bims-imicid 2023-12-31 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023–12–31
fiveteen papers selected by
Dylan Ryan, University of Cambridge

Adenine is an anti-inflammatory metabolite found to be more abundant in M-CSF over GM-CSF-differentiated human macrophages.
Inhibition of voltage-gated Hv1 alleviates LPS-induced neuroinflammation via regulation of microglial metabolic reprogramming.
Potassium ion efflux induces exaggerated mitochondrial damage and non-pyroptotic necrosis when energy metabolism is blocked.
Estrobolome dysregulation is associated with altered immunometabolism in a mouse model of endometriosis.
The pathogenic role of metabolism in Sjögren's syndrome.
Heterogeneous ferroptosis susceptibility of macrophages caused by focal iron overload exacerbates rheumatoid arthritis.
Ochratoxin A-enhanced glycolysis induces inflammatory responses in human gastric epithelium cells through mTOR/HIF-1α signaling pathway.
Pathological shifts in tryptophan metabolism in human term placenta exposed to LPS or poly I:C.
TREM2-IGF1 Mediated Glucometabolic Enhancement Underlies Microglial Neuroprotective Properties During Ischemic Stroke.
Urine Metabolite Analysis to Identify Pathomechanisms of Long COVID: A Pilot Study.
Exercise-induced crosstalk between immune cells and adipocytes in humans: Role of oncostatin-M.
Identification of metabolite biomarkers in Salmonella enteritidis-contaminated chickens using UHPLC-QTRAP-MS-based targeted metabolomics.
A computational model of Pseudomonas syringae metabolism unveils a role for branched-chain amino acids in Arabidopsis leaf colonization.
A comprehensive metabolite fingerprint of fibrostenosis in patients with Crohn's disease.
Psoriasis comorbid with atherosclerosis meets in lipid metabolism.

Immunol Lett. 2023 Dec 22. pii: S0165-2478(23)00204-3. [Epub ahead of print]

Adenine is an anti-inflammatory metabolite found to be more abundant in M-CSF over GM-CSF-differentiated human macrophages.

Karl J Harber, Thuc-Anh Nguyen, Bauke V Schomakers, Daan A F Heister, Helga E de Vries, Michel van Weeghel, Jan Van den Bossche, Menno P J de Winther.

  Immunometabolism has been unveiled in the last decade to play a major role in controlling macrophage metabolism and inflammation. There has been a constant effort to understand the immunomodulating properties of regulated metabolites during inflammation with the aim of controlling and re-wiring aberrant macrophages in inflammatory diseases. M-CSF and GM-CSF-differentiated macrophages play a key role in mounting successful innate immune responses. When a resolution phase is not achieved however, GM-CSF macrophages contribute substantially more towards an adverse inflammatory milieu than M-CSF macrophages, consequently driving disease progression. Whether there are specific immunometabolites that determine the homeostatic or inflammatory nature of M-CSF and GM-CSF-differentiated macrophages is still unknown. As such, we performed metabolomics analysis on LPS and IL-4-stimulated M-CSF and GM-CSF-differentiated human macrophages to identify differentially accumulating metabolites. Adenine was distinguished as a metabolite significantly higher in M-CSF-differentiated macrophages after both LPS or IL-4 stimulation. Human macrophages treated with adenine before LPS stimulation showed a reduction in inflammatory gene expression, cytokine secretion and surface marker expression. Adenine caused macrophages to become more quiescent by lowering glycolysis and OXPHOS which resulted in reduced ATP production. Moreover, typical metabolite changes seen during LPS-induced macrophage metabolic reprogramming were absent in the presence of adenine. Phosphorylation of metabolic signaling proteins AMPK, p38 MAPK and AKT were not responsible for the suppressed metabolic activity of adenine-treated macrophages. Altogether, in this study we highlight the immunomodulating capacity of adenine in human macrophages and its function in driving cellular quiescence.

