Psychological stress has profound impacts on the gastrointestinal tract via the brain‒gut axis. However, its effects on intestinal stem cells (ISCs) and the resulting implication for intestinal homeostasis remain poorly understood. Here, we observed a notable reduction in both the quantity and proliferative capacity of ISCs under chronic stress conditions, driven by elevated levels of corticosterone resulting from activation of the hypothalamic‒pituitary‒adrenal (HPA) axis. Mechanistically, corticosterone directly interacts with its receptor, nuclear receptor subfamily 3 group c member 1 (NR3C1), leading to increased expression of FKBP prolyl isomerase 5 (FKBP5) in ISCs. Subsequently, FKBP5 negatively regulates AKT activation by facilitating its dephosphorylation at Ser473, ultimately enhancing nuclear translocation of forkhead box O (FoxO) and inhibiting ISC proliferative activity. Consequently, ISC dysfunction contributes to the stress-driven exacerbation of DSS-induced colitis. Collectively, these findings reveal an intrinsic brain-to-gut regulatory pathway whereby psychological stress impairs ISC activity via corticosterone elevation, providing a mechanistic explanation for stress-enhanced susceptibility to colitis.
© 2025. The Author(s).

Leptospirosis is a globally neglected re-emerging zoonosis affecting all mammals, albeit with variable outcomes. Humans are susceptible to leptospirosis; infection with Leptospira interrogans species can cause severe disease in humans, with multi-organ failure, mainly affecting kidney, lung and liver function, leading to death in 10% of cases. Mice and rats are more resistant to acute disease and can carry leptospires asymptomatically in the kidneys and act as reservoirs, shedding leptospires into the environment. The incidence of leptospirosis is higher in tropical countries, and countries with poor sanitation, where heavy rainfall and flooding favour infection. Diagnosis of leptospirosis is difficult because of the many different serovars and the variety of clinical symptoms that can be confused with viral infections. The physiopathology is poorly understood, and leptospirosis is often regarded as an inflammatory disease, like sepsis.
To investigate the causes of death in lethal leptospirosis, we compared intraperitoneal infection of male and female C57BL6/J mice with 108Leptospira of two strains of pathogenic L. interrogans. One strain, L. interrogans Manilae L495, killed the mice 4 days after infection, whereas the other strain, L. interrogans Icterohaemorrhagiae Verdun, did not induce any major symptoms in the mice. On day 3 post infection, the mice were humanely euthanised and blood and organs were collected. Bacterial load, biochemical parameters, cytokine production and leucocyte population were assessed by qPCR, ELISA, cytometry and immunohistochemistry.
Neither lung, liver, pancreas or kidney damage nor massive necroptosis or cytokine storm could explain the lethality. Although we did not find pro-inflammatory cytokines, we did find elevated levels of the anti-inflammatory cytokine IL-10 and the chemokine RANTES in the serum and organs of Leptospira-infected mice. In contrast, severe leptospirosis was associated with neutrophilia and vascular permeability, unexpectedly due to neutrophils and not only due to Leptospira infection. Strikingly, the main cause of death was myocarditis, an overlooked complication of human leptospirosis.
Despite clinical similarities between bacterial sepsis and leptospirosis, striking differences were observed, in particular a lack of cytokine storm in acute leptospirosis. The fact that IL-10 was increased in infected mice may explain the lack of pro-inflammatory cytokines, emphasising the covert nature of Leptospira infections. Neutrophilia is a hallmark of human leptospirosis. Our findings confirm the ineffective control of infection by neutrophils and highlight their deleterious role in vascular permeability, previously only attributed to the ability of leptospires to damage and cross endothelial junctions. Finally, the identification of death due to myocarditis rather than kidney, liver or liver failure may reflect an overlooked but common symptom associated with poor prognosis in human leptospirosis. These features of neutrophilia and myocarditis are also seen in patients, making this mouse model a paradigm for better understanding human leptospirosis and designing new therapeutic strategies.
The Boneca laboratory was supported by the following programmes: Investissement d'Avenir program, Laboratoire d'Excellence "Integrative Biology of Emerging Infectious Diseases" (ANR-10-LABX-62-IBEID) and by R&D grants from Danone and MEIJI. CW received an ICRAD/ANR grant (S-CR23012-ANR 22 ICRD 0004 01). SP received a scholarship by Université Paris Cité (formerly Université Paris V - Descartes) through Doctoral School BioSPC (ED562, BioSPC). SP has additionally received a scholarship "Fin de Thèse de Science" number FDT202404018322 granted by "Fondation pour la Recherche Médicale (FRM)". The funders had no implication in the design, analysis and reporting of the study.
Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.

Naïve B cells become activated and differentiate into antibody-secreting plasma cells (PCs) when encountering antigens. Here, we reveal that the WW domain-containing adapter protein with coiled-coil (Wac), which is important for histone H2B ubiquitination (ubH2B), is essential for PC differentiation. We demonstrate that B cell-specific Wac knockout mice have severely compromised T cell-dependent and -independent antibody responses. PC differentiation is drastically compromised despite undisturbed germinal center B cell response in the mutant mice. We also observe a significant reduction in global ubH2B in Wac-deficient B cells, which is correlated with downregulated expression of some genes critical for cell metabolism. Thus, our findings demonstrate an essential role of Wac-mediated ubH2B in PC differentiation and shed light on the epigenetic mechanisms underlying this process.
© 2023 Federation of European Biochemical Societies.

Neural stem cells (NSCs) in the adult murine subependymal zone balance their self-renewal capacity and glial identity with the potential to generate neurons during the lifetime. Adult NSCs exhibit lineage priming via pro-neurogenic fate determinants. However, the protein levels of the neural fate determinants are not sufficient to drive direct differentiation of adult NSCs, which raises the question of how cells along the neurogenic lineage avoid different conflicting fate choices, such as self-renewal and differentiation. Here, we identify RNA-binding protein MEX3A as a post-transcriptional regulator of a set of stemness associated transcripts at critical transitions in the subependymal neurogenic lineage. MEX3A regulates a quiescence-related RNA signature in activated NSCs that is needed for their return to quiescence, playing a role in the long-term maintenance of the NSC pool. Furthermore, it is required for the repression of the same program at the onset of neuronal differentiation. Our data indicate that MEX3A is a pivotal regulator of adult murine neurogenesis acting as a translational remodeller.
© 2023. The Author(s).

Cell differentiation involves profound changes in global gene expression that often has to occur in coordination with cell cycle exit. Because cyclin-dependent kinase inhibitor p27 reportedly regulates proliferation of neural progenitor cells in the subependymal neurogenic niche of the adult mouse brain, but can also have effects on gene expression, we decided to molecularly analyze its role in adult neurogenesis and oligodendrogenesis. At the cell level, we show that p27 restricts residual cyclin-dependent kinase activity after mitogen withdrawal to antagonize cycling, but it is not essential for cell cycle exit. By integrating genome-wide gene expression and chromatin accessibility data, we find that p27 is coincidentally necessary to repress many genes involved in the transit from multipotentiality to differentiation, including those coding for neural progenitor transcription factors SOX2, OLIG2 and ASCL1. Our data reveal both a direct association of p27 with regulatory sequences in the three genes and an additional hierarchical relationship where p27 repression of Sox2 leads to reduced levels of its downstream targets Olig2 and Ascl1. In vivo, p27 is also required for the regulation of the proper level of SOX2 necessary for neuroblasts and oligodendroglial progenitor cells to timely exit cell cycle in a lineage-dependent manner.
© 2023. The Author(s).