bims-ainimu 2026-02-08 papers

Issue of 2026–02–08
four papers selected by
Pedro Escoll Guerrero, Institut Pasteur

Front Immunol. 2025 ;16 1679493

Metabolic reprogramming tailors T cell immunity in sepsis.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, characterized by persistently high morbidity and mortality. Current treatment strategies have limitations, particularly the persistence of an immunosuppressed state. Recent studies have revealed that sepsis not only causes immune system dysregulation but also leads to metabolic disturbances, specifically metabolic reprogramming in T cells-a field still in its early stages. This review systematically explores the mechanisms of T-cell metabolic reprogramming in sepsis, including enhanced glycolysis, mitochondrial dysfunction, and dysregulated amino acid metabolism. It further analyzes how these alterations, mediated by signaling pathways such as HIF-1α, mTOR, and AMPK, as well as key metabolic enzymes, exacerbate T-cell exhaustion and immunosuppression. The article elaborates on the role of metabolic reprogramming in T-cell dysfunction and susceptibility to secondary infections, and summarizes potential therapeutic strategies targeting metabolic pathways-such as IL-7 therapy and IDO1 inhibitors-for restoring T-cell function, offering new directions for sepsis immunotherapy.

Keywords: T-cell immunity; immunosuppression; metabolic reprogramming; sepsis; therapeutic strategies

DOI: https://doi.org/10.3389/fimmu.2025.1679493

Cell Chem Biol. 2026 Feb 04. pii: S2451-9456(26)00023-1. [Epub ahead of print]

Aerobic glycolysis promotes NLRP3 inflammasome activation via NLRP3 lactylation.

Wei Liu, Tianyi Zhang, Bohong Wang, Hang Yin.

Bacteria-infected macrophages undergo pyroptosis to release inflammatory cytokines, which contributes to host defense. It has been known that activated macrophages involve metabolic reprogramming. However, the metabolic changes and the role of metabolites in pyroptotic macrophages are not fully understood. Here, we revealed that aerobic glycolysis product, lactate, could promote NLRP3 inflammasome activation induced pyroptosis. We found that endogenous lactate facilitates ASC recruitment to NLRP3 cores on the organelle membrane, thus inducing NLRP3 inflammasome complex formation. Mechanistically, we identified NLRP3 as a target protein modified by lactate, which is lactylated by AARS2. We confirmed lactylated sites on NLRP3 by LC-MS/MS analysis and verified that lactylation at K24 and K565 of NLRP3 facilitates inflammasome activation in macrophage. In vivo, inhibition of lactate production alleviates inflammatory responses in polymicrobial sepsis. Overall, our results indicate the role of lactate in regulating macrophage pyroptosis and the crosstalk between metabolism and innate immunity.

Keywords: NLRP3 inflammasome; lactylation; pyroptosis

DOI: https://doi.org/10.1016/j.chembiol.2026.01.003

Mater Today Bio. 2025 Dec;35 102266

A pathogen peptidoglycan scaffold coated with artificial biomembrane promotes broad resistance to bacterial infections by dynamically reprogramming macrophage metabolism.

Junjie Guo, Shuo Jia, Zibo Mai, Chaonan Wang, Zheng Jia, Jiaqing Wang, Xinran Yao, Jiaqi Liu, Fang Wang, Junwei Ge.

The increasing severity of multidrug-resistant (MDR) bacteria and the shortage of effective treatment strategies urgently require the development of new immunotherapies to combat superbug infections. Trained immunity may offer a novel and effective mechanism to combat resistant superbugs. However, there are currently few materials capable of effectively activating trained immunity, highlighting the need for new agents that provide more durable protection. In this study, we developed a bacterium-like particle (BLP) based on protein-free artificial biomembrane coating immune activator, named LM@pBLP, which features a simple and rapid preparation process, excellent biocompatibility, long-term stability, and a cost-effective advantage. LM@pBLP trains the immune system to target a broad range of pathogens, offering rapid, broad-spectrum, and long-lasting protection against MDR infections. After stimulation with LM@pBLP, it activates glutathione metabolism and amino acid metabolism, induces macrophage metabolic and epigenetic reprogramming changes, and regulates phagocytosis and inflammatory responses to infection. Additionally, LM@pBLP regulates reactive oxygen species (ROS), thereby maintaining oxidative stress homeostasis. Our study demonstrates that LM@pBLP primarily provides rapid, broad-spectrum, and long-lasting protection for experimental animals by activating trained immunity, which opens a new avenue for addressing MDR infections.

Keywords: Artificial biomembrane coating; Immune modulation; MRSA; Metabolic reprogramming; Trained immunity

DOI: https://doi.org/10.1016/j.mtbio.2025.102266

Clin Chest Med. 2026 Mar;pii: S0272-5231(25)00100-5. [Epub ahead of print]47(1): 119-128

The Gut Microbiome and Short-Chain Fatty Acid Metabolites in Sepsis.

Mark D Adame, Kathleen A Stringer, Robert P Dickson.

Sepsis profoundly perturbs the intestinal microbiome and its metabolite output, yet the mechanisms by which these changes influence organ injury remain incompletely defined. In this review, we focus on short-chain fatty acids (SCFAs) as key mediators linking gut microbes to sepsis pathophysiology. We first summarize how sepsis and its treatments reshape gut communities, depleting SCFA-producing anaerobes and altering the gut metabolome. We then examine determinants of SCFA concentrations in the intestinal lumen and describe how gut-blood trafficking of these charged metabolites depends on epithelial transporters and tight-junction-regulated paracellular pathways. We highlight emerging data on how leak and pore pathways, including claudin-2-dependent pores, are upregulated in sepsis and may misdirect microbial products into the portal and systemic circulation. Finally, we synthesize experimental and human evidence for organ-specific effects of individual SCFAs: butyrate as a colonocyte fuel and barrier stabilizer, propionate as a modulator of lung immune tone, and acetate as a systemic immunometabolite that shapes inflammatory responses and sepsis outcomes. Across these sections, we outline therapeutic strategies that aim to preserve or restore SCFA-producing microbes, modify diet, target transport and permeability pathways, or deliver microbial metabolites directly. Together, these data position SCFAs and their trafficking as central to the gut-sepsis axis and as promising targets for future precision therapies.

Keywords: Metabolism; Metabolites; Microbiome; Sepsis; Short chain fatty acids

DOI: https://doi.org/10.1016/j.ccm.2025.11.006