bims-ainimu 2026-01-18 papers

bims-ainimu

Biomed News

on AI & infection immunometabolism

Issue of 2026–01–18
six papers selected by
Pedro Escoll Guerrero, Institut Pasteur

Probiotic extracellular vesicles reprogram macrophage immunometabolism: From gut crosstalk to host health.
A Closed Computational-Experimental Loop Identifies Metabolic Collapse at the Root of Macrophage Dysfunction due to Zinc Dyshomeostasis.
Immunometabolism: Is cyanide a missing link between metabolic pathways and immune function?
Pseudopaline-mediated zinc uptake by Pseudomonas aeruginosa drives clinically relevant phenotypes and infection outcomes.
NK cell-derived exosomes restrict Mycobacterium tuberculosis infection by inhibiting cellular ferroptosis.
Artificial intelligence-enabled "inherited noninvasive intracellular recording" for prolonged monitoring of cardiac action potentials.

Gut Microbes. 2026 Dec 31. 18(1): 2614115

Probiotic extracellular vesicles reprogram macrophage immunometabolism: From gut crosstalk to host health.

Yan Li, Yihong Liu, Xubiao Wei, Changfa Wang, Muhammad Zahoor Khan, Qingshan Ma.

  Probiotic-derived extracellular vesicles (PEVs) are functional nanovesicles secreted by various microbiota. As a novel class of microbial signals, they encapsulate proteins, nucleic acids, lipids, and microbial-associated molecular patterns, emerging as potent modulators of communication between gut microbiota and host immune cells, such as macrophages. Macrophages, as a crucial component of the innate immune system, rely heavily on specific metabolic reprogramming to execute their immune functions effectively. Recent evidence demonstrates the pivotal role of macrophage immunometabolism in orchestrating inflammatory responses and regulating systemic metabolic health. This review provides the first comprehensive synthesis of current evidence linking PEVs to the function and metabolic reprogramming of macrophages. We first conducted a detailed exploration of the release rationale, biosynthesis, composition, uptake by macrophages, and biological activity of PEVs. Subsequently, we elucidated how these vesicles and their cargo influence macrophage polarization through several metabolic pathways, including glycolysis, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and amino acid metabolism. We further explore the implications of macrophage immunometabolism in chronic inflammation and metabolic disorders, including inflammatory bowel disease (IBD), neurodegenerative diseases, and atherosclerosis. Additionally, emerging evidence indicates that PEVs may be influenced by various factors, which in turn can affect host immunity and metabolism. Finally, we briefly discuss the limitations and future challenges in this field. This review highlights new research targets concerning the impact of gut microbiota on host immunity and metabolism.

Keywords:  Probiotics; bacterial extracellular vesicles; immunometabolism; macrophage; metabolic pathways

DOI:  https://doi.org/10.1080/19490976.2026.2614115
bioRxiv. 2026 Jan 11. pii: 2026.01.09.698698. [Epub ahead of print]

A Closed Computational-Experimental Loop Identifies Metabolic Collapse at the Root of Macrophage Dysfunction due to Zinc Dyshomeostasis.

Sunayana Malla, Deandra R Smith, Ashley M Peer, Derrick R Samuelson, Daren L Knoell, Rajib Saha.

Zinc plays a crucial role in immune regulation, the oxidative stress response, and epithelial barrier integrity, yet zinc's precise role in regulating metabolic and immunological functions in myeloid cells remains poorly understood. Here, we employ a systems biology approach using constraint-based modeling to elucidate the consequences of myeloid-specific loss of ZIP8 on macrophage metabolic function and antibacterial capabilities. We demonstrate that macrophage populations in the lung of ZIP8 knockout ( Zip8 KO) mice exhibit widespread metabolic disruption, spanning glycolysis, butanoate metabolism, amino acid metabolism, and mitochondrial function. Specifically, Zip8 KO macrophages exhibit impaired nutrient uptake and dysregulated energy metabolism, which is exacerbated following Streptococcus pneumoniae infection. Genome-scale metabolic modeling and flux analysis revealed a paradoxical pattern of metabolic suppression prior to infection, followed by overcompensation post-infection, potentially driving immune dysfunction. Consistent with these predictions Zip8 KO bone marrow-derived macrophages displayed increased ATP demand and disrupted mitochondrial energetics, compromising their ability to control infection. Importantly, we identified succinate, and kynurenic acid as metabolites capable of restoring immune responses and validated their ability to enhance bacterial clearance in Zip8 KO BMDMs. Together, these findings establish ZIP8 as a central regulator of immune-metabolic homeostasis and suggest potential therapeutic avenues to restore immune function in settings of zinc deficiency.

