bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2024–03–10
thirty papers selected by
Dylan Ryan, University of Cambridge
  1. Circulating N-lactoyl-amino acids and N-formyl-methionine reflect mitochondrial dysfunction and predict mortality in septic shock.
  2. Inactivation of cytidine triphosphate synthase 1 prevents fatal auto-immunity in mice.
  3. Fatty acid oxidation fuels natural killer cell responses against infection and cancer.
  4. Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression.
  5. Immunometabolic Maladaptations to the Tumor Microenvironment.
  6. Metabolic regulation of neutrophil functions in homeostasis and diseases.
  7. Not just sugar: Metabolic control of neutrophil development and effector functions.
  8. Itaconate boosts malaria via induction of PD-L1.
  9. Metabolic adaptations determine whether natural killer cells fail or thrive within the tumor microenvironment.
  10. Itaconate in host inflammation and defense.
  11. Supercharging cancer-fighting T cells with lithium carbonate.
  12. Detection of nitric oxide-mediated metabolic effects using real-time extracellular flux analysis.
  13. Differential mRNA profiles reveal the potential roles of genes involved in lactate stimulation in mouse macrophages.
  14. Peroxiredoxin 3 has a crucial role in the macrophage polarization by regulating mitochondrial homeostasis.
  15. Shotgun metagenomics and systemic targeted metabolomics highlight indole-3-propionic acid as a protective gut microbial metabolite against influenza infection.
  16. Carnosine facilitates lysosomal release of inhibitors of T cell surveillance.
  17. UHPLC/MS-based metabolomics of asthmatic mice reveals metabolic changes in group 2 innate lymphoid cells.
  18. Targeting tryptophan catabolism in ovarian cancer to attenuate macrophage infiltration and PD-L1 expression.
  19. The effects of metabolism on the immune microenvironment in colorectal cancer.
  20. Lactic acid in macrophage polarization: A factor in carcinogenesis and a promising target for cancer therapy.
  21. A glutamine tug-of-war between cancer and immune cells: recent advances in unraveling the ongoing battle.
  22. Functional consequence of Iron dyshomeostasis and ferroptosis in systemic lupus erythematosus and lupus nephritis.
  23. Stem Leydig cells support macrophage immunological homeostasis through mitochondrial transfer in mice.
  24. A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate.
  25. Blood metabolomic and transcriptomic signatures stratify patient subgroups in multiple sclerosis according to disease severity.
  26. Excess fermentation and lactic acidosis as detrimental functions of the gut microbes in treatment-naive TB patients.
  27. PMI-controlled mannose metabolism and glycosylation determines tissue tolerance and virus fitness.
  28. Modulation of nucleotide metabolism by picornaviruses.
  29. A human milk oligosaccharide prevents intestinal inflammation in adulthood via modulating gut microbial metabolism.
  30. Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy.
  1. Metabolomics. 2024 Mar 06. 20(2): 36
    Circulating N-lactoyl-amino acids and N-formyl-methionine reflect mitochondrial dysfunction and predict mortality in septic shock.
    Robert S Rogers, Rohit Sharma, Hardik B Shah, Owen S Skinner, Xiaoyan A Guo, Apekshya Panda, Rahul Gupta, Timothy J Durham, Kelsey B Shaughnessy, Jared R Mayers, Kathryn A Hibbert, Rebecca M Baron, B Taylor Thompson, Vamsi K Mootha.
       INTRODUCTION: Sepsis is a highly morbid condition characterized by multi-organ dysfunction resulting from dysregulated inflammation in response to acute infection. Mitochondrial dysfunction may contribute to sepsis pathogenesis, but quantifying mitochondrial dysfunction remains challenging.
    OBJECTIVE: To assess the extent to which circulating markers of mitochondrial dysfunction are increased in septic shock, and their relationship to severity and mortality.
    METHODS: We performed both full-scan and targeted (known markers of genetic mitochondrial disease) metabolomics on plasma to determine markers of mitochondrial dysfunction which distinguish subjects with septic shock (n = 42) from cardiogenic shock without infection (n = 19), bacteremia without sepsis (n = 18), and ambulatory controls (n = 19) - the latter three being conditions in which mitochondrial function, proxied by peripheral oxygen consumption, is presumed intact.
    RESULTS: Nine metabolites were significantly increased in septic shock compared to all three comparator groups. This list includes N-formyl-L-methionine (f-Met), a marker of dysregulated mitochondrial protein translation, and N-lactoyl-phenylalanine (lac-Phe), representative of the N-lactoyl-amino acids (lac-AAs), which are elevated in plasma of patients with monogenic mitochondrial disease. Compared to lactate, the clinical biomarker used to define septic shock, there was greater separation between survivors and non-survivors of septic shock for both f-Met and the lac-AAs measured within 24 h of ICU admission. Additionally, tryptophan was the one metabolite significantly decreased in septic shock compared to all other groups, while its breakdown product kynurenate was one of the 9 significantly increased.
    CONCLUSION: Future studies which validate the measurement of lac-AAs and f-Met in conjunction with lactate could define a sepsis subtype characterized by mitochondrial dysfunction.
    Keywords:  Kynurenine; Lac-Phe; Lactoyl; Sepsis; Septic shock; f-Met
    DOI:  https://doi.org/10.1007/s11306-024-02089-z
  2. Nat Commun. 2024 Mar 04. 15(1): 1982
    Inactivation of cytidine triphosphate synthase 1 prevents fatal auto-immunity in mice.
    Claire Soudais, Romane Schaus, Camille Bachelet, Norbert Minet, Sara Mouasni, Cécile Garcin, Caique Lopes Souza, Pierre David, Clara Cousu, Hélène Asnagli, Andrew Parker, Paul Palmquist-Gomes, Fernando E Sepulveda, Sébastien Storck, Sigolène M Meilhac, Alain Fischer, Emmanuel Martin, Sylvain Latour.
      De novo synthesis of the pyrimidine, cytidine triphosphate (CTP), is crucial for DNA/RNA metabolism and depends on the CTP synthetases, CTPS1 and -2. Partial CTPS1 deficiency in humans has previously been shown to lead to immunodeficiency, with impaired expansion of T and B cells. Here, we examine the effects of conditional and inducible inactivation of Ctps1 and/or Ctps2 on mouse embryonic development and immunity. We report that deletion of Ctps1, but not Ctps2, is embryonic-lethal. Tissue and cells with high proliferation and renewal rates, such as intestinal epithelium, erythroid and thymic lineages, activated B and T lymphocytes, and memory T cells strongly rely on CTPS1 for their maintenance and growth. However, both CTPS1 and CTPS2 are required for T cell proliferation following TCR stimulation. Deletion of Ctps1 in T cells or treatment with a CTPS1 inhibitor rescued Foxp3-deficient mice from fatal systemic autoimmunity and reduced the severity of experimental autoimmune encephalomyelitis. These findings support that CTPS1 may represent a target for immune suppression.
