bims-imicid 2025-10-05 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–10–05
twenty-two papers selected by
Dylan Ryan, University of Cambridge

Steroid hormone regulation of immunometabolism and inflammation.
Improving Immune Checkpoint Therapy in the Tumor Microenvironment by Targeting T Cell Metabolism.
Effect of antibiotics on Kupffer cell immunometabolism relative to intracellular killing of S. aureus using NAD(P)H fluorescence lifetime imaging.
Immunometabolic reprogramming of macrophages by gut microbiota-derived cadaverine controls colon inflammation.
Fatty acid binding protein 2 (FATP2/SLC27A2) blockade with Lipofermata elicits dual effects on inflammatory responses in human monocytes and macrophages.
Metabolic profiling of antigen-specific CD8+ T cells by spectral flow cytometry.
Acetyl-CoA carboxylase-1 inhibition increases regulatory T-Cell metabolism and graft-vs-host disease treatment efficacy via mitochondrial fusion.
HBV and host metabolic crosstalk: reprogramming pathways for viral replication and pathogenesis.
Macrophage plasticity and glucose metabolism: the role of immunometabolism in pulmonary arterial hypertension.
IRG1 catalyzed energy metabolite itaconic acid restrains type I interferon-dependent immune responses by alkylation of TBK1.
Metabolic adaptation to host acetate facilitates oxidative stress resistance and intracellular survival of Neisseria meningitidis in macrophages.
Targeting mitochondrial Kv1.3 enables precise autoreactive T cell therapy for multiple sclerosis.
Targeting Tryptophan Metabolism for Tuberculosis Biomarkers and Host Directed Therapy.
Dietary cysteine enhances intestinal stemness via CD8+ T cell-derived IL-22.
Effect of the gut microbiota-derived tryptophan metabolite indole-3-acetic acid in pneumonia.
The MyD88 inhibitor TJ-M2010-5 protects against obesity in mice by suppressing macrophage-induced metabolic inflammation.
Microglial glycolytic reprogramming in alzheimer's disease: association with impaired phagocytic function and altered vascular proximity.
The role of dietary fibre in lung inflammation: microbiota, metabolites, and immune crosstalk.
Toxoplasma gondii alters gut microbiota and systemic metabolism in cats: A multi-omics approach.
Palmitic acid induces macrophage sialylation via TLR4/MyD88/TRAF6/NF-κB signaling.
cGAS Inhibits ALDH2 to Suppress Lipid Droplet Function and Regulate MASLD Progression.
Bmal1 is involved in the regulation of macrophage cholesterol homeostasis.

Front Immunol. 2025 ;16 1654034

Steroid hormone regulation of immunometabolism and inflammation.

Ley Cody Smith, Mohankumar Ramar, Gregory L Riley, Clinton B Mathias, Ji-Young Lee.

  The metabolism of immune cells adapts to support the energy demands for their activation, differentiation, and effector functions through a process known as metabolic reprogramming. This metabolic plasticity is influenced by both extrinsic and intrinsic factors, including steroid hormones such as glucocorticoids, androgens, progestogens, and estrogens. These critical mediators modulate immune function and inflammatory responses through genomic and non-genomic regulation of intracellular metabolic pathways, including glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation. Interestingly, these effects appear to be dependent on cell type, hormonal concentration, and microenvironmental context. Herein, we discuss how steroid hormones regulate inflammation and immunometabolism and summarize recent studies highlighting immunometabolic regulation by steroid hormones as the key driver of their immunomodulatory effects. We also address potential mechanisms contributing to their seemingly dichotomous and context-specific regulation. Understanding the link between steroid hormone signaling, immunometabolism, host defense, chronic inflammation, and immunity will expand our understanding about how biological sex and stress influence the immune system and facilitate more precise therapeutic targeting of immune cell activity to mitigate inflammation- and immune-mediated diseases.

Keywords:  glycolysis; immune; immunometabolism; inflammation; oxidative phosphorylation; steroid hormones

DOI:  https://doi.org/10.3389/fimmu.2025.1654034
Endocr Metab Immune Disord Drug Targets. 2025 Sep 02.

Improving Immune Checkpoint Therapy in the Tumor Microenvironment by Targeting T Cell Metabolism.

Jun Wei, Baozhen An, Renchao Dong, Xinyi Tu, Yifei Dong, Yuang Liu, Yanqiu Liu.

  To meet the increased nutrient requirements associated with rapid cellular proliferation, tumor cells undergo metabolic reprogramming, characterized by a substantial increase in the production of energy and precursor molecules necessary for biosynthetic processes. Similarly, T cells experience metabolic reprogramming to support their proliferation and immunological functions, leading to metabolic competition with tumor cells within the tumor microenvironment (TME). This metabolic competition adversely affects T cell activation, proliferation, and immune function, primarily due to the limited availability of glucose, lipids, and amino acids. Furthermore, cytokines and immune checkpoints significantly impact T cell-mediated immunoreactivity. Modulating the metabolism of tumor cells and T cell-mediated immune evasion within the TME is of paramount importance. Notably, the metabolism of small-molecule target agents has garnered considerable attention in the context of the TME. This study aimed to examine the influence of various microenvironmental factors on T cell metabolism and explore corresponding innovative therapeutic approaches, thereby offering a comprehensive array of potential clinical strategies for cancer prevention and treatment.

Keywords:  T cell metabolism; combination therapy.; immune checkpoint; nutrient competition; tumor immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.2174/0118715303400871250821103310
mBio. 2025 Sep 30. e0212425

Effect of antibiotics on Kupffer cell immunometabolism relative to intracellular killing of S. aureus using NAD(P)H fluorescence lifetime imaging.