Keywords:  Adenine; GM-CSF; Immunometabolism; Inflammation; M-CSF; Macrophage

DOI:  https://doi.org/10.1016/j.imlet.2023.12.003
Int Immunopharmacol. 2023 Dec 24. pii: S1567-5769(23)01688-0. [Epub ahead of print]127 111361

Inhibition of voltage-gated Hv1 alleviates LPS-induced neuroinflammation via regulation of microglial metabolic reprogramming.

Lingbin Sun, Xihua Wang, Shuyuan Guan, Laiting Chi, Mingjin Liang, Xiao Lu, Tao Luo.

  A growing body of evidence highlights the crucial role of metabolic reprogramming in activated immune cells, significantly contributing to both the initiation and progression of neuroinflammation and neurodegenerative diseases. The voltage-gated H channel (Hv1) has been reported to be involved in microglial activation and acts as a key driver of neuroinflammation. This study aimed to explore how Hv1-mediated metabolic reprogramming contributes to neuroinflammation and to assess the therapeutic potential of the Hv1 inhibitor 2-GBI in a model of lipopolysaccharide (LPS)-induced neuroinflammation. We investigated the influence of 2-GBI on the generation of ROS, metabolic reprogramming, and pro-inflammatory mediator production in vitro and examined the therapeutic effect of 2-GBI on microglial activation and hippocampal neuroinflammation in vivo. The results indicated that 2-GBI attenuated the LPS-induced pro-inflammatory response and aerobic glycolysis in microglia, specifically mitigating HIF1α-mediated upregulation of glycolysis. 2-GBI exerted a protective effect against LPS-induced neuroinflammation through HIF1α pathway-regulated aerobic glycolysis. Using a transwell coculture system, we demonstrated that 2-GBI reversed PC12 cell death caused by BV2-mediated neuroinflammation. In vivo experiments further suggested that 2-GBI mitigated neuroinflammatory processes and cognitive dysfunction via microglial metabolic reprogramming. Collectively, our results highlight the potential of Hv1 inhibition as a therapeutic strategy for alleviating LPS-induced neuroinflammation by modulating microglial metabolic reprogramming.

Keywords:  Hv1; Metabolic reprogramming; Microglia; Neuroinflammation

DOI:  https://doi.org/10.1016/j.intimp.2023.111361
Free Radic Biol Med. 2023 Dec 25. pii: S0891-5849(23)01186-3. [Epub ahead of print]

Potassium ion efflux induces exaggerated mitochondrial damage and non-pyroptotic necrosis when energy metabolism is blocked.

Rong Xu, Li-Sha Yuan, Ying-Qing Gan, Na Lu, Ya-Ping Li, Zhi-Ya Zhou, Qing-Bing Zha, Xian-Hui He, Tak-Sui Wong, Dong-Yun Ouyang.

  Damage-associated molecular patterns (DAMPs) such as extracellular ATP and nigericin (a bacterial toxin) not only act as potassium ion (K+) efflux inducers to activate NLRP3 inflammasome, leading to pyroptosis, but also induce cell death independently of NLRP3 expression. However, the roles of energy metabolism in determining NLRP3-dependent pyroptosis and -independent necrosis upon K+ efflux are incompletely understood. Here we established cellular models by pharmacological blockade of energy metabolism, followed by stimulation with a K+ efflux inducer (ATP or nigericin). Two energy metabolic inhibitors, namely CPI-613 that targets α-ketoglutarate dehydrogenase and pyruvate dehydrogenase (a rate-limiting enzyme) and 2-deoxy-d-glucose (2-DG) that targets hexokinase, are recruited in this study, and Nlrp3 gene knockout macrophages were used. Our data showed that CPI-613 and 2-DG dose-dependently inhibited NLRP3 inflammasome activation, but profoundly increased cell death in the presence of ATP or nigericin. The cell death was K+ efflux-induced but NLRP3-indendent, which was associated with abrupt reactive oxygen species (ROS) production, reduction of mitochondrial membrane potential, and oligomerization of mitochondrial proteins, all indicating mitochondrial damage. Notably, the cell death induced by K+ efflux and blockade of energy metabolism was distinct from pyroptosis, apoptosis, necroptosis or ferroptosis. Furthermore, fructose 1,6-bisphosphate, a high-energy intermediate of glycolysis, significantly suppressed CPI-613+nigericin-induced mitochondrial damage and cell death. Collectively, our data show that energy deficiency diverts NLRP3 inflammasome activation-dependent pyroptosis to Nlrp3-independent necrosis upon K+ efflux inducers, which can be dampened by high-energy intermediate, highlighting a critical role of energy metabolism in cell survival and death under inflammatory conditions.