    DOI:  https://doi.org/10.1038/s41467-024-45805-y
  3. Proc Natl Acad Sci U S A. 2024 Mar 12. 121(11): e2319254121
    Fatty acid oxidation fuels natural killer cell responses against infection and cancer.
    Sam Sheppard, Katja Srpan, Wendy Lin, Mariah Lee, Rebecca B Delconte, Mark Owyong, Peter Carmeliet, Daniel M Davis, Joao B Xavier, Katharine C Hsu, Joseph C Sun.
      Natural killer (NK) cells are a vital part of the innate immune system capable of rapidly clearing mutated or infected cells from the body and promoting an immune response. Here, we find that NK cells activated by viral infection or tumor challenge increase uptake of fatty acids and their expression of carnitine palmitoyltransferase I (CPT1A), a critical enzyme for long-chain fatty acid oxidation. Using a mouse model with an NK cell-specific deletion of CPT1A, combined with stable 13C isotope tracing, we observe reduced mitochondrial function and fatty acid-derived aspartate production in CPT1A-deficient NK cells. Furthermore, CPT1A-deficient NK cells show reduced proliferation after viral infection and diminished protection against cancer due to impaired actin cytoskeleton rearrangement. Together, our findings highlight that fatty acid oxidation promotes NK cell metabolic resilience, processes that can be optimized in NK cell-based immunotherapies.
    Keywords:  NK cells; T cells; cancer; metabolism; virus infection
    DOI:  https://doi.org/10.1073/pnas.2319254121
  4. Nat Commun. 2024 Mar 05. 15(1): 1987
    Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression.
    Fatima Khan, Yiyun Lin, Heba Ali, Lizhi Pang, Madeline Dunterman, Wen-Hao Hsu, Katie Frenis, R Grant Rowe, Derek A Wainwright, Kathleen McCortney, Leah K Billingham, Jason Miska, Craig Horbinski, Maciej S Lesniak, Peiwen Chen.
      Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase inhibitor stiripentol emerges as the top hit. Combined profiling and functional studies demonstrate that lactate dehydrogenase A (LDHA)-directed extracellular signal-regulated kinase (ERK) pathway activates yes-associated protein 1 (YAP1)/ signal transducer and activator of transcription 3 (STAT3) transcriptional co-activators in glioblastoma cells to upregulate C-C motif chemokine ligand 2 (CCL2) and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.
    DOI:  https://doi.org/10.1038/s41467-024-46193-z
  5. Cold Spring Harb Perspect Med. 2024 Mar 04. pii: a041547. [Epub ahead of print]
    Immunometabolic Maladaptations to the Tumor Microenvironment.
    Emma S Hathaway, Erin Q Jennings, Jeffrey C Rathmell.
      Tumors consist of cancer cells and a wide range of tissue resident and infiltrating cell types. Tumor metabolism, however, has largely been studied on whole tumors or cancer cells and the metabolism of infiltrating immune cells remains poorly understood. It is now clear from a range of analyses and metabolite rescue studies that metabolic adaptations to the tumor microenvironment (TME) directly impede T-cell and macrophage effector functions. The drivers of metabolic adaptation to the TME and metabolic immune suppression include depletion of essential nutrients, accumulation of waste products or immune suppression metabolites, and metabolic signaling through altered posttranslational modifications. Each infiltrating immune cell subset differs, however, with specific metabolic requirements and adaptations that can be maladaptive for antitumor immunity. Here, we review T-cell and macrophage adaptation and metabolic immune suppression in solid tumors. Ultimately, understanding and addressing these challenges will improve cancer immunotherapy and adoptive chimeric antigen receptor T-cell therapies.
    DOI:  https://doi.org/10.1101/cshperspect.a041547
  6. J Leukoc Biol. 2024 Mar 07. pii: qiae025. [Epub ahead of print]
    Metabolic regulation of neutrophil functions in homeostasis and diseases.
    Pier-Olivier Leblanc, Sylvain G Bourgoin, Patrice E Poubelle, Philippe A Tessier, Martin Pelletier.
      Neutrophils are the most abundant leukocytes in humans and play a role in the innate immune response by being the first cells attracted to the site of infection. While early studies presented neutrophils as almost exclusively glycolytic cells, recent advances show that these cells use several metabolic pathways other than glycolysis, such as the pentose phosphate pathway, oxidative phosphorylation, fatty acid oxidation, and glutaminolysis, which they modulate to perform their functions. Metabolism shifts from fatty acid oxidation-mediated mitochondrial respiration in immature neutrophils to glycolysis in mature neutrophils. Tissue environments largely influence neutrophil metabolism according to nutrient sources, inflammatory mediators, and oxygen availability. Inhibition of metabolic pathways in neutrophils results in impairment of certain effector functions, such as NETosis, chemotaxis, degranulation, and reactive oxygen species generation. Alteration of these neutrophil functions is implicated in certain human diseases, such as antiphospholipid syndrome, coronavirus disease 2019, and bronchiectasis. Metabolic regulators such as AMPK, HIF-1α, mTOR, and Arf6 are linked to neutrophil metabolism and function and could potentially be targeted for the treatment of diseases associated with neutrophil dysfunction. This review details the effects of alterations in neutrophil metabolism on the effector functions of these cells.
    Keywords:  TCA cycle; diseases; fatty acid oxidation; functions; glutaminolysis; glycolysis; immunometabolism; neutrophils; oxidative phosphorylation; pentose phosphate pathway
    DOI:  https://doi.org/10.1093/jleuko/qiae025
  7. J Leukoc Biol. 2024 Mar 07. pii: qiae057. [Epub ahead of print]
    Not just sugar: Metabolic control of neutrophil development and effector functions.
    Paul Ettel, Thomas Weichhart.