Brent Beadell, Annie Wong-Beringer.

  Staphylococcus aureus bacteremia (SAB) remains a significant clinical burden with high mortality rates. Kupffer cells (KCs) are integral to clearing Staphylococcus aureus (SA) from the bloodstream yet also serve as a pathogenic reservoir, driving persistence and treatment failure. KCs utilize their metabolic plasticity to coordinate successful antimicrobial responses, and this process may be therapeutically targeted. We investigated the immunometabolic effects of antistaphylococcal antibiotics (vancomycin, ceftobiprole, daptomycin, and tedizolid) on KCs relative to clearance of intracellular SA through gene expression analysis and optical metabolic imaging using fluorescence lifetime imaging microscopy. We observed differential effects of antibiotics on KC polarization and metabolic signatures, with ceftobiprole inducing the strongest pro-inflammatory M1 expression profile and shortest mean NAD(P)H fluorescence lifetime in KCs in the absence of infection, and a retained M1 expression profile but longest NAD(P)H lifetime during infection. Daptomycin and tedizolid most effectively cleared intracellular SA, induced significantly longer NAD(P)H lifetimes, and exhibited decreased M1 gene expression. Vancomycin failed to control intracellular infection showing blunted M1 expression without altering NAD(P)H lifetimes. Stratification of NAD(P)H lifetime signals revealed daptomycin significantly increased binding to PDH-like enzymes and nitric oxide synthase 2 compared to other antibiotics. These findings reveal novel insights into antibiotic modulation of KC immunometabolism during SA infection, which may influence treatment outcomes in SAB.IMPORTANCEStaphylococcus aureus bloodstream infection is a leading cause of sepsis and is associated with up to 30% mortality. Despite treatment with guideline-recommended antibiotics, persistent bacteremia develops in one in three patients, which may be attributed in part to survival of bacteria inside liver-resident macrophages known as KCs. Using gene expression and optical metabolic profiling, we demonstrated that antistaphylococcal antibiotics differentially affect KC metabolism and function, thereby contributing to the overall killing of intracellular bacteria. Daptomycin, ceftobiprole, and tedizolid exert distinct effects on KC metabolism that correspond to effective intracellular killing and prompt resolution of inflammatory response. Vancomycin, however, did not affect KC metabolism and was unable to control bacterial growth inside the cells. These findings suggest that choosing antibiotics based on direct antimicrobial activity as well as indirect effects on host immune function could improve treatment outcomes for patients with S. aureus bloodstream infection.

Keywords:  Kupffer cells; Staphylococcus aureus; antibiotics; bloodstream infections; ceftobiprole; daptomycin; immunometabolism; macrophages; tedizolid; vancomycin

DOI:  https://doi.org/10.1128/mbio.02124-25
Cell Host Microbe. 2025 Sep 30. pii: S1931-3128(25)00375-0. [Epub ahead of print]

Immunometabolic reprogramming of macrophages by gut microbiota-derived cadaverine controls colon inflammation.

Rodrigo de Oliveira Formiga, Qing Li, Yining Zhao, Márcio Augusto Campos Ribeiro, Perle Guarino-Vignon, Rand Fatouh, Leonard Dubois, Laura Creusot, Virginie Puchois, Salomé Amouyal, Iria Alonso Salgueiro, Marius Bredon, Loïc Chollet, Tatiana Ledent, Cyril Scandola, Jean-Philippe Auger, Camille Danne, Gerhard Krönke, Emma Tkacz, Patrick Emond, Guillaume Chevreux, Hang Phuong Pham, Clément Pontoizeau, Antonin Lamaziere, Rafael José Argüello, Nathalie Rolhion, Marie-Laure Michel, Timothy Wai, Harry Sokol.

  Cadaverine is a polyamine produced by the gut microbiota with links to health and disease, notably inflammatory bowel disease (IBD). Here, we show that cadaverine shapes monocyte-macrophage immunometabolism in a context- and concentration-dependent fashion to impact macrophage functionality. At baseline, cadaverine is taken up via L-lysine transporters and activates the thioredoxin system, while during inflammation, cadaverine signals through aconitate decarboxylase 1 (Acod1)-itaconate. Both pathways induce activation of transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), which supports mitochondrial respiration and promotes immunoregulatory macrophage polarization. Conversely, under higher concentrations, cadaverine acts via histamine 4 receptor, leading to glycolysis-driven inflammation and pro-inflammatory functions in macrophages. Likewise, cadaverine exhibits paradoxical effects in experimental colitis, either protective or detrimental, evoking opposite fates on macrophages depending on levels dictated by Enterobacteriaceae. In IBD patients, elevated cadaverine correlated with higher flare risk. Our findings implicate cadaverine as a microbiota-derived metabolite manipulating macrophage energy metabolism with consequences in intestinal inflammation and implications for IBD pathogenesis.

Keywords:  IBD; cadaverine; cell energy metabolism; gut microbiota; macrophage; metabolite; microbiome; monocyte

DOI:  https://doi.org/10.1016/j.chom.2025.09.009
Immunol Lett. 2025 Sep 25. pii: S0165-2478(25)00125-7. [Epub ahead of print]277 107092

Fatty acid binding protein 2 (FATP2/SLC27A2) blockade with Lipofermata elicits dual effects on inflammatory responses in human monocytes and macrophages.

Nico Hahn, Serhii Chornyi, Daan Heister, Helga E de Vries, Martin Giera, Mariëtte R Boon, Gijs Kooij, Jan Van den Bossche.

