC ICB therapy.
© 2024 The Author(s).

During chronic infection, virus-specific CD8+ cytotoxic T lymphocytes (CTLs) progressively lose their ability to mount effective antiviral responses. This "exhaustion" is coupled to persistent upregulation of inhibitory receptor programmed death-1 (PD-1) (Pdcd1)-key in suppressing antiviral CTL responses. Here, we investigate allelic Pdcd1 subnuclear localization and transcription during acute and chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. Pdcd1 alleles dissociate from transcriptionally repressive chromatin domains (lamin B) in virus-specific exhausted CTLs but not in naive or effector CTLs. Relative to naive CTLs, nuclear positioning and Pdcd1-lamina dissociation in exhausted CTLs reflect loss of Pdcd1 promoter methylation and greater PD-1 upregulation, although a direct correlation is not observed in effector cells, 8 days post-infection. Genetic deletion of B lymphocyte-induced maturation protein 1 (Blimp-1) enhances Pdcd1-lamina dissociation in effector CTLs, suggesting that Blimp-1 contributes to maintaining Pdcd1 localization to repressive lamina. Our results identify mechanisms governing Pdcd1 subnuclear localization and the broader role of chromatin dynamics in T cell exhaustion.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Mutations in susceptibility alleles correlate with gut-inflammatory diseases, such as Crohn's disease; however, this does not often impact the disease progression indicating the existence of compensatory genes. We show that a reduction in Foxo3a expression in IL-10-deficient mice results in a spontaneous and aggressive Crohn's- like disease with 100% penetrance, which is rescued by deletion of myeloid cells, T cells and inhibition of mTORC1. In Foxo3a-/- IL-10-/- mice, there is poor cell death of myeloid cells in the gut, leading to increased accumulation of myeloid and T cells in the gut. Myeloid cells express high levels of inflammatory cytokines, and regulatory T cells are dysfunctional despite increased abundance. Foxo3a signaling represses the transcription of glutaminase (GLS/GLS2) to prevent over-consumption of glutamine by activated T cells and its conversion to glutamate that contributes to the TCA cycle and mTORC1 activation. Finally, we show that Foxo3a restricts the abundance of colitogenic microbiota in IL-10-deficient mice. Thus, by suppressing glutaminolysis in activated T cells Foxo3a mediates a critical checkpoint that prevents the development of fulminant gut inflammatory disease.
© 2021. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.

Brain tumor–initiating cells (BTICs) drive glioblastoma growth through not fully understood mechanisms. Here, we found that about 8% of cells within the human glioblastoma microenvironment coexpress programmed cell death 1 (PD-1) and BTIC marker. Gain- or loss-of-function studies revealed that tumor-intrinsic PD-1 promoted proliferation and self-renewal of BTICs. Phosphorylation of tyrosines within the cytoplasmic tail of PD-1 recruited Src homology 2–containing phosphatase 2 and activated the nuclear factor kB in BTICs. Notably, the tumor-intrinsic promoting effects of PD-1 did not require programmed cell death ligand 1(PD-L1) ligation; thus, the therapeutic antibodies inhibiting PD-1/PD-L1 interaction could not overcome the growth advantage of PD-1 in BTICs. Last, BTIC-intrinsic PD-1 accelerated intracranial tumor growth, and this occurred in mice lacking T and B cells. These findings point to a critical role for PD-1 in BTICs and uncover a nonimmune resistance mechanism of patients with glioblastoma to PD-1– or PD-L1–blocking therapies.