      The mammalian immune system is constantly surveying our tissues to clear pathogens and maintain tissue homeostasis. In order to fulfill these tasks, immune cells take up nutrients to supply energy for survival and for directly regulating effector functions via their cellular metabolism; a process now known as immunometabolism. Neutrophilic granulocytes, the most abundant leukocytes in the human body, have a short half-life and are permanently needed in the defense against pathogens. According to a long-standing view, neutrophils were thought to primarily fuel their metabolic demands via glycolysis. Yet, this view has been challenged as other metabolic pathways recently emerged to contribute to neutrophil homeostasis and effector functions. In particular during neutrophilic development, the pentose phosphate pathway, glycogen synthesis, oxidative phosphorylation, and fatty acid oxidation crucially promote neutrophil maturation. At steady state, both glucose and lipid metabolism sustain neutrophil survival and maintain the intracellular redox balance. This review aims to comprehensively discuss how neutrophilic metabolism adapts during development, which metabolic pathways fuel their functionality and how these processes are reconfigured in case of various diseases. We provide several examples of hereditary diseases, where mutations in metabolic enzymes validate their critical role for neutrophil function.
    Keywords:  immunometabolism; innate immunity; metabolism; neutrophil
    DOI:  https://doi.org/10.1093/jleuko/qiae057
  8. Cell Metab. 2024 Mar 05. pii: S1550-4131(24)00051-2. [Epub ahead of print]36(3): 457-458
    Itaconate boosts malaria via induction of PD-L1.
    Yukun Min, Luke A J O'Neill.
      The Krebs-cycle-derived metabolite itaconate has been shown to be immunomodulatory, targeting multiple processes in macrophages. Ramalho et al. reveal an additional role for itaconate in malaria.1Plasmodium Chabaudi induces itaconate in dendritic cells (DCs), leading to programmed death-ligand 1 (PD-L1) induction. This suppresses CD8+ T cells, important for host defense against malaria, thereby promoting parasitemia.
    DOI:  https://doi.org/10.1016/j.cmet.2024.02.005
  9. Immunol Rev. 2024 Mar 09.
    Metabolic adaptations determine whether natural killer cells fail or thrive within the tumor microenvironment.
    Adnan Moinuddin, Sophie M Poznanski, Ana L Portillo, Jonathan K Monteiro, Ali A Ashkar.
      Natural Killer (NK) cells are a top contender in the development of adoptive cell therapies for cancer due to their diverse antitumor functions and ability to restrict their activation against nonmalignant cells. Despite their success in hematologic malignancies, NK cell-based therapies have been limited in the context of solid tumors. Tumor cells undergo various metabolic adaptations to sustain the immense energy demands that are needed to support their rapid and uncontrolled proliferation. As a result, the tumor microenvironment (TME) is depleted of nutrients needed to fuel immune cell activity and contains several immunosuppressive metabolites that hinder NK cell antitumor functions. Further, we now know that NK cell metabolic status is a main determining factor of their effector functions. Hence, the ability of NK cells to withstand and adapt to these metabolically hostile conditions is imperative for effective and sustained antitumor activity in the TME. With this in mind, we review the consequences of metabolic hostility in the TME on NK cell metabolism and function. We also discuss tumor-like metabolic programs in NK cell induced by STAT3-mediated expansion that adapt NK cells to thrive in the TME. Finally, we examine how other approaches can be applied to enhance NK cell metabolism in tumors.
    Keywords:  cancer immunotherapy; immunometabolism; metabolic reprogramming; natural killer cells; tumor metabolism
    DOI:  https://doi.org/10.1111/imr.13316
  10. Trends Endocrinol Metab. 2024 Mar 05. pii: S1043-2760(24)00033-X. [Epub ahead of print]
    Itaconate in host inflammation and defense.
    Dan Ye, Pu Wang, Lei-Lei Chen, Kun-Liang Guan, Yue Xiong.
      Immune cells undergo rapid and extensive metabolic changes during inflammation. In addition to contributing to energetic and biosynthetic demands, metabolites can also function as signaling molecules. Itaconate (ITA) rapidly accumulates to high levels in myeloid cells under infectious and sterile inflammatory conditions. This metabolite binds to and regulates the function of diverse proteins intracellularly to influence metabolism, oxidative response, epigenetic modification, and gene expression and to signal extracellularly through binding the G protein-coupled receptor (GPCR). Administration of ITA protects against inflammatory diseases and blockade of ITA production enhances antitumor immunity in preclinical models. In this article, we review ITA metabolism and its regulation, discuss its target proteins and mechanisms, and conjecture a rationale for developing ITA-based therapeutics to treat inflammatory diseases and cancer.
    Keywords:  IRG1/ACOD1; cancer; inflammatory diseases; itaconate
    DOI:  https://doi.org/10.1016/j.tem.2024.02.004
  11. Cell Metab. 2024 Mar 05. pii: S1550-4131(24)00052-4. [Epub ahead of print]36(3): 463-465
    Supercharging cancer-fighting T cells with lithium carbonate.
    Yue Xu, Kaili Ma, Lianjun Zhang, Guideng Li.
      Lactate influences the behavior of various immune cell types. In a recent Nature Immunology study, Ma et al. revealed that lithium carbonate induces monocarboxylate transporter 1 translocation to mitochondria, enhancing cytoplasmic lactate transport into the mitochondria and increasing lactate mitochondrial metabolism, thereby promoting T cell effector function.
    DOI:  https://doi.org/10.1016/j.cmet.2024.02.006
  12. PLoS One. 2024 ;19(3): e0299294
    Detection of nitric oxide-mediated metabolic effects using real-time extracellular flux analysis.
    Bay Vagher, Eyal Amiel.
      Dendritic cell (DC) activation is marked by key events including: (I) rapid induction and shifting of metabolism favoring glycolysis for generation of biosynthetic metabolic intermediates and (II) large scale changes in gene expression including the upregulation of the antimicrobial enzyme inducible nitric oxide synthase (iNOS) which produces the toxic gas nitric oxide (NO). Historically, acute metabolic reprogramming and NO-mediated effects on cellular metabolism have been studied at specific timepoints during the DC activation process, namely at times before and after NO production. However, no formal method of real time detection of NO-mediated effects on DC metabolism have been fully described. Here, using Real-Time Extracellular Flux Analysis, we experimentally establish the phenomenon of an NO-dependent mitochondrial respiration threshold, which shows how titration of an activating stimulus is inextricably linked to suppression of mitochondrial respiration in an NO-dependent manner. As part of this work, we explore the efficacy of two different iNOS inhibitors in blocking the iNOS reaction kinetically in real time and explore/discuss parameters and considerations for application using Real Time Extracellular Flux Analysis technology. In addition, we show, the temporal relationship between acute metabolic reprogramming and NO-mediated sustained metabolic reprogramming kinetically in single real-time assay. These findings provide a method for detection of NO-mediated metabolic effects in DCs and offer novel insight into the timing of the DC activation process with its associated key metabolic events, revealing a better understanding of the nuances of immune cell biology.