  Inflammatory responses often involve metabolic rewiring within immune cells to support effector functions. Targeting metabolic pathways in immune cells therefore represents a promising strategy to modulate inflammatory diseases and improve therapeutic outcomes. Acyl-CoA synthesis by fatty acid transporter 2 (FATP2/SLC27A2) facilitates the transport of long-chain fatty acids into the cell. It represents a key step in fatty acid metabolism and the subsequent production of bioactive lipid mediators (LMs) with immunoregulatory functions. While the FATP2 inhibitor Lipofermata is currently evaluated for lipid-lowering therapies in metabolic diseases, and to revert the suppressive nature of myeloid cells in cancer, its effect on inflammatory responses in human macrophages remains elusive. Here, we show that Lipofermata reduced LPS-induced inflammatory responses in whole blood and human monocytes. This anti-inflammatory effect was paralleled by a decreased biosynthesis of arachidonic acid-derived inflammatory LMs, including prostaglandin E2 (PGE2) and thromboxane 2 (TxB2). These findings suggest an anti-inflammatory effect mediated by Lipofermata-mediated redirection of lipid metabolism in monocytes. Conversely, in mature human monocyte-derived macrophages, Lipofermata treatment enhanced LPS-induced cytokine production and induced cell death, likely through inflammasome activation. Together, these results underscore the cell type-specific effects of FATP2 inhibition and highlight the dual role of Lipofermata in modulating inflammatory immune responses. As such, targeting lipid metabolism with Lipofermata could have therapeutic potential with both anti- and pro-inflammatory applications, depending on the target cell type and context.

Keywords:  Fatty acid metabolism; Human monocyte-derived macrophages; Immunology; Immunometabolism; Metabolism

DOI:  https://doi.org/10.1016/j.imlet.2025.107092
Cell Rep Methods. 2025 Sep 26. pii: S2667-2375(25)00221-8. [Epub ahead of print] 101185

Metabolic profiling of antigen-specific CD8+ T cells by spectral flow cytometry.

Nils Mülling, J Fréderique de Graaf, Graham A Heieis, Kristina Boss, Benjamin Wilde, Bart Everts, Ramon Arens.

  Cytotoxic CD8+ T cells are essential mediators of immune responses against viral infections and tumors. Upon antigen encounter, antigen-specific CD8+ T cells undergo clonal expansion and produce effector cytokines, processes that require dynamic metabolic adaptation. However, profiling antigen-specific T cells at single-cell resolution remains technically challenging. We present a spectral flow cytometry-based workflow enabling metabolic profiling of antigen-specific CD8+ T cells identified via major histocompatibility complex (MHC) class I tetramers or CD137 upregulation. The approach integrates the analysis of metabolic protein expression to infer pathway activity, uptake of fluorescent probes to measure functional metabolism and metabolite utilization, and assays evaluating cellular energy metabolism. Applied to human and mouse samples, this method defined the metabolic profiles of cytomegalovirus-, SARS-CoV-2-, and tumor-specific CD8+ T cells across distinct activation states and tissues. By detailing each component of the workflow, we provide practical guidance for applying metabolic spectral flow cytometry to dissect disease mechanisms and therapeutic responses.

Keywords:  CP: immunology; CP: metabolism; T cell; antigen-specific; metabolism; spectral flow cytometry

DOI:  https://doi.org/10.1016/j.crmeth.2025.101185
J Clin Invest. 2025 Sep 30. pii: e182480. [Epub ahead of print]

Acetyl-CoA carboxylase-1 inhibition increases regulatory T-Cell metabolism and graft-vs-host disease treatment efficacy via mitochondrial fusion.

Cameron McDonald-Hyman, Ethan G Aguilar, Ewoud B Compeer, Michael C Zaiken, Stephanie Y Rhee, Fathima A Mohamed, Jemma H Larson, Michael L Loschi, Christopher Lees, Govindarajan Thangavelu, Margaret L Sleeth, Kyle D Smith, Jennifer S Whangbo, Jerome Ritz, Tim D Sparwasser, Roddy S O'Connor, Peter A Crawford, Jeffrey C Rathmell, Leslie S Kean, Robert Zeiser, Keli L Hippen, Michael L Dustin, Bruce R Blazar.

  Regulatory T-cells (Treg) are critical for maintaining immune homeostasis, and their adoptive transfer can treat murine inflammatory disorders. In patients, Treg therapies have been variably efficacious. Therefore, new strategies to enhance Treg therapeutic efficacy are needed. Treg predominantly depend upon oxidative phosphorylation (OXPHOS) for energy and suppressive function. Fatty acid oxidation (FAO) contributes to Treg OXPHOS and can be important for Treg "effector" differentiation, but FAO activity is inhibited by coordinated activity of isoenzymes acetyl-CoA Carboxylase-1 and -2 (ACC1/2). Here, we show that small molecule inhibition or Treg-specific genetic deletion of ACC1 significantly increases Treg suppressive function in vitro and in mice with established chronic GVHD. ACC1 inhibition skewed Treg towards an "effector" phenotype and enhanced FAO-mediated OXPHOS, mitochondrial function, and mitochondrial fusion. Inhibiting mitochondrial fusion diminished the effect of ACC1 inhibition. Reciprocally, promoting mitochondrial fusion, even in the absence of ACC1 modulation, resulted in a Treg functional and metabolic phenotype similar to ACC1 inhibition, indicating a key role for mitochondrial fusion in Treg suppressive potency. Ex vivo expanded, ACC1 inhibitor treated human Treg similarly augmented suppressor function as observed with murine Treg. Together, these data suggest that ACC1 manipulation may be exploited to modulate Treg function in patients.