DOI: https://doi.org/10.64898/2026.01.09.698698
Biochem Pharmacol. 2026 Jan 08. pii: S0006-2952(26)00025-0. [Epub ahead of print]245 117694

Immunometabolism: Is cyanide a missing link between metabolic pathways and immune function?

Brian J Day.

  Immunometabolism is an emerging field that explores how metabolic pathways shape immune cell function, fate, and response. Immune cells undergo dynamic metabolic reprogramming to meet the energetic and biosynthetic demands of activation, differentiation, and effector activity. While glycolysis and oxidative phosphorylation (OxPhos) are well-established regulators of immune responses, recent discoveries suggest that endogenously produced cyanide may serve as a novel modulator of mitochondrial metabolism. Traditionally viewed as a toxic compound, cyanide is now being recognized for its potential role in regulating OxPhos through inhibition of complex IV in the electron transport chain, thereby influencing the balance between glycolysis and mitochondrial respiration. This review synthesizes current knowledge on the metabolic regulation of immune cells-including T cells, macrophages, dendritic cells, B cells, and natural killer (NK) cells-and highlights the role of core pathways such as glycolysis, fatty acid oxidation (FAO), and amino acid metabolism. It also explores how cyanide formation and metabolism intersect with innate immunity, particularly through the generation of thiocyanate and its role in antimicrobial defense. Furthermore, the review discusses how nutritional status integrate with metabolic cues to fine-tune immune responses. Finally, the clinical implications of immunometabolic regulation are examined in the context of autoimmune diseases, cancer, infections, and metabolic disorders. The potential of cyanide as a therapeutic modulator of immune metabolism is considered, offering new perspectives on immune regulation and disease intervention.

Keywords:  Cancer; Immunity; Infection; Inflammation; Metabolic disorders; Metabolic switch; Therapeutics

DOI:  https://doi.org/10.1016/j.bcp.2026.117694
Infect Immun. 2026 Jan 14. e0045325

Pseudopaline-mediated zinc uptake by Pseudomonas aeruginosa drives clinically relevant phenotypes and infection outcomes.

Lola Bosc, Thomas Sécher, Geneviève Ball, Deborah Le Pennec, Mathilde Tribout, Moly Ba, Yingjie Bai, Laurent Ouerdane, Pascal Arnoux, Yann Denis, Xiaoguang Lei, Christophe Bordi, Nathalie Heuzé-Vourc'h, Susanne Häussler, Nicolas Oswaldo Gomez, Romé Voulhoux.

  Biological metals are vital trace elements required by metalloproteins, which are involved in virtually every cellular, structural, and catalytic function of the bacterial cell. Bacterial pathogenesis involves a tug-of-war between the host's nutritional immunity sequestering essential metals and the invading pathogens that deploy adapted high-metal affinity uptake strategies, such as metallophores, in order to efficiently circumvent these defense mechanisms. Pseudopaline is a metallophore produced and secreted by Pseudomonas aeruginosa to acquire zinc when the bioavailability of this metal is severely restricted, as in the presence of a strong metal chelator such as EDTA, or during infections when the nutritional immunity of the host is active. We show that when facing strong metal chelation, the general Znu zinc uptake pathway becomes ineffective and only the pseudopaline pathway is capable of supplying the bacteria with the necessary zinc to maintain their growth, establishing that the pseudopaline pathway is the last-resort pathway for the bacteria to acquire zinc under such restricted growth conditions. Based on this statement, the present study explores the pleiotropic role of pseudopaline-mediated zinc acquisition on clinically relevant phenotypes such as biofilm formation and associated antibiotic tolerance, as well as its capacity to determine infection outcomes using cell-culture and murine models. The expression of pseudopaline-dependent phenotypes in such a diversity of biological contexts demonstrates the essentiality of this specific metal uptake system for P. aeruginosa pathogenicity during infection. We therefore identify this machinery as a promising therapeutic target for P. aeruginosa infections.