    DOI:  https://doi.org/10.1371/journal.pone.0299294
  13. Genomics. 2024 Mar 02. pii: S0888-7543(24)00035-1. [Epub ahead of print]116(2): 110814
    Differential mRNA profiles reveal the potential roles of genes involved in lactate stimulation in mouse macrophages.
    Limian Cao, Chencheng Feng, Haoming Ye, Heng Zhao, Zhimin Shi, Jun Li, Yayun Wu, Ruojue Wang, Qianru Li, Jinquan Liang, Qiang Ji, Hao Gu, Min Shao.
      Lactate is a glycolysis end product, and its levels are markedly associated with disease severity, morbidity, and mortality in sepsis. It modulates key functions of immune cells, including macrophages. In this investigation, transcriptomic analysis was performed using lactic acid, sodium lactate, and hydrochloric acid-stimulated mouse bone marrow-derived macrophages (iBMDM), respectively, to identify lactate-associated signaling pathways. After 24 h of stimulation, 896 differentially expressed genes (DEG) indicated were up-regulation, whereas 792 were down-regulated in the lactic acid group, in the sodium lactate group, 128 DEG were up-regulated, and 41 were down-regulated, and in the hydrochloric acid group, 499 DEG were up-regulated, and 285 were down-regulated. Subsequently, clinical samples were used to further verify the eight genes with significant differences, among which Tssk6, Ypel4, Elovl3, Trp53inp1, and Cfp were differentially expressed in patients with high lactic acid, indicating their possible involvement in lactic acid-induced inflammation and various physiological diseases caused by sepsis. However, elongation of very long chain fatty acids protein 3 (Elovl3) was negatively correlated with lactic acid content in patients. The results of this study provide a necessary reference for better understanding the transcriptomic changes caused by lactic acid and explain the potential role of high lactic acid in the regulation of macrophages in sepsis.
    Keywords:  Lactate; Macrophage; Sepsis; Transcriptome sequencing
    DOI:  https://doi.org/10.1016/j.ygeno.2024.110814
  14. Respir Res. 2024 Mar 02. 25(1): 110
    Peroxiredoxin 3 has a crucial role in the macrophage polarization by regulating mitochondrial homeostasis.
    Wenhui Huang, Lianfang Wang, Zhipeng Huang, Zhichao Sun, Bojun Zheng.
      Acute lung injury (ALI) is one of the life-threatening complications of sepsis, and macrophage polarization plays a crucial role in the sepsis-associated ALI. However, the regulatory mechanisms of macrophage polarization in ALI and in the development of inflammation are largely unknown. In this study, we demonstrated that macrophage polarization occurs in sepsis-associated ALI and is accompanied by mitochondrial dysfunction and inflammation, and a decrease of PRDX3 promotes the initiation of macrophage polarization and mitochondrial dysfunction. Mechanistically, PRDX3 overexpression promotes M1 macrophages to differentiate into M2 macrophages, and enhances mitochondrial functional recovery after injury by reducing the level of glycolysis and increasing TCA cycle activity. In conclusion, we identified PRDX3 as a critical hub integrating oxidative stress, inflammation, and metabolic reprogramming in macrophage polarization. The findings illustrate an adaptive mechanism underlying the link between macrophage polarization and sepsis-associated ALI.
    Keywords:  Macrophage polarization; Metabolic reprogram; Mitochondrial function; PRDX3; Sepsis-associated acute lung injury
    DOI:  https://doi.org/10.1186/s12931-024-02739-9
  15. Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2325067
    Shotgun metagenomics and systemic targeted metabolomics highlight indole-3-propionic acid as a protective gut microbial metabolite against influenza infection.
    Séverine Heumel, Vinícius de Rezende Rodovalho, Charlotte Urien, Florian Specque, Patrícia Brito Rodrigues, Cyril Robil, Lou Delval, Valentin Sencio, Amandine Descat, Lucie Deruyter, Stéphanie Ferreira, Marina Gomes Machado, Adeline Barthelemy, Fabiola Silva Angulo, Joel T Haas, Jean François Goosens, Isabelle Wolowczuk, Corinne Grangette, Yves Rouillé, Ghjuvan Grimaud, Marie Lenski, Benjamin Hennart, Marco Aurélio Ramirez Vinolo, François Trottein.
      The gut-to-lung axis is critical during respiratory infections, including influenza A virus (IAV) infection. In the present study, we used high-resolution shotgun metagenomics and targeted metabolomic analysis to characterize influenza-associated changes in the composition and metabolism of the mouse gut microbiota. We observed several taxonomic-level changes on day (D)7 post-infection, including a marked reduction in the abundance of members of the Lactobacillaceae and Bifidobacteriaceae families, and an increase in the abundance of Akkermansia muciniphila. On D14, perturbation persisted in some species. Functional scale analysis of metagenomic data revealed transient changes in several metabolic pathways, particularly those leading to the production of short-chain fatty acids (SCFAs), polyamines, and tryptophan metabolites. Quantitative targeted metabolomics analysis of the serum revealed changes in specific classes of gut microbiota metabolites, including SCFAs, trimethylamine, polyamines, and indole-containing tryptophan metabolites. A marked decrease in indole-3-propionic acid (IPA) blood level was observed on D7. Changes in microbiota-associated metabolites correlated with changes in taxon abundance and disease marker levels. In particular, IPA was positively correlated with some Lactobacillaceae and Bifidobacteriaceae species (Limosilactobacillus reuteri, Lactobacillus animalis) and negatively correlated with Bacteroidales bacterium M7, viral load, and inflammation markers. IPA supplementation in diseased animals reduced viral load and lowered local (lung) and systemic inflammation. Treatment of mice with antibiotics targeting IPA-producing bacteria before infection enhanced viral load and lung inflammation, an effect inhibited by IPA supplementation. The results of this integrated metagenomic-metabolomic analysis highlighted IPA as an important contributor to influenza outcomes and a potential biomarker of disease severity.
    Keywords:  Influenza; disease severity; gut microbiota; indole-3-propionic acid; metabolomics; shotgun metagenomics
    DOI:  https://doi.org/10.1080/19490976.2024.2325067
  16. Cell Metab. 2024 Mar 05. pii: S1550-4131(24)00049-4. [Epub ahead of print]36(3): 461-462
    Carnosine facilitates lysosomal release of inhibitors of T cell surveillance.
    Pawel Swietach, Marja Jäättelä, Shari Pillon-Thomas, Ebbe Boedtkjer.