Keywords:  Bone marrow transplantation; Immunology; Metabolism; Mitochondria; T cells

DOI:  https://doi.org/10.1172/JCI182480
Virol Sin. 2025 Sep 27. pii: S1995-820X(25)00134-8. [Epub ahead of print]

HBV and host metabolic crosstalk: reprogramming pathways for viral replication and pathogenesis.

YanYing Yan, Zhiqiang Wei, Min Zheng, Mengji Lu, Xueyu Wang.

  Hepatitis B virus (HBV) establishes chronic infection through strategic manipulation of host metabolic networks, driving a spectrum of hepatic pathologies ranging from hepatitis to cirrhosis and hepatocellular carcinoma. Mechanistically, HBV reprograms core metabolic pathways, including glycolysis, tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and lipid homeostasis, to fuel its replication machinery and evade immune surveillance. This review systematically synthesizes current evidence on HBV-induced glucose/lipid metabolic rewiring, with particular emphasis on how viral-host crosstalk at the metabolic interface sustains viral pathogenesis.

Keywords:  HBV; TCA cycle; glycolysis; lipid metabolism; metabolic rewiring; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.virs.2025.09.008
Clin Sci (Lond). 2025 Oct 01. pii: CS20257363. [Epub ahead of print]138(19):

Macrophage plasticity and glucose metabolism: the role of immunometabolism in pulmonary arterial hypertension.

Lindsay Jefferson, Patricia D A Lima, Stephen L Archer.

  Pulmonary arterial hypertension (PAH) is a syndrome characterized by a mean pulmonary artery pressure >20 mmHg and elevated pulmonary vascular resistance >2 Wood Units in the absence of left heart disease, chronic lung disease or hypoxia, and chronic thromboembolic disease. PAH is an obliterative pulmonary arteriopathy that leads to morbidity and mortality, often due to right ventricular failure (RVF). Emerging evidence from preclinical research, using chemical inhibition or genetic depletion of inflammatory mediators, reveals a role for inflammation in the adverse pulmonary vascular remodelling in PAH. More recently, studies have also identified inflammation of the right ventricle (RV) as a potential contributor to RV decompensation and failure. While inflammation contributes to the pathogenesis of PAH, no approved PH-targeted therapies specifically target inflammation. Macrophages are myeloid cells that play a critical role in inflammation and PAH. Their cellular plasticity enables the acquisition of tissue-specific phenotypes and functions that may promote either resolution or exacerbation of inflammatory signalling. Macrophage plasticity in PAH is poorly understood. We examine how alterations in glucose metabolism, particularly the uncoupling of glycolysis from glucose oxidation-a notable feature of PAH observed in various cell populations-impact macrophage polarization and the inflammatory phenotype associated with PAH. The study of immune cell metabolism, known as immunometabolism, is an emerging field that has yet to be explored in PAH. Improving understanding of the inflammatory mechanisms in PAH, particularly novel pathways related to macrophage immunometabolism, may identify new targets for anti-inflammatory therapies for PAH.

Keywords:  NOD-like receptor protein 3 (NLRP3); interleukin 1 beta (IL-1β); itaconate; mitochondrial metabolism; pyruvate dehydrogenase kinase; succinate dehydrogenase

DOI:  https://doi.org/10.1042/CS20257363
Cell Rep. 2025 Sep 26. pii: S2211-1247(25)01107-6. [Epub ahead of print]44(10): 116336

IRG1 catalyzed energy metabolite itaconic acid restrains type I interferon-dependent immune responses by alkylation of TBK1.

Li Chai, Chaoqun Li, Xuefeng Wang, Yanyang Qin, Hemin Sun, Jie Du, Liu Yang, Dongmei Hu, Jianan Xiong, Zhiyuan Zhao, Rong Gong, Tao Wu, Meng Wu, Meng Nie, Jialin Gao, Jihui Jia, Chengjiang Gao, Wei Zhao, Huan Zhou, Dongwei Kang, Mutian Jia.

  Perturbation of energy metabolism is an essential feature during infection and inflammation. TANK-binding kinase 1 (TBK1) is crucial for initiating the innate immune response against viral infection, although aberrant and ongoing TBK1 activation induces excessive production of type I interferons (IFN-I). Nonetheless, the mechanisms whereby energy metabolism controls TBK1 activation remain unclear. Here, we elucidate a mechanism linking energy metabolism to the inhibition of TBK1-induced IFN-I responses via the immune response gene 1 (IRG1)-itaconic acid axis. Mechanistically, itaconic acid and its derivatives alkylated TBK1 at Cys605, thereby disrupting TBK1 dimerization and rapid activation. IRG1, the enzyme that catalyzes itaconic acid production, is upregulated during late-phase viral infection and acts as a feedback regulator to restrain TBK1 activity. We developed itaconic acid-based compounds ITA-5/ITA-9 as alternative TBK1 inhibitors. ITA-5/ITA-9 effectively limited excess IFN-I-mediated hyperinflammation. These findings provide a promising therapeutic strategy for treating diseases mediated by aberrant TBK1 activation.

Keywords:  CP: Immunology; IRG1; TBK1; antiviral immune response; energy metabolism; itaconic acid

DOI:  https://doi.org/10.1016/j.celrep.2025.116336
Virulence. 2025 Dec;16(1): 2566242

Metabolic adaptation to host acetate facilitates oxidative stress resistance and intracellular survival of Neisseria meningitidis in macrophages.

Tiyasa Haldar, Divya Tripathi, Sunil D Saroj.