Keywords:  Fructose-1,6-bisphosphate; Glucose metabolism; Mitochondrial damage; NLRP3 inflammasome activation; Potassium efflux; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.12.029
Front Endocrinol (Lausanne). 2023 ;14 1261781

Estrobolome dysregulation is associated with altered immunometabolism in a mouse model of endometriosis.

Hasan Alghetaa, Amira Mohammed, Narendra P Singh, Ryan F Bloomquist, Ioulia Chatzistamou, Mitzi Nagarkatti, Prakash Nagarkatti.

   Introduction: Endometriosis is a painful disease that affects around 5% of women of reproductive age. In endometriosis, ectopic endometrial cells or seeded endometrial debris grow in abnormal locations including the peritoneal cavity. Common manifestations of endometriosis include dyspareunia, dysmenorrhea, chronic pelvic pain and often infertility and symptomatic relief or surgical removal are mainstays of treatment. Endometriosis both promotes and responds to estrogen imbalance, leading to intestinal bacterial estrobolome dysregulation and a subsequent induction of inflammation.
Methods: In the current study, we investigated the linkage between gut dysbiosis and immune metabolic response in endometriotic mice. Ovariectomized BALB/c mice received intraperitoneal transplantation of endometrial tissue from OVX donors (OVX+END). Control groups included naïve mice (Naïve), naïve mice that received endometrial transplants (Naive+END) and OVX mice that received the vehicle (OVX+VEH). Colonic content was collected 2 weeks post-transplantation for 16s rRNA pyrosequencing and peritoneal fluid was collected to determine the phenotype of inflammatory cells by flow cytometry.
Results: We noted a significant increase in the number of peritoneal fluid cells, specifically, T cells, natural killer (NK) cells, and NKT cells in OVX+END mice. Phylogenetic taxonomy analysis showed significant dysbiosis in OVX+END mice, with an increase in abundance of Phylum Tenericutes, Class Mollicutes, Order Aneroplasmatales, and Genus Aneroplasma, and a decrease in Order Clostridiales, and Genus Dehalobacterium, when compared to OVX+VEH controls. The metabolomic profile showed an increase in some tricarboxylic acid cycle (TCA)-related metabolites accompanied by a reduction in short-chain fatty acids (SCFA) such as butyric acid in OVX+END mice. Additionally, the mitochondrial and ATP production of immune cells was enforced to a maximal rate in OVX+END mice when compared to OVX+VEH mice.
Conclusion: The current study demonstrates that endometriosis alters the gut microbiota and associated immune metabolism.

Keywords:  T-cell metabolism; endometriosis; estrobolome; immunometabolism; metabolome; microbiome; short chain fatty acids

DOI:  https://doi.org/10.3389/fendo.2023.1261781
Clin Exp Rheumatol. 2023 Dec;41(12): 2538-2546

The pathogenic role of metabolism in Sjögren's syndrome.

Serena Colafrancesco, Edoardo Simoncelli, Roberta Priori, Michele Bombardieri.