      Cancer metabolism produces large fluxes of lactate and H+, which are extruded by membrane transporters. However, H+ production and extrusion must be coupled by diffusion, facilitated by mobile buffers. Yan et al. propose that carnosine, generated by CARNS2, provides this mobile buffering and enables lysosomal functions that block T cell surveillance.
    DOI:  https://doi.org/10.1016/j.cmet.2024.02.003
  17. Int Immunopharmacol. 2024 Mar 01. pii: S1567-5769(24)00293-5. [Epub ahead of print]130 111775
    UHPLC/MS-based metabolomics of asthmatic mice reveals metabolic changes in group 2 innate lymphoid cells.
    Min Tang, Xianzong Da, Zhiwei Xu, Xiaoman Zhao, Haoquan Zhou.
      Helper Th2-type immune responses are essential in allergic airway diseases, including asthma and allergic rhinitis. Recent studies have indicated that group 2 innate lymphoid cells (ILC2s) play a crucial role in the occurrence and development of asthma. However, the metabolic profile of ILC2s and their regulatory mechanisms in asthma remain unclear. Therefore, we established two asthma mouse models: an ovalbumin (OVA)-induced asthma model and an IL-33-induced asthma model. We then used ultra-high-performance liquid chromatography/mass spectrometry (UHPLC/MS) to conduct high-throughput untargeted metabolic analysis of ILC2s in the lung tissues of the asthma models. The identified metabolites primarily consisted of lipids, lipid-like molecules, benzene, organic acids, derivatives, and organic oxidation compounds. Specifically, 34 differentially accumulated metabolites influenced the metabolic profiles of the control and OVA-induced asthma model groups. Moreover, the accumulation of 39 metabolites significantly differed between the Interleukin 33 (IL-33) and control groups. These differentially accumulated metabolites were mainly involved in pathways such as sphingolipid, oxidative phosphorylation, and fatty acid metabolism. This metabolomic study revealed, for the first time, the key metabolites and metabolic pathways of ILC2s, revealing new aspects of cellular metabolism in the context of airway inflammation. These findings not only contribute to unraveling the pathogenesis of asthma but also provide a crucial theoretical foundation for the future development of therapeutic strategies targeting ILC2s.
    Keywords:  Asthma; Biomarker; Group 2 innate lymphoid cells; Metabolic pathway analysis; Untargeted metabolomics
    DOI:  https://doi.org/10.1016/j.intimp.2024.111775
  18. Cancer Res Commun. 2024 Mar 07.
    Targeting tryptophan catabolism in ovarian cancer to attenuate macrophage infiltration and PD-L1 expression.
    Lyndsey S Crump, Jessica L Floyd, Li-Wei Kuo, Miriam D Post, Mike Bickerdike, Kathleen O'Neill, Kayla Sompel, Kimberly R Jordan, Bradley R Corr, Nicole Marjon, Elizabeth R Woodruff, Jennifer K Richer, Benjamin G Bitler.
      High grade serous carcinoma (HGSC) of the fallopian tube, ovary and peritoneum is the most common type of ovarian cancer and is predicted to be immunogenic since the presence of tumor-infiltrating lymphocytes conveys a better prognosis. However, the efficacy of immunotherapies has been limited due to the immune-suppressed tumor microenvironment (TME). Tumor metabolism and immune-suppressive metabolites directly affect immune cell function through the depletion of nutrients and activation of immune-suppressive transcriptional programs. Tryptophan (TRP) catabolism is a contributor to HGSC disease progression. Two structurally distinct rate-limiting TRP catabolizing enzymes, Indoleamine 2,3-Dioxygenase 1 (IDO1) and Tryptophan 2,3-Dioxygenase 2 (TDO2), evolved separately to catabolize TRP. IDO1/TDO2 are aberrantly expressed in carcinomas and metabolize TRP into the immune-suppressive metabolite kynurenine (KYN), which can engage the aryl hydrocarbon receptor (AhR) to drive immunosuppressive transcriptional programs. To date, IDO inhibitors tested in clinical trials have had limited efficacy, but those inhibitors did not target TDO2, and we find that HGSC cell lines and clinical outcomes are more dependent on TDO2 than IDO1. To identify inflammatory HGSC cancers with poor prognosis, we stratified patient ascites samples by IL6 status, which correlates with poor prognosis. Metabolomics revealed that IL6 high patient samples had enriched KYN. TDO2 knockdown significantly inhibited HGSC growth and TRP catabolism. The orally available dual IDO1/TDO2 inhibitor, AT-0174, significantly inhibited tumor progression, reduced tumor-associated macrophages, and reduced expression of immune-suppressive proteins on immune and tumor cells. These studies demonstrate the importance of TDO2 and the therapeutic potential of AT-0174 to overcome an immune-suppressed TME.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-23-0513
  19. Cell Death Discov. 2024 Mar 07. 10(1): 118
    The effects of metabolism on the immune microenvironment in colorectal cancer.
    Xingzhao Chen, Zhiyuan Ma, Zhiqiang Yi, Enqin Wu, Zhengye Shang, Biguang Tuo, Taolang Li, Xuemei Liu.
      Colorectal cancer (CRC) is a malignancy that is widely prevalent worldwide. Due to its unsatisfactory treatment outcome and extremely poor prognosis, many studies on the molecular mechanisms and pathological mechanisms of CRC have been published in recent years. The tumor microenvironment (TME) is an extremely important feature of tumorigenesis and one of the hallmarks of tumor development. Metabolic reprogramming is currently a hot topic in tumor research, and studies on this topic have provided important insights into CRC development. In particular, metabolic reprogramming in cancer causes changes in the composition of energy and nutrients in the TME. Furthermore, it can alter the complex crosstalk between immune cells and associated immune factors, such as associated macrophages and T cells, which play important immune roles in the TME, in turn affecting the immune escape of tumors by altering immune surveillance. In this review, we summarize several metabolism-related processes affecting the immune microenvironment of CRC tumors. Our results showed that the immune microenvironment is regulated by metabolic reprogramming and influences the development of CRC.
    DOI:  https://doi.org/10.1038/s41420-024-01865-z
  20. Biochem Pharmacol. 2024 Feb 29. pii: S0006-2952(24)00081-9. [Epub ahead of print]222 116098
    Lactic acid in macrophage polarization: A factor in carcinogenesis and a promising target for cancer therapy.
    Mobarakeh Ajam-Hosseini, Romina Heydari, Milad Rasouli, Fatemeh Akhoondi, Niloofar Asadi Hanjani, Sander Bekeschus, Mohammad Doroudian.