Keywords:  Pseudomonas aeruginosa; biofilm; metal uptake; metallophore; pathogenicity; pseudopaline; virulence

DOI:  https://doi.org/10.1128/iai.00453-25
J Trace Elem Med Biol. 2026 Jan 07. pii: S0946-672X(26)00003-9. [Epub ahead of print]93 127817

NK cell-derived exosomes restrict Mycobacterium tuberculosis infection by inhibiting cellular ferroptosis.

Linzhi Yue, Xuan Wang, Tao Ma, Yumei Dai, Wenya Du, Tongrui Fang, Ziyan Shang, Guofu Wang, Ling Geng, Tao Wang, Lixian Wu.

   BACKGROUND: Tuberculosis (TB) continues to pose a formidable global health threat, prompting the exploration of novel treatment strategies. The role of trace elements, especially iron, in TB pathogenesis is becoming increasingly recognized. Ferroptosis, an iron-dependent cell death process, has emerged as a key antimicrobial mechanism. This study aims to investigate whether exosomes derived from natural killer cells (NK-exo) can enhance host immune resistance to Mycobacterium tuberculosis (MTB) through the regulation of ferroptosis.
METHODS: We evaluated the therapeutic potential of NK-exo in both MTB-infected Ana-1 macrophages and a mouse model. Western blotting and RT-qPCR were employed to detect changes in the expression of ferroptosis proteins. Histopathological damage was assessed via H&E staining, and bacterial loads were quantified by CFU assays. To establish ferroptosis suppression as the mechanism through which NK-exo mitigates MTB infection, we treated cells with the ferroptosis activator RSL3 and examine whether this intervention consequently reversed the protective effects of NK-exo.
RESULTS: In both infected macrophages and mouse lung tissues, NK-exo treatment reduced the MTB load and effectively suppressed ROS accumulation and ferroptosis. Mechanistically, NK-exo exhibited dual regulation of the ferroptosis pathway by upregulating the expression of GPX4 while concomitantly downregulating the expression of SLC7A11, ACSL4, and TFRC. Crucially, the protective effects of NK-exo were abolished by co-treatment with RSL3, confirming that its mechanism hinges on the regulation of the ferroptosis pathway.
CONCLUSION: NK-exo mitigates MTB infection-induced lipid peroxidation and histopathological damage by targeting pivotal regulators of ferroptosis. These findings highlight the promise of NK-exo as a novel, cell-free immunotherapeutic strategy for Tuberculosis.

Keywords:  Ferroptosis; Mycobacterium tuberculosis; NK-exo; ROS; Tuberculosis

DOI:  https://doi.org/10.1016/j.jtemb.2026.127817
Sci Adv. 2026 Jan 16. 12(3): eady3617

Artificial intelligence-enabled "inherited noninvasive intracellular recording" for prolonged monitoring of cardiac action potentials.

Suhang Liu, Xingyuan Xu, Yijing Cai, Chuanjie Yao, Zhengjie Liu, Lisheng Hou, Minghao Li, Xiaotong Li, Yan Li, Guanbin Li, Mingqiang Li, Shuang Huang, Xinshuo Huang, Xi Chen, Ji Wang, Jing Liu, Hui-Jiuan Chen, Xi Xie.

Intracellular action potential (AP) recording that allows long-term monitoring is challenging because permanent membrane penetration is impossible due to cell death or resealing of perforated cell membrane. Herein, an "inherited noninvasive intracellular recording" methodology was proposed, which was based on the fusion of artificial intelligence (AI) with microelectrode array (MEA)-electroporation system (AI-MEA-EP) to enable prolonged monitoring of intracellular APs in cardiomyocytes. It used MEA-electroporation (MEA-EP) for minimally invasive collection of intracellular signals transiently (~1 minute), as well as noninvasive recording of extracellular signals in long term. The recorded extracellular APs were converted into corresponding intracellular APs by a convolutional neural network-long short-term memory-based AI model enhanced by model self-calibration. The intracellular APs detected by the AI-MEA-EP exhibited high consistency with those physically obtained through MEA-EP. It was demonstrated to monitor cardiac intracellular AP under drug treatments and glucose challenging during >5 consecutive days. This method offers a unique solution to achieve prolonged recording of intracellular signals for advancing cardiac research.

DOI: https://doi.org/10.1126/sciadv.ady3617