The link between immune cell function and cell metabolic reprogramming is currently known under the term "immunometabolism". Similarly to the Warburg's effect described in cancer cells, in activated immune cells an up-regulation of specific metabolic pathways has been described and seems to be pathogenic in different inflammatory conditions.Sjӧgren's syndrome (SS) is a systemic autoimmune disease that affects the exocrine glands and is characterised by a progressive loss of secretory function. Despite the increasing amount of evidence on the ability of metabolism in regulating cell behaviour in inflammatory or tumoral conditions, the field of metabolism in SS is still for the most part unexplored.The aim of this review is to summarise currently available studies evaluating cell metabolism in SS with a particular focus on the possible pathogenic role of metabolic changes in immune and non-immune cells in this condition.

DOI: https://doi.org/10.55563/clinexprheumatol/hhbqej
Redox Biol. 2023 Dec 20. pii: S2213-2317(23)00409-3. [Epub ahead of print]69 103008

Heterogeneous ferroptosis susceptibility of macrophages caused by focal iron overload exacerbates rheumatoid arthritis.

Yan Liu, Xiqing Luo, Ye Chen, Junlong Dang, Donglan Zeng, Xinghua Guo, Weizhen Weng, Jun Zhao, Xiaoyi Shi, Jingrong Chen, Bo Dong, Shuyuan Zhong, Jianhua Ren, Yuhang Li, Julie Wang, Jingwen Zhang, Jianbo Sun, Hanshi Xu, Yan Lu, David Brand, Song Guo Zheng, Yunfeng Pan.

  Focal iron overload is frequently observed in patients with rheumatoid arthritis (RA), yet its functional significance remains elusive. Herein, we report that iron deposition in lesion aggravates arthritis by inducing macrophage ferroptosis. We show that excessive iron in synovial fluid positively correlates with RA disease severity as does lipid hyperoxidation of focal monocyte/macrophages. Further study reveals high susceptibility to iron induced ferroptosis of the anti-inflammatory macrophages M2, while pro-inflammatory M1 are less affected. Distinct glutathione peroxidase 4 (GPX4) degradation depending on p62/SQSTM1 in the two cell types make great contribution mechanically. Of note, ferroptosis inhibitor liproxstatin-1 (LPX-1) can alleviate the progression of K/BxN serum-transfer induced arthritis (STIA) mice accompanied with increasing M2 macrophages proportion. We thus propose that the heterogeneous ferroptosis susceptibility of macrophage subtypes as well as consequent inflammation and immune disorders are potential biomarkers and therapeutic targets in RA.

Keywords:  Ferroptosis; GPX4; Iron overload; Macrophage; Rheumatoid arthritis

DOI:  https://doi.org/10.1016/j.redox.2023.103008
Ecotoxicol Environ Saf. 2023 Dec 23. pii: S0147-6513(23)01372-6. [Epub ahead of print]270 115868

Ochratoxin A-enhanced glycolysis induces inflammatory responses in human gastric epithelium cells through mTOR/HIF-1α signaling pathway.

Yuan Wang, Man Zhao, Jinfeng Cui, Hongguang Lian, Zengfang Hao, Lei Lou, Xin Jia, Wei Zhao, Haitao Shen, Lingxiao Xing, Xianghong Zhang.

  Ochratoxin A (OTA) is a mycotoxin commonly found in several food commodities worldwide with potential nephrotoxic, hepatotoxic and carcinogenic effects. We previously showed for the first time that OTA treatment enhanced glycolysis in human gastric epithelium (GES-1) cells in vitro. Here, we found that OTA exposure activated inflammatory responses, evidenced by increasing of NF-κB signaling pathway-related protein (p-p65 and p-IκBα) expressions and elevating of inflammatory cytokine (IL-1β and IL-6) mRNA expressions in GES-1 cells. To elucidate the role of glycolysis in inflammatory effects triggered by OTA, we pretreated GES-1 cells with glycolysis inhibitor (2-deoxy-D-glucose, 2-DG) before OTA exposure. The result showed that 2-DG reduced the protein expressions of p-p65 and p-IκBα and alleviated the mRNA expressions of inflammatory cytokines in OTA-treated GES-1 cells. Furthermore, OTA activated the mTOR/HIF-1α pathway by increasing the protein expressions of p-mTOR, p-eIF4E and HIF-1α, and inhibition of mTOR with rapamycin or silencing HIF-1α with siRNA significantly attenuated OTA-enhanced glycolysis by reducing glycolysis related genes and thereby decreasing inflammatory effects of GES-1 cells. These results demonstrate that OTA activates inflammatory responses in GES-1 cells and this is controlled by mTOR/HIF-1α pathway-mediated glycolysis enhancement. Our findings provide a novel mechanistic view into OTA-induced gastric cytotoxicity.