      Cancer remains a formidable challenge, continually revealing its intricate nature and demanding novel treatment approaches. Within this intricate landscape, the tumor microenvironment and its dynamic components have gained prominence, particularly macrophages that can adopt diverse polarization states, exerting a profound influence on cancer progression. Recent revelations have spotlighted lactic acid as a pivotal player in this complex interplay. This review systematically explores lactic acid's multifaceted role in macrophage polarization, focusing on its implications in carcinogenesis. We commence by cultivating a comprehensive understanding of the tumor microenvironment and the pivotal roles played by macrophages. The dynamic landscape of macrophage polarization, typified by M1 and M2 phenotypes, is dissected to reveal its substantial impact on tumor progression. Lactic acid, a metabolic byproduct, emerges as a key protagonist, and we meticulously unravel the mechanisms underpinning its generation within cancer cells, shedding light on its intimate association with glycolysis and its transformative effects on the tumor microenvironment. Furthermore, we decipher the intricate molecular framework that underlies lactic acid's pivotal role in facilitating macrophage polarization. Our review underscores lactic acid's dual role in carcinogenesis, orchestrating tumor growth and immune modulation within the tumor microenvironment, thereby profoundly influencing the balance between pro-tumor and anti-tumor immune responses. This duality highlights the therapeutic potential of selectively manipulating lactic acid metabolism for cancer treatment. Exploring strategies to inhibit lactic acid production by tumor cells, novel approaches to impede lactic acid transport in the tumor microenvironment, and the burgeoning field of immunotherapeutic cancer therapies utilizing lactic acid-induced macrophage polarization form the core of our investigation.
    Keywords:  Blocking strategies; Cancer therapy; Lactic acid; Macrophage polarization; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.bcp.2024.116098
  21. J Exp Clin Cancer Res. 2024 Mar 08. 43(1): 74
    A glutamine tug-of-war between cancer and immune cells: recent advances in unraveling the ongoing battle.
    Bolin Wang, Jinli Pei, Shengnan Xu, Jie Liu, Jinming Yu.
      Glutamine metabolism plays a pivotal role in cancer progression, immune cell function, and the modulation of the tumor microenvironment. Dysregulated glutamine metabolism has been implicated in cancer development and immune responses, supported by mounting evidence. Cancer cells heavily rely on glutamine as a critical nutrient for survival and proliferation, while immune cells require glutamine for activation and proliferation during immune reactions. This metabolic competition creates a dynamic tug-of-war between cancer and immune cells. Targeting glutamine transporters and downstream enzymes involved in glutamine metabolism holds significant promise in enhancing anti-tumor immunity. A comprehensive understanding of the intricate molecular mechanisms underlying this interplay is crucial for developing innovative therapeutic approaches that improve anti-tumor immunity and patient outcomes. In this review, we provide a comprehensive overview of recent advances in unraveling the tug-of-war of glutamine metabolism between cancer and immune cells and explore potential applications of basic science discoveries in the clinical setting. Further investigations into the regulation of glutamine metabolism in cancer and immune cells are expected to yield valuable insights, paving the way for future therapeutic interventions.
    Keywords:  Cancer; Glutamine metabolism; Immune cells; Therapeutic strategies; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13046-024-02994-0
  22. Clin Immunol. 2024 Mar 06. pii: S1521-6616(24)00072-X. [Epub ahead of print] 110181
    Functional consequence of Iron dyshomeostasis and ferroptosis in systemic lupus erythematosus and lupus nephritis.
    Laurence Morel, Yogesh Scindia.
      Systemic lupus erythematosus (SLE) and its renal manifestation Lupus nephritis (LN) are characterized by a dysregulated immune system, autoantibodies, and injury to the renal parenchyma. Iron accumulation and ferroptosis in the immune effectors and renal tubules are recently identified pathological features in SLE and LN. Ferroptosis is an iron dependent non-apoptotic form of regulated cell death and ferroptosis inhibitors have improved disease outcomes in murine models of SLE, identifying it as a novel druggable target. In this review, we discuss novel mechanisms by which iron accumulation and ferroptosis perpetuate immune cell mediated pathology in SLE/LN. We highlight intra-renal dysregulation of iron metabolism and ferroptosis as an underlying pathogenic mechanism of renal tubular injury. The basic concepts of iron biology and ferroptosis are also discussed to expose the links between iron, cell metabolism and ferroptosis, that identify intracellular pro-ferroptotic enzymes and their protein conjugates as potential targets to improve SLE/LN outcomes.
    Keywords:  Ferroptosis; Iron; Lupus nephritis; SLE
    DOI:  https://doi.org/10.1016/j.clim.2024.110181
  23. Nat Commun. 2024 Mar 08. 15(1): 2120
    Stem Leydig cells support macrophage immunological homeostasis through mitochondrial transfer in mice.
    Ani Chi, Bicheng Yang, Hao Dai, Xinyu Li, Jiahui Mo, Yong Gao, Zhihong Chen, Xin Feng, Menghui Ma, Yanqing Li, Chao Yang, Jie Liu, Hanchao Liu, Zhenqing Wang, Feng Gao, Yan Liao, Xuetao Shi, Chunhua Deng, Min Zhang.
      As testicular mesenchymal stromal cells, stem Leydig cells (SLCs) show great promise in the treatment of male hypogonadism. The therapeutic functions of mesenchymal stromal cells are largely determined by their reciprocal regulation by immune responses. However, the immunoregulatory properties of SLCs remain unclear. Here, we observe that SLCs transplantation restore male fertility and testosterone production in an ischemia‒reperfusion injury mouse model. SLCs prevent inflammatory cascades through mitochondrial transfer to macrophages. Reactive oxygen species (ROS) released from activated macrophages inducing mitochondrial transfer from SLCs to macrophages in a transient receptor potential cation channel subfamily member 7 (TRPM7)-mediated manner. Notably, knockdown of TRPM7 in transplanted SLCs compromised therapeutic outcomes in both testicular ischemia‒reperfusion and testicular aging mouse models. These findings reveal a new mechanism of SLCs transplantation that may contribute to preserve testis function in male patients with hypogonadism related to immune disorders.
    DOI:  https://doi.org/10.1038/s41467-024-46190-2
  24. Cell Stem Cell. 2024 Mar 07. pii: S1934-5909(24)00047-X. [Epub ahead of print]31(3): 359-377.e10
    A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate.
    Massimo Bonora, Claudia Morganti, Nick van Gastel, Kyoko Ito, Enrica Calura, Ilaria Zanolla, Letizia Ferroni, Yang Zhang, Yookyung Jung, Gabriele Sales, Paolo Martini, Takahisa Nakamura, Francesco Massimo Lasorsa, Toren Finkel, Charles P Lin, Barbara Zavan, Paolo Pinton, Irene Georgakoudi, Chiara Romualdi, David T Scadden, Keisuke Ito.