  Neisseria meningitidis encounters a dynamic nutrient landscape during host colonization, which necessitates its metabolic adaptation to different host metabolites such as acetate. Acetate, a short chain fatty acid (SCFA) within the host milieu, found to regulate host defense and inflammation during bacterial infection. In macrophage acetate gets converted into acetyl-CoA to provide energy via TCA cycle. Also, acetate is a crucial metabolic intermediate that takes part in lipid biosynthesis and protein acetylation. Acetate acts as an immunomodulator which improves the bactericidal effect of macrophage by activating the inflammasome. Therefore, to persist in nutrient limited conditions encountered in macrophages pathogens should resort to effective utilization of energy sources. We demonstrate that N. meningitidis can potentially utilize host acetate as a carbon source and regulate its virulence. The utilization of acetate enhanced the survival of N. meningitidis in H2O2 induced oxidative stress which can be correlated with the macrophage infection assay. Moreover, our investigation into underlying mechanism suggests that acetate exposure upregulates bacterial oxidative stress response by significantly increasing catalase and superoxide dismutase activity. We demonstrated that acetate metabolism also upregulated expression of nitric oxide detoxification genes fnr, narQ which mitigate reactive oxygen and nitrogen species produced in macrophages. Therefore, we conclude that bacterial utilization of physiologically relevant host acetate levels represents an important strategy to consume or detoxify macrophage-mediated oxidative stress, thereby facilitating bacterial survival.

Keywords:  Oxidative stress; acetate; carbon sources; nitric oxide detoxification; reactive oxygen species

DOI:  https://doi.org/10.1080/21505594.2025.2566242
EMBO Mol Med. 2025 Sep 29.

Targeting mitochondrial Kv1.3 enables precise autoreactive T cell therapy for multiple sclerosis.

Stefano Pluchino, Cory M Willis.

DOI: https://doi.org/10.1038/s44321-025-00306-3
J Infect Dis. 2025 Oct 01. pii: jiaf510. [Epub ahead of print]

Targeting Tryptophan Metabolism for Tuberculosis Biomarkers and Host Directed Therapy.

Jeffrey M Collins, Nestani Tukvadze, Russell R Kempker.

  Greater understanding of the role of tryptophan metabolism in the immune response to tuberculosis (TB) has provided promising avenues to explore new diagnostic and therapeutic modalities. Animal and human studies have demonstrated that host indoleamine 2,3-dioxygenase-1 (IDO1) is upregulated in response to infection with Mycobacterium tuberculosis resulting in increased tryptophan metabolism to kynurenine. In TB disease, this is evidenced by elevation of the plasma kynurenine to tryptophan ratio, which is reversed with effective TB treatment thus showing utility as a potential diagnostic and therapeutic biomarker. Kynurenine and downstream metabolites promote an immunosuppressive microenvironment in TB granulomas, which may facilitate immune evasion. IDO inhibition in non-human primates has highlighted its potential role as host-directed therapy by demonstrating increased T cell trafficking to the granuloma core, reduced bacterial burden, and decreased immunopathology. To realize the potential of exploiting the tryptophan to kynurenine metabolic pathway, innovative biomarker and host-directed therapy trials are needed.

Keywords:  IDO; host-directed therapy; tryptophan; tuberculosis

DOI:  https://doi.org/10.1093/infdis/jiaf510
Nature. 2025 Oct 01.

Dietary cysteine enhances intestinal stemness via CD8+ T cell-derived IL-22.

Fangtao Chi, Qiming Zhang, Jessica E S Shay, Shixun Han, Johanna Ten Hoeve, Yin Yuan, Zhenning Yang, Heaji Shin, Samuel Block, Sumeet Solanki, Yatrik M Shah, Matthew G Vander Heiden, Judith Agudo, Ömer H Yilmaz.

A fundamental question in physiology is understanding how tissues adapt and alter their cellular composition in response to dietary cues1-8. The mammalian small intestine is maintained by rapidly renewing LGR5+ intestinal stem cells (ISCs) that respond to macronutrient changes such as fasting regimens and obesogenic diets, yet how specific amino acids control ISC function during homeostasis and injury remains unclear. Here we demonstrate that dietary cysteine, a semi-essential amino acid, enhances ISC-mediated intestinal regeneration following injury. Cysteine contributes to coenzyme A (CoA) biosynthesis in intestinal epithelial cells, which promotes expansion of intraepithelial CD8αβ+ T cells and their production of interleukin-22 (IL-22). This enhanced IL-22 signalling directly augments ISC reparative capacity after injury. The mechanistic involvement of the pathway in driving the effects of cysteine is demonstrated by several findings: CoA supplementation recapitulates cysteine effects, epithelial-specific loss of the cystine transporter SLC7A11 blocks the response, and mice with CD8αβ+ T cells lacking IL-22 or a depletion of CD8αβ+ T cells fail to show enhanced regeneration despite cysteine treatment. These findings highlight how coupled cysteine metabolism between ISCs and CD8+ T cells augments intestinal stemness, providing a dietary approach that exploits ISC and immune cell crosstalk for ameliorating intestinal damage.

DOI: https://doi.org/10.1038/s41586-025-09589-5
Nat Commun. 2025 Sep 29. 16(1): 8565

Effect of the gut microbiota-derived tryptophan metabolite indole-3-acetic acid in pneumonia.

Robert F J Kullberg, Christine C A van Linge, Bastiaan W Haak, Prasanjit S Paul, Joe M Butler, Nora Wolff, Tjitske S R van Engelen, Jonne J Sikkens, Marije K Bomers, Antoine Lefèvre, Olaf L Cremer, Joris J T H Roelofs, Bruno Sovran, René van den Wijngaard, Alex F de Vos, Wouter J de Jonge, Tom van der Poll, W Joost Wiersinga.