Keywords:  Gastric epithelium cell; Glycolysis; HIF-1α; Inflammatory responses; MTOR; Ochratoxin A

DOI:  https://doi.org/10.1016/j.ecoenv.2023.115868
Biol Reprod. 2023 Dec 25. pii: ioad181. [Epub ahead of print]

Pathological shifts in tryptophan metabolism in human term placenta exposed to LPS or poly I:C.

Cilia Abad, Rona Karahoda, Anna Orbisova, Petr Kastner, Heblik Daniel, Radim Kucera, Ramon Portillo, Frantisek Staud.

  Maternal immune activation during pregnancy is a risk factor for offspring neuropsychiatric disorders. Among the mechanistic pathways by which maternal inflammation can affect fetal brain development and programming, those involving tryptophan (TRP) metabolism have drawn attention because various TRP metabolites have neuroactive properties. This study evaluates the effect of bacterial (LPS) and viral (poly I:C) placental infection on TRP metabolism using an ex vivo model. Human placenta explants were exposed to LPS or Poly I:C, and the release of TRP metabolites was analyzed together with the expression of related genes and proteins and the functional activity of key enzymes in TRP metabolism. The rate-limiting enzyme in the serotonin pathway, tryptophan hydroxylase, showed reduced expression and functional activity in explants exposed to LPS or Poly I:C. Conversely, the rate-limiting enzyme in the kynurenine (KYN) pathway, indoleamine dioxygenase, exhibited increased activity, gene, and protein expression, suggesting that placental infection mainly promotes TRP metabolism via the KYN pathway. Furthermore, we observed that treatment with LPS or Poly I:C increased activity in the kynurenine monooxygenase branch of the KYN pathway. We conclude that placental infection impairs TRP homeostasis, resulting in decreased production of serotonin and an imbalance in the ratio between quinolinic acid and kynurenic acid. This disrupted homeostasis may eventually expose the fetus to suboptimal/toxic levels of neuroactive molecules and impair fetal brain development.

Keywords:  Intrauterine infections; fetal brain development; placenta; programming; tryptophan metabolism

DOI:  https://doi.org/10.1093/biolre/ioad181
Adv Sci (Weinh). 2023 Dec 27. e2305614

TREM2-IGF1 Mediated Glucometabolic Enhancement Underlies Microglial Neuroprotective Properties During Ischemic Stroke.

Sheng Yang, Chuan Qin, Man Chen, Yun-Hui Chu, Yue Tang, Luo-Qi Zhou, Hang Zhang, Ming-Hao Dong, Xiao-Wei Pang, Lian Chen, Long-Jun Wu, Dai-Shi Tian, Wei Wang.

  Microglia, the major resident immune cells in the central nervous system, serve as the frontline soldiers against cerebral ischemic injuries, possibly along with metabolic alterations. However, signaling pathways involved in the regulation of microglial immunometabolism in ischemic stroke remain to be further elucidated. In this study, using single-nuclei RNA sequencing, a microglial subcluster up-regulated in ischemic brain tissues is identified, with high expression of Igf1 and Trem2, neuroprotective transcriptional signature and enhanced oxidative phosphorylation. Microglial depletion by PLX3397 exacerbates ischemic brain damage, which is reversed by repopulating the microglia with high Igf1 and Trem2 phenotype. Mechanistically, Igf1 serves as one of the major down-stream molecules of Trem2, and Trem2-Igf1 signaling axis regulates microglial functional and metabolic profiles, exerting neuroprotective effects on ischemic stroke. Overexpression of Igf1 and supplementation of cyclocreatine restore microglial glucometabolic levels and cellular functions even in the absence of Trem2. These findings suggest that Trem2-Igf1 signaling axis reprograms microglial immunometabolic profiles and shifts microglia toward a neuroprotective phenotype, which has promising therapeutic potential in treating ischemic stroke.