      Mitochondrial fatty acid oxidation (FAO) is essential for hematopoietic stem cell (HSC) self-renewal; however, the mechanism by which mitochondrial metabolism controls HSC fate remains unknown. Here, we show that within the hematopoietic lineage, HSCs have the largest mitochondrial NADPH pools, which are required for proper HSC cell fate and homeostasis. Bioinformatic analysis of the HSC transcriptome, biochemical assays, and genetic inactivation of FAO all indicate that FAO-generated NADPH fuels cholesterol synthesis in HSCs. Interference with FAO disturbs the segregation of mitochondrial NADPH toward corresponding daughter cells upon single HSC division. Importantly, we have found that the FAO-NADPH-cholesterol axis drives extracellular vesicle (EV) biogenesis and release in HSCs, while inhibition of EV signaling impairs HSC self-renewal. These data reveal the existence of a mitochondrial NADPH-cholesterol axis for EV biogenesis that is required for hematopoietic homeostasis and highlight the non-stochastic nature of HSC fate determination.
    Keywords:  HSC self-renewal; NADPH; cholesterol; exosomes; extracellular vesicles; fate determination; fatty acid oxidation; hematopoietic stem cell; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.stem.2024.02.004
  25. iScience. 2024 Mar 15. 27(3): 109225
    Blood metabolomic and transcriptomic signatures stratify patient subgroups in multiple sclerosis according to disease severity.
    Alexandra E Oppong, Leda Coelewij, Georgia Robertson, Lucia Martin-Gutierrez, Kirsty E Waddington, Pierre Dönnes, Petra Nytrova, Rachel Farrell, Inés Pineda-Torra, Elizabeth C Jury.
      There are no blood-based biomarkers distinguishing patients with relapsing-remitting (RRMS) from secondary progressive multiple sclerosis (SPMS) although evidence supports metabolomic changes according to MS disease severity. Here machine learning analysis of serum metabolomic data stratified patients with RRMS from SPMS with high accuracy and a putative score was developed that stratified MS patient subsets. The top differentially expressed metabolites between SPMS versus patients with RRMS included lipids and fatty acids, metabolites enriched in pathways related to cellular respiration, notably, elevated lactate and glutamine (gluconeogenesis-related) and acetoacetate and bOHbutyrate (ketone bodies), and reduced alanine and pyruvate (glycolysis-related). Serum metabolomic changes were recapitulated in the whole blood transcriptome, whereby differentially expressed genes were also enriched in cellular respiration pathways in patients with SPMS. The final gene-metabolite interaction network demonstrated a potential metabolic shift from glycolysis toward increased gluconeogenesis and ketogenesis in SPMS, indicating metabolic stress which may trigger stress response pathways and subsequent neurodegeneration.
    Keywords:  Classification Description; Machine learning; Metabolomics; Molecular network; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.109225
  26. Front Cell Infect Microbiol. 2024 ;14 1331521
    Excess fermentation and lactic acidosis as detrimental functions of the gut microbes in treatment-naive TB patients.
    Milyausha Yunusbaeva, Liliya Borodina, Darya Terentyeva, Anna Bogdanova, Aigul Zakirova, Shamil Bulatov, Radick Altinbaev, Fanil Bilalov, Bayazit Yunusbayev.
       Introduction: The link between gut microbiota and host immunity motivated numerous studies of the gut microbiome in tuberculosis (TB) patients. However, these studies did not explore the metabolic capacity of the gut community, which is a key axis of impact on the host's immunity.
    Methods: We used deep sequencing of fecal samples from 23 treatment-naive TB patients and 48 healthy donors to reconstruct the gut microbiome's metabolic capacity and strain/species-level content.
    Results: We show that the systematic depletion of the commensal flora of the large intestine, Bacteroidetes, and an increase in Actinobacteria, Firmicutes, and Proteobacteria such as Streptococcaceae, Erysipelotrichaceae, Lachnospiraceae, and Enterobacteriaceae explains the strong taxonomic divergence of the gut community in TB patients. The cumulative expansion of diverse disease-associated pathobionts in patients reached 1/4 of the total gut microbiota, suggesting a heavy toll on host immunity along with MTB infection. Reconstruction of metabolic pathways showed that the microbial community in patients shifted toward rapid growth using glycolysis and excess fermentation to produce acetate and lactate. Higher glucose availability in the intestine likely drives fermentation to lactate and growth, causing acidosis and endotoxemia.
    Discussion: Excessive fermentation and lactic acidosis likely characterize TB patients' disturbed gut microbiomes. Since lactic acidosis strongly suppresses the normal gut flora, directly interferes with macrophage function, and is linked to mortality in TB patients, our findings highlight gut lactate acidosis as a novel research focus. If confirmed, gut acidosis may be a novel potential host-directed treatment target to augment traditional TB treatment.
    Keywords:  anaerobic fermentation; dysbiosis; gut microbiome; gut-derived lactic acidosis; tuberculosis
    DOI:  https://doi.org/10.3389/fcimb.2024.1331521
  27. Nat Commun. 2024 Mar 08. 15(1): 2144
    PMI-controlled mannose metabolism and glycosylation determines tissue tolerance and virus fitness.
    Ronghui Liang, Zi-Wei Ye, Zhenzhi Qin, Yubin Xie, Xiaomeng Yang, Haoran Sun, Qiaohui Du, Peng Luo, Kaiming Tang, Bodan Hu, Jianli Cao, Xavier Hoi-Leong Wong, Guang-Sheng Ling, Hin Chu, Jiangang Shen, Feifei Yin, Dong-Yan Jin, Jasper Fuk-Woo Chan, Kwok-Yung Yuen, Shuofeng Yuan.
      Host survival depends on the elimination of virus and mitigation of tissue damage. Herein, we report the modulation of D-mannose flux rewires the virus-triggered immunometabolic response cascade and reduces tissue damage. Safe and inexpensive D-mannose can compete with glucose for the same transporter and hexokinase. Such competitions suppress glycolysis, reduce mitochondrial reactive-oxygen-species and succinate-mediated hypoxia-inducible factor-1α, and thus reduce virus-induced proinflammatory cytokine production. The combinatorial treatment by D-mannose and antiviral monotherapy exhibits in vivo synergy despite delayed antiviral treatment in mouse model of virus infections. Phosphomannose isomerase (PMI) knockout cells are viable, whereas addition of D-mannose to the PMI knockout cells blocks cell proliferation, indicating that PMI activity determines the beneficial effect of D-mannose. PMI inhibition suppress a panel of virus replication via affecting host and viral surface protein glycosylation. However, D-mannose does not suppress PMI activity or virus fitness. Taken together, PMI-centered therapeutic strategy clears virus infection while D-mannose treatment reprograms glycolysis for control of collateral damage.