Gut microbiota influence the severity of pneumonia by producing metabolites that enhance systemic and pulmonary immune responses. Preclinical studies suggested that gut microbiota-derived indoles have protective effects against numerous diseases, including influenza and abdominal infections. However, the precise role of tryptophan metabolites during pneumonia is unknown. Here, we perform translational analyses in a large general-population cohort (n = 13,464), critically ill patients with severe community-acquired pneumonia (CAP; n = 158; NCT01905033), a randomized human intervention trial on antibiotic-mediated microbiota modulation (NCT03051698), and mice to investigate the effects of tryptophan metabolites, specifically indole-3-acetic acid (IAA), on pneumonia. In the population-based cohort, baseline IAA is associated with a higher risk of future hospital admission for pneumonia (cause-specific hazard ratio 1.15, 95% confidence interval 1.09-1.22 p < 0.0001). In patients with severe CAP higher levels of IAA are associated with increased mortality, independent from potential confounders (hazard ratio 1.30 per log2 increase, 95% confidence interval 1.02-1.68, p = 0.037). In a mouse model of bacterial pneumonia, IAA supplementation aggravates pulmonary damage while reducing systemic dissemination, which is mediated by the aryl hydrocarbon receptor (AhR) and increased release of reactive oxygen species from neutrophils. In summary, these findings from general population and severe pneumonia cohorts, and murine pneumonia experiments, show that the gut microbiota-derived tryptophan metabolite IAA affects pneumonia, suggesting that various indoles may have diverging, context-dependent effects.

DOI: https://doi.org/10.1038/s41467-025-63611-y
Biochem Pharmacol. 2025 Oct 01. pii: S0006-2952(25)00643-4. [Epub ahead of print] 117378

The MyD88 inhibitor TJ-M2010-5 protects against obesity in mice by suppressing macrophage-induced metabolic inflammation.

Xi Yang, Fu-Rong Liang, Yi-Chi Wu, Fu-Cheng Meng, Huan-Yu Wang, Ling Hou, Ping Zhou, Cai Zhang, Xiao-Ping Luo.

  Metabolic inflammation is an important link in exacerbating obesity and insulin resistance, and the M1 polarization of macrophages is the key to the generation and maintenance of metabolic inflammation. As an inflammatory regulator, the toll-like receptor 4 (TLR4) / myeloid differentiation factor 88 (MyD88) signaling pathway plays an important role in the M1 polarization of macrophages. We previously proved that TJ-M2010-5 is a novel MyD88 inhibitor. However, the protective effect and underlying mechanisms of the MyD88 inhibitor TJ-M2010-5 against obesity induced by high fat diet (HFD) have not been reported. This study revealed that TJ-M2010-5 significantly improved the body weight, blood glucose and lipid levels of HFD mice. Histologically, TJ-M2010-5 alleviated lipid deposition in liver and adipose tissue. The proportion of M1 macrophages and the protein levels of TLR4, MyD88 and the phosphorylation ratio of nuclear factor-κB (NF-κB) in liver and epididymis adipose tissue of HFD mice were decreased after TJ-M2010-5 intervention. In vitro, TJ-M2010-5 inhibited the activation of TLR4 and MyD88 in bone marrow-derived macrophage (BMDM), significantly reduced the proportion of M1 polarization of BMDM. TJ-M2010-5 can improve obesity and its related glucose and lipid metabolism abnormalities induced by HFD through alleviating M1 polarization of macrophages and metabolic inflammation via inhibiting TLR4/MyD88 pathway.

Keywords:  Macrophage; Metabolic inflammation; Obesity; TJ-M2010-5

DOI:  https://doi.org/10.1016/j.bcp.2025.117378
J Neuroinflammation. 2025 Oct 02. 22(1): 223

Microglial glycolytic reprogramming in alzheimer's disease: association with impaired phagocytic function and altered vascular proximity.

Ning Lu, Zhongman Jin, Nian Liu, Caiyun Zhu, Hui Wei, Qi Xu.

   BACKGROUND: Alzheimer's disease (AD) is characterized by chronic neuroinflammation alongside amyloid-beta plaque and phosphorylated tau (p-Tau) tangle accumulation. Microglia, as resident immune cells, undergo glycolytic reprogramming that may exacerbate inflammation and impede toxic protein clearance. Specifically, the glycolytic enzyme pyruvate kinase M2 (PKM2) drives proinflammatory microglial phenotypes linked to neurodegeneration. This study investigates how PKM2-mediated microglial glycolytic reprogramming and inflammatory responses alongside Aβ/p-Tau clearance in human AD brains.
METHODS AND RESULTS: Hippocampal-entorhinal cortex (HP-EC) tissues from 8 AD patients and 8 matched controls underwent multiplex immunohistochemistry and high-resolution spatial analysis. PKM2+Iba1+ microglia density significantly increased in AD versus controls (p < 0.001), predominantly displaying a disease-associated microglial (HAM-like) phenotype (ABCA7+) with concurrent lipid-droplet accumulation (PLIN3+; LDAM phenotype). Spatially, glycolytic PKM2+Iba1+ microglia accumulated near Aβ plaques, p-Tau tangles, and cerebral vasculature. Notably, their distribution around plaques/tau showed anomalous increasing density with distance (p < 0.001), suggesting impaired chemotaxis. Perivascular localization lacked clear chemotactic gradients. Functionally, overall phagocytic activity (CD68+) decreased significantly in AD (p = 0.001), primarily attributed to PKM2- subsets, whereas PKM2+Iba1+ microglia exhibited pronounced phagocytic exhaustion (PLIN2+; p < 0.001), consistent around both Aβ and p-Tau lesions (all p < 0.001).
CONCLUSION: Our study establishes that microglial glycolytic reprogramming via PKM2 promotes a proinflammatory HAM-like phenotype, phagocytic exhaustion, and peri-pathological accumulation with aggregates and cerebral vessels. Targeting glycolytic pathways represents a viable therapeutic strategy for alleviating microglial dysfunction and neuroinflammation in AD.