Keywords:  Trem2-Igf1 signaling pathway; ischemic stroke; microglia; oxidative phosphorylation

DOI:  https://doi.org/10.1002/advs.202305614
Int J Tryptophan Res. 2023 ;16 11786469231220781

Urine Metabolite Analysis to Identify Pathomechanisms of Long COVID: A Pilot Study.

Maja Taenzer, Judith Löffler-Ragg, Andrea Schroll, Pablo Monfort-Lanzas, Sabine Engl, Günter Weiss, Natascha Brigo, Katharina Kurz.

   Background: Around 10% of people who had COVID-9 infection suffer from persistent symptoms such as fatigue, dyspnoea, chest pain, arthralgia/myalgia, sleep disturbances, cognitive dysfunction and impairment of mental health. Different underlying pathomechanisms appear to be involved, in particular inflammation, alterations in amino acid metabolism, autonomic dysfunction and gut dysbiosis.
Aim: As routine tests are often inconspicuous in patients with Long COVID (LC), similarly to patients suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), accessible biomarkers indicating dysregulation of specific pathways are urgently needed to identify underlying pathomechanisms and enable personalized medicine treatment. Within this pilot study we aimed to proof traceability of altered metabolism by urine analysis.
Patients and Methods: Urine metabolome analyses were performed to investigate the metabolic signature of patients with LC (n = 25; 20 women, 5 men) in comparison to healthy controls (Ctrl, n = 8; 7 women, 1 man) and individuals with ME/CFS (n = 8; 2 women, 6 men). Concentrations of neurotransmitter precursors tryptophan, phenylalanine and their downstream metabolites, as well as their association with symptoms (fatigue, anxiety and depression) in the patients were examined.
Results and Conclusion: Phenylalanine levels were significantly lower in both the LC and ME/CFS patient groups when compared to the Ctrl group. In many LC patients, the concentrations of downstream metabolites of tryptophan and tyrosine, such as serotonin, dopamine and catecholamines, deviated from the reference ranges. Several symptoms (sleep disturbance, pain or autonomic dysfunction) were associated with certain metabolites. Patients experiencing fatigue had lower levels of kynurenine, phenylalanine and a reduced kynurenine to tryptophan ratio (Kyn/Trp). Lower concentrations of gamma-aminobutyric acid (GABA) and higher activity of kynurenine 3-monooxygenase (KMO) were observed in patients with anxiety. Conclusively, our results suggest that amino acid metabolism and neurotransmitter synthesis is disturbed in patients with LC and ME/CFS. The identified metabolites and their associated dysregulations could serve as potential biomarkers for elucidating underlying pathomechanisms thus enabling personalized treatment strategies for these patient populations.

Keywords:  IFN-gamma mediated pathway; Long-COVID; fatigue; gut dysbiosis; urine metabolites

DOI:  https://doi.org/10.1177/11786469231220781
Cell Rep Med. 2023 Dec 21. pii: S2666-3791(23)00565-7. [Epub ahead of print] 101348

Exercise-induced crosstalk between immune cells and adipocytes in humans: Role of oncostatin-M.

Lucile Dollet, Leonidas S Lundell, Alexander V Chibalin, Logan A Pendergrast, Nicolas J Pillon, Elizabeth L Lansbury, Merve Elmastas, Scott Frendo-Cumbo, Jutta Jalkanen, Thais de Castro Barbosa, Daniel T Cervone, Kenneth Caidahl, Oksana Dmytriyeva, Atul S Deshmukh, Romain Barrès, Mikael Rydén, Harriet Wallberg-Henriksson, Juleen R Zierath, Anna Krook.