    DOI:  https://doi.org/10.1038/s41467-024-46415-4
  28. PLoS Pathog. 2024 Mar;20(3): e1012036
    Modulation of nucleotide metabolism by picornaviruses.
    Lonneke V Nouwen, Martijn Breeuwsma, Esther A Zaal, Chris H A van de Lest, Inge Buitendijk, Marleen Zwaagstra, Pascal Balić, Dmitri V Filippov, Celia R Berkers, Frank J M van Kuppeveld.
      Viruses actively reprogram the metabolism of the host to ensure the availability of sufficient building blocks for virus replication and spreading. However, relatively little is known about how picornaviruses-a large family of small, non-enveloped positive-strand RNA viruses-modulate cellular metabolism for their own benefit. Here, we studied the modulation of host metabolism by coxsackievirus B3 (CVB3), a member of the enterovirus genus, and encephalomyocarditis virus (EMCV), a member of the cardiovirus genus, using steady-state as well as 13C-glucose tracing metabolomics. We demonstrate that both CVB3 and EMCV increase the levels of pyrimidine and purine metabolites and provide evidence that this increase is mediated through degradation of nucleic acids and nucleotide recycling, rather than upregulation of de novo synthesis. Finally, by integrating our metabolomics data with a previously acquired phosphoproteomics dataset of CVB3-infected cells, we identify alterations in phosphorylation status of key enzymes involved in nucleotide metabolism, providing insight into the regulation of nucleotide metabolism during infection.
    DOI:  https://doi.org/10.1371/journal.ppat.1012036
  29. mBio. 2024 Mar 05. e0029824
    A human milk oligosaccharide prevents intestinal inflammation in adulthood via modulating gut microbial metabolism.
    Kasey M Schalich, Matthew A Buendia, Harpreet Kaur, Yash A Choksi, M Kay Washington, Gabriela S Codreanu, Stacy D Sherrod, John A McLean, Richard M Peek, Sari A Acra, Steven D Townsend, Fang Yan.
      Observational evidence suggests that human milk oligosaccharides (HMOs) promote the growth of commensal bacteria in early life and adulthood. However, the mechanisms by which HMOs benefit health through modulation of gut microbial homeostasis remain largely unknown. 2'-fucosyllactose (2'-FL) is the most abundant oligosaccharide in human milk and contributes to the essential health benefits associated with human milk consumption. Here, we investigated how 2'-FL prevents colitis in adulthood through its effects on the gut microbial community. We found that the gut microbiota from adult mice that consumed 2'-FL exhibited an increase in abundance of several health-associated genera, including Bifidobacterium and Lactobacillus. The 2'-FL-modulated gut microbial community exerted preventive effects on colitis in adult mice. By using Bifidobacterium infantis as a 2'-FL-consuming bacterial model, exploratory metabolomics revealed novel 2'-FL-enriched secretory metabolites by Bifidobacterium infantis, including pantothenol. Importantly, pantothenate significantly protected the intestinal barrier against oxidative stress and mitigated colitis in adult mice. Furthermore, microbial metabolic pathway analysis identified 26 dysregulated metabolic pathways in fecal microbiota from patients with ulcerative colitis, which were significantly regulated by 2'-FL treatment in adult mice, indicating that 2'-FL has the potential to rectify dysregulated microbial metabolism in colitis. These findings support the contribution of the 2'-FL-shaped gut microbial community and bacterial metabolite production to the protection of intestinal integrity and prevention of intestinal inflammation in adulthood.IMPORTANCEAt present, neither basic research nor clinical studies have revealed the exact biological functions or mechanisms of action of individual oligosaccharides during development or in adulthood. Thus, it remains largely unknown whether human milk oligosaccharides could serve as effective therapeutics for gastrointestinal-related diseases. Results from the present study uncover 2'-FL-driven alterations in bacterial metabolism and identify novel B. infantis-secreted metabolites following the consumption of 2'-FL, including pantothenol. This work further demonstrates a previously unrecognized role of pantothenate in significantly protecting the intestinal barrier against oxidative stress and mitigating colitis in adult mice. Remarkably, 2'-FL-enhanced bacterial metabolic pathways are found to be dysregulated in the fecal microbiota of ulcerative colitis patients. These novel metabolic pathways underlying the bioactivities of 2'-FL may lay a foundation for applying individual oligosaccharides for prophylactic intervention for diseases associated with impaired intestinal homeostasis.
    Keywords:  2′-fucosyllactose; Bifidobacterium longum subsp. infantis; human milk oligosaccharide; inflammatory bowel diseases; intestinal barrier; pantothenate; the gut microbiota
    DOI:  https://doi.org/10.1128/mbio.00298-24
  30. J Exp Med. 2024 Apr 01. pii: e20232000. [Epub ahead of print]221(4):
    Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy.
    Danira Toral-Rios, Justin M Long, Jason D Ulrich, Jinsheng Yu, Michael R Strickland, Xianlin Han, David M Holtzman, Anil G Cashikar, Steven M Paul.
      Alzheimer's disease (AD) is characterized by amyloid plaques and neurofibrillary tangles, in addition to neuroinflammation and changes in brain lipid metabolism. 25-Hydroxycholesterol (25-HC), a known modulator of both inflammation and lipid metabolism, is produced by cholesterol 25-hydroxylase encoded by Ch25h expressed as a "disease-associated microglia" signature gene. However, whether Ch25h influences tau-mediated neuroinflammation and neurodegeneration is unknown. Here, we show that in the absence of Ch25h and the resultant reduction in 25-HC, there is strikingly reduced age-dependent neurodegeneration and neuroinflammation in the hippocampus and entorhinal/piriform cortex of PS19 mice, which express the P301S mutant human tau transgene. Transcriptomic analyses of bulk hippocampal tissue and single nuclei revealed that Ch25h deficiency in PS19 mice strongly suppressed proinflammatory signaling in microglia. Our results suggest a key role for Ch25h/25-HC in potentiating proinflammatory signaling to promote tau-mediated neurodegeneration. Ch25h may represent a novel therapeutic target for primary tauopathies, AD, and other neuroinflammatory diseases.
    DOI:  https://doi.org/10.1084/jem.20232000
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