Keywords:  Alzheimer’s disease; Glycolysis; Microglia; Neuroinflammation; PKM2

DOI:  https://doi.org/10.1186/s12974-025-03546-9
Inflamm Res. 2025 Oct 03. 74(1): 135

The role of dietary fibre in lung inflammation: microbiota, metabolites, and immune crosstalk.

Aishat Azeez, John A Baugh.

   BACKGROUND: Lung disease remains a leading cause of global morbidity and mortality, with prevalence strongly influenced by lifestyle factors, including dietary patterns such as the Western diet. Chronic lung inflammation, driven by dysregulated immune responses, is a hallmark of many pulmonary conditions and exacerbates disease progression and severity Emerging evidence highlights potentially critical role of for Dietary fibre and it's metabolites particularly short chain fatty acids (SCFAs), acetate, butyrate and propionate, in modulating the gut-lung axis and regulating pulmonary immune response.
OBJECTIVE: This review summarizes current evidence on how dietary fibre and SCFAs influence pulmonary immunity and inflammation through systemic and local mechanisms.MethodsLiterature on dietary fibre intake, SCFA production, and immune regulation in the context of lung disease was reviewed to identify key effects and mechanistic insights.
FINDINGS: SCFAs, including acetate, butyrate, and propionate, are produced by gut microbial fermentation of fibre and act via G-protein coupled receptor signalling and histone deacetylase inhibition. These metabolites modulate epithelial and immune cell function, reduce inflammation, and enhance lung immune protection. Beyond local effects, SCFAs influence hematopoietic cells in the bone marrow, altering their recruitment and activity in the lung.
CONCLUSIONS: Dietary fibre intake and SCFA-mediated gut-lung immune regulation represent a promising area for therapeutic development. A deeper understanding of these pathways may support novel strategies for the prevention and treatment of respiratory diseases.

Keywords:  Gut-lung axis; dietary fibre; inflammation; pulmonary immunity; short-chain fatty acids

DOI:  https://doi.org/10.1007/s00011-025-02098-1
Vet J. 2025 Sep 25. pii: S1090-0233(25)00159-5. [Epub ahead of print]314 106455

Toxoplasma gondii alters gut microbiota and systemic metabolism in cats: A multi-omics approach.

Ji-Xin Zhao, Xue-Yao Wang, Xuancheng Zhang, Lu-Yao Tang, Shi-Chen Xie, Yi-Han Lv, Zhi Zheng, Ying-Qian Gao, Jing Jiang, Xiao-Xuan Zhang, He Ma.

  Toxoplasma gondii (T. gondii) is an obligate intracellular parasite with a complex life cycle that culminates in cats-its only definitive host. While its immunological impact is well studied, how T. gondii shapes the feline gut microbiota and systemic metabolism remains largely unexplored. To investigate host-parasite-microbiome interactions, we performed a multi-omics study combining metagenomic sequencing and untargeted serum metabolomics in cats before and after T. gondii infection. Fecal samples were used to construct a comprehensive microbial gene catalog and assess functional shifts, while serum samples were analyzed via liquid chromatography-tandem mass spectrometry (LC-MS/MS) to capture systemic metabolic changes. Infection with T. gondii, particularly during its sexual replication phase, significantly disrupted gut microbial diversity, composition, and function. Functional annotation revealed downregulation of microbial genes involved in vitamin, cofactor, and energy metabolism, alongside upregulation of carbohydrate metabolism pathways. Concurrently, metabolomic profiling showed marked alterations in lipid profiles, amino acid pathways, and folate-mediated one-carbon metabolism. Integrated analysis uncovered strong correlations between specific microbial taxa-such as Bifidobacterium adolescentis and Ligilactobacillus animalis-and host metabolites, underscoring a tight link between microbial function and host metabolic responses to infection. To our knowledge, this is the first study to comprehensively map the microbiome and metabolic landscape of T. gondii infection in the feline host. Our findings reveal profound parasite-induced shifts in microbial function and systemic metabolism, offering new insights into the molecular interplay between host, parasite, and microbiota. These insights may inform future strategies for therapeutic modulation of host responses in toxoplasmosis.

Keywords:  Cats; Gut microbiome; Host–parasite interaction; Serum metabolomics; Toxoplasma gondii

DOI:  https://doi.org/10.1016/j.tvjl.2025.106455
Biochim Biophys Acta Mol Basis Dis. 2025 Sep 30. pii: S0925-4439(25)00412-0. [Epub ahead of print] 168064

Palmitic acid induces macrophage sialylation via TLR4/MyD88/TRAF6/NF-κB signaling.

Niting Wu, Pengbo Wang, Xiaodong Ran, Lin Li, Yuanting She, Jiawei Wang, Dongfeng Zeng, Xiaohui Li, Yi Jia, Yan Huang.