  The discovery of exercise-regulated circulatory factors has fueled interest in organ crosstalk, especially between skeletal muscle and adipose tissue, and the role in mediating beneficial effects of exercise. We studied the adipose tissue transcriptome in men and women with normal glucose tolerance or type 2 diabetes following an acute exercise bout, revealing substantial exercise- and time-dependent changes, with sustained increase in inflammatory genes in type 2 diabetes. We identify oncostatin-M as one of the most upregulated adipose-tissue-secreted factors post-exercise. In cultured human adipocytes, oncostatin-M enhances MAPK signaling and regulates lipolysis. Oncostatin-M expression arises predominantly from adipose tissue immune cell fractions, while the corresponding receptors are expressed in adipocytes. Oncostatin-M expression increases in cultured human Thp1 macrophages following exercise-like stimuli. Our results suggest that immune cells, via secreted factors such as oncostatin-M, mediate a crosstalk between skeletal muscle and adipose tissue during exercise to regulate adipocyte metabolism and adaptation.

Keywords:  adipose tissue; crosstalk; exercise; human; immune cells; inflammation; oncostatin-M; skeletal muscle; type 2 diabetes

DOI:  https://doi.org/10.1016/j.xcrm.2023.101348
Food Chem X. 2023 Dec 30. 20 100966

Identification of metabolite biomarkers in Salmonella enteritidis-contaminated chickens using UHPLC-QTRAP-MS-based targeted metabolomics.

Lan Chen, Tao Zhang, Hao Ding, Xing Xie, Yali Zhu, Guojun Dai, Yushi Gao, Genxi Zhang, Kaizhou Xie.

  This study aimed to characterize the metabolic profile of Salmonella enteritidis (S. enteritidis) in chicken matrix and to identify metabolic biomarkers of S. enteritidis in chicken. The UHPLC-QTRAP-MS high-throughput targeted metabolomics approach was employed to analyze the metabolic profiles of contaminated and control group chickens. A total of 348 metabolites were quantified, and the application of deep learning least absolute shrinkage and selection operator (LASSO) modelling analysis obtained eight potential metabolite biomarkers for S. enteritidis. Metabolic abundance change analysis revealed significantly enriched abundances of anthranilic acid, l-pyroglutamic acid, 5-hydroxylysine, n,n-dimethylarginine, 4-hydroxybenzoic acid, and menatetrenone in contaminated chicken samples. The receiver operating characteristic (ROC) curve analysis demonstrated the strong ability of these six metabolites as biomarkers to distinguish S. enteritidis contaminated and fresh chicken samples. The findings presented in this study offer a theoretical foundation for developing an innovative approach to identify and detect foodborne contamination caused by S. enteritidis.

Keywords:  Chicken; Metabolite biomarkers; S. enteritidis; UHPLC-QTRAP-MS

DOI:  https://doi.org/10.1016/j.fochx.2023.100966
PLoS Comput Biol. 2023 Dec 27. 19(12): e1011651

A computational model of Pseudomonas syringae metabolism unveils a role for branched-chain amino acids in Arabidopsis leaf colonization.

Philip J Tubergen, Greg Medlock, Anni Moore, Xiaomu Zhang, Jason A Papin, Cristian H Danna.

Bacterial pathogens adapt their metabolism to the plant environment to successfully colonize their hosts. In our efforts to uncover the metabolic pathways that contribute to the colonization of Arabidopsis thaliana leaves by Pseudomonas syringae pv tomato DC3000 (Pst DC3000), we created iPst19, an ensemble of 100 genome-scale network reconstructions of Pst DC3000 metabolism. We developed a novel approach for gene essentiality screens, leveraging the predictive power of iPst19 to identify core and ancillary condition-specific essential genes. Constraining the metabolic flux of iPst19 with Pst DC3000 gene expression data obtained from naïve-infected or pre-immunized-infected plants, revealed changes in bacterial metabolism imposed by plant immunity. Machine learning analysis revealed that among other amino acids, branched-chain amino acids (BCAAs) metabolism significantly contributed to the overall metabolic status of each gene-expression-contextualized iPst19 simulation. These predictions were tested and confirmed experimentally. Pst DC3000 growth and gene expression analysis showed that BCAAs suppress virulence gene expression in vitro without affecting bacterial growth. In planta, however, an excess of BCAAs suppress the expression of virulence genes at the early stages of infection and significantly impair the colonization of Arabidopsis leaves. Our findings suggesting that BCAAs catabolism is necessary to express virulence and colonize the host. Overall, this study provides valuable insights into how plant immunity impacts Pst DC3000 metabolism, and how bacterial metabolism impacts the expression of virulence.

DOI: https://doi.org/10.1371/journal.pcbi.1011651
Sci Rep. 2023 Dec 27. 13(1): 23036

A comprehensive metabolite fingerprint of fibrostenosis in patients with Crohn's disease.

Simon Bos, Triana Lobatón, Martine De Vos, Sophie Van Welden, Vera Plekhova, Ellen De Paepe, Lynn Vanhaecke, Debby Laukens.

Intestinal fibrostenosis in patients with Crohn's disease (CD) is a common and untreatable comorbidity that is notoriously difficult to monitor. We aimed to find metabolites associated with the presence of fibrostenosis in patients with CD using targeted and untargeted metabolomics analyses of serum and primary cell cultures using hyphenated ultra-high performance liquid chromatography high-resolution mass spectrometry. Targeted metabolomics revealed 11 discriminating metabolites in serum, which were enriched within the arginine and proline metabolism pathway. Based on untargeted metabolomics and discriminant analysis, 166 components showed a high predictive value. In addition, human intestinal fibroblasts isolated from stenotic tissue were characterized by differential levels of medium-chain dicarboxylic acids, which are proposed as an energy source through beta-oxidation, when oxidative phosphorylation is insufficient. Another energy providing pathway in such situations is anaerobic glycolysis, a theory supported by increased expression of hexokinase 2 and solute carrier family 16 member 1 in stenotic fibroblasts. Of interest, four (unannotated) metabolic components showed a negative correlation with hexokinase 2 gene expression. Together, this study provides a discriminative metabolic fingerprint in the serum and in intestinal fibroblasts of stenotic and non-stenotic patients with CD suggestive for increased production of building blocks for collagen synthesis and increased glycolysis.

DOI: https://doi.org/10.1038/s41598-023-50461-1
Front Pharmacol. 2023 ;14 1308965

Psoriasis comorbid with atherosclerosis meets in lipid metabolism.

Liuping Chen, Huiqi Chen, Sien Guo, Zhijun Chen, Haifeng Yang, Yanjiao Liu, Xiaoling Chen, Xinming Chen, Tingting Du, Xinyao Long, Jiaxiong Zhao, Mingli Guo, Tianfeng Lao, DongHui Huang, Lei Wang, Jing Chen, Chunping Liu.

  Psoriasis (PSO) is a common skin disease affecting approximately 1%-3% of the population, and the incidence rate is increasing yearly. PSO is associated with a dramatically increased risk of cardiovascular disease, the most common of which is atherosclerosis (AS). In the past, inflammation was considered to be the triggering factor of the two comorbidities, but in recent years, studies have found that lipid metabolism disorders increase the probability of atherosclerosis in patients with psoriasis. In this review, we discuss epidemiological studies, clinical treatment methods, risk factors, and lipid metabolism of psoriasis and atherosclerosis comorbidities.

Keywords:  atherosclerosis; comorbidity; inflammation; lipid metabolism; psoriasis

DOI:  https://doi.org/10.3389/fphar.2023.1308965