   OBJECTIVE: Globalization has spread Western diets and lifestyles beyond traditional boundaries. These patterns increase the risk of metabolic disorders and promote low-grade inflammation. However, the role of macrophage glycosylation in this context is still not fully elucidated. In this study, we examined the impact of PA-induced macrophage inflammation on cellular sialylation and its functional consequences.
APPROACH AND RESULTS: In vitro, immunofluorescence, flow cytometry, and Western blot analyses showed that TLR4/MyD88/TRAF6/NF-κB signaling activation promotes macrophage polarization 24 h after PA treatment. Metabolomics, Neu5Ac tracing, immunofluorescence, transwell assays, and Western blot demonstrated that PA upregulates Cytidine monophosphate N-acetylneuraminic acid synthetase (CMAS) and ST3 beta-galactoside alpha-2, 3-sialyltransferase III (ST3Gal-III) expression, promoting CMP-Neu5Ac and Neu5Ac metabolism, macrophage sialylation, and migration. TLR4-in-C34 blockade reversed these effects. In vivo, blood biochemical analysis, ELISA, flow cytometry, and liver tissue sectioning showed that a high-fat diet increases serum and hepatic lipid levels, promotes sialylation, and increases peritoneal and hepatic macrophage numbers. Immunofluorescence, flow cytometry, and Western blot confirmed that a high-fat diet activates TLR4 signaling in macrophages, driving M1 polarization and CMAS/ST3Gal-III upregulation.
CONCLUSION: A high-fat diet increases PA levels and activates the TLR4/MyD88/TRAF6/NF-κB signaling pathway in macrophages, thereby upregulating CMAS and ST3Gal-III expression. Thus, it not only induces the M1 polarization of macrophages, thereby augmenting the inflammatory response, but also modulates sialylation, facilitating the recruitment of macrophages to tissues.

Keywords:  CMAS; Inflammation; Macrophages; Palmitic acid; Sialylation; TLR4

DOI:  https://doi.org/10.1016/j.bbadis.2025.168064
Adv Sci (Weinh). 2025 Oct 03. e08576

cGAS Inhibits ALDH2 to Suppress Lipid Droplet Function and Regulate MASLD Progression.

Ying Wang, Yu Deng, Jianfeng Chen, Quentin Hahn, David S Umbaugh, Zhigang Zhang, Yanqiong Zhang, Sarah E Rowe, Lupeng Li, Laura E Herring, Brian P Conlon, Edward A Miao, Blossom Damania, Anna Mae Diehl, Pengda Liu.

  Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor essential for host defense against microbial infections, but its role beyond innate immunity remains unclear. Here, a non-canonical function of cGAS in regulating aldehyde metabolism and lipid homeostasis is identified. This is demonstrated that cGAS directly binds to and suppresses ALDH2 (aldehyde dehydrogenase 2), a key enzyme in ethanol metabolism and lipid peroxidation. Loss of cGAS activates ALDH2, thereby enhancing ethanol tolerance in mice. Elevated ALDH2 activity upon cGAS loss increases aldehyde conversion into acetyl-CoA, promoting histone acetylation and transcription of lipid synthesis genes, which drives lipid droplet accumulation in cells and in cGas-/- mouse livers. These lipid droplets confer resistance to ferroptosis but simultaneously induce ER stress, impairing STING (stimulator of interferon genes) activation. Functionally, cGas-/- mice fed with a modified high-fat diet develop exacerbated metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by excessive lipid droplet accumulation in livers compared to wild-type controls. In human MASLD patient cohorts, increased cGAS but reduced ALDH2 mRNA expression is observed relative to healthy individuals. Together, this findings uncover a previously unrecognized role of cGAS in metabolic regulation, independent of its innate immune function. By suppressing ALDH2, cGAS controls lipid droplet biogenesis and stress responses, with direct implications for MASLD pathogenesis.

Keywords:  ALDH2; HFD; MASLD; cGAS; lipid droplets

DOI:  https://doi.org/10.1002/advs.202508576
JCI Insight. 2025 Sep 30. pii: e194304. [Epub ahead of print]

Bmal1 is involved in the regulation of macrophage cholesterol homeostasis.

Xiaoyue Pan, John O'Hare, Cyrus Mowdawalla, Samantha Mota, Nan Wang, M Mahmood Hussain.

  Atherosclerotic cardiovascular disease is a major contributor to the global disease burden. Atherosclerosis initiation depends on cholesterol accumulation in subendothelial macrophages (Mφs). To clarify the role of Bmal1 in Mφ function and atherosclerosis, we used several global and myeloid-specific Bmal1 deficient mouse models. Myeloid-specific Bmal1 deficient mice had higher Mφ cholesterol and displayed greater atherosclerosis compared to controls. Bmal1-deficient Mφs exhibited: (1) elevated expression of Cd36 and uptake of oxLDL; (2) diminished expression of Abca1 and Abcg1, and decreased cholesterol efflux and reverse cholesterol transport; and (3) reduced Npc1 and Npc2 expression, and diminished cholesterol egress from lysosomes. Molecular studies revealed that Bmal1 directly regulates basal and cyclic expression of Npc1 and Npc2 by binding the E-boxes in their promoters and indirectly regulates the basal and temporal regulation of Cd36 and Abca1/Abcg1 involving Rev-erbα and Znf202 repressors, respectively. In conclusion, Mφ Bmal1 is a key regulator of the uptake of modified lipoproteins, cholesterol efflux, lysosomal cholesterol egress and atherosclerosis, and therefore may be a master regulator of cholesterol metabolism in Mφs. Restoration of Mφ Bmal1 expression or blocking of factors that decrease its activity may be effective in preventing atherosclerosis.

Keywords:  Atherosclerosis; Lipoproteins; Macrophages; Metabolism; Vascular biology

DOI:  https://doi.org/10.1172/jci.insight.194304