bims-imicid 2022-10-09 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022‒10‒09
28 papers selected by
Dylan Ryan
University of Cambridge

GAB functions as a bioenergetic and signalling gatekeeper to control T cell inflammation.
Plasma iron controls neutrophil production and function.
Comparative Photoaffinity Profiling of Omega-3 Signaling Lipid Probes Reveals Prostaglandin Reductase 1 as a Metabolic Hub in Human Macrophages.
Enforcing GLUT3 expression in CD8+ T cells improves fitness and tumor control by promoting glucose uptake and energy storage.
Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid clearance.
The role of immunomodulatory metabolites in shaping the inflammatory response of macrophages.
Hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes.
Lipid metabolic features of T cells in the Tumor Microenvironment.
The effects of 1,25(OH)2D3 treatment on metabolic reprogramming and maturation in bone marrow-derived dendritic cells from control and diabetic mice.
CD36-mediated metabolic crosstalk between tumor cells and macrophages affects liver metastasis.
Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy.
Isocitrate binds to the itaconic acid-responsive LysR-type transcriptional regulator RipR in Salmonella pathogenesis.
Temperature induces metabolic reprogramming in fish during bacterial infection.
Dietary sugar lowers immunity and microbiota that protect against metabolic disease.
TNFα and IFNγ rapidly activate PI3K-AKT signaling to drive glycolysis that confers mesenchymal stem cells enhanced anti-inflammatory property.
Defective Mitochondrial Quality Control during Dengue Infection Contributes to Disease Pathogenesis.
Metabolic regulation by prostaglandin E2 impairs lung group 2 innate lymphoid cell responses.
Potential mechanisms by which impaired ketogenesis links metabolism to T-cell dysfunction in patients with severe COVID-19.
Unfermented β-fructan fibers fuel inflammation in select inflammatory bowel disease patients.
BAFF antagonism via the BAFF receptor 3 binding site attenuates BAFF 60-mer-induced classical NF-κB signaling and metabolic reprogramming of B cells.
Metabolomic and transcriptomic study to understand changes in metabolic and immune responses in steers under heat stress.
Choline kinase: An underappreciated rheumatoid arthritis therapeutic target.
Succinate communicates pro-inflammatory signals to the host and regulates bile acid enterohepatic metabolism in a pig model.
Mitochondrial fatty acid β-oxidation is important for normal osteoclast formation in growing female mice.
GOT2: An Unexpected Mediator of Immunosuppression in Pancreatic Cancer.
Bifidobacterium spp. and their metabolite lactate protect against acute pancreatitis via inhibition of pancreatic and systemic inflammatory responses.
Potential of gut-derived short-chain fatty acids to control enteric pathogens.
Association of COVID-19 with hepatic metabolic dysfunction.

Nat Metab. 2022 Oct 03.

GAB functions as a bioenergetic and signalling gatekeeper to control T cell inflammation.

Siwen Kang, Lingling Liu, Tingting Wang, Matthew Cannon, Penghui Lin, Teresa W-M Fan, David A Scott, Hsin-Jung Joyce Wu, Andrew N Lane, Ruoning Wang.

γ-Aminobutyrate (GAB), the biochemical form of (GABA) γ-aminobutyric acid, participates in shaping physiological processes, including the immune response. How GAB metabolism is controlled to mediate such functions remains elusive. Here we show that GAB is one of the most abundant metabolites in CD4+ T helper 17 (TH17) and induced T regulatory (iTreg) cells. GAB functions as a bioenergetic and signalling gatekeeper by reciprocally controlling pro-inflammatory TH17 cell and anti-inflammatory iTreg cell differentiation through distinct mechanisms. 4-Aminobutyrate aminotransferase (ABAT) funnels GAB into the tricarboxylic acid (TCA) cycle to maximize carbon allocation in promoting TH17 cell differentiation. By contrast, the absence of ABAT activity in iTreg cells enables GAB to be exported to the extracellular environment where it acts as an autocrine signalling metabolite that promotes iTreg cell differentiation. Accordingly, ablation of ABAT activity in T cells protects against experimental autoimmune encephalomyelitis (EAE) progression. Conversely, ablation of GABAA receptor in T cells worsens EAE. Our results suggest that the cell-autonomous control of GAB on CD4+ T cells is bimodal and consists of the sequential action of two processes, ABAT-dependent mitochondrial anaplerosis and the receptor-dependent signalling response, both of which are required for T cell-mediated inflammation.

DOI: https://doi.org/10.1038/s42255-022-00638-1
Sci Adv. 2022 Oct 07. 8(40): eabq5384

Plasma iron controls neutrophil production and function.

Joe N Frost, Sarah K Wideman, Alexandra E Preston, Megan R Teh, Zhichao Ai, Lihui Wang, Amy Cross, Natasha White, Yavuz Yazicioglu, Michael Bonadonna, Alexander J Clarke, Andrew E Armitage, Bruno Galy, Irina A Udalova, Hal Drakesmith.

Low plasma iron (hypoferremia) induced by hepcidin is a conserved inflammatory response that protects against infections but inhibits erythropoiesis. How hypoferremia influences leukocytogenesis is unclear. Using proteomic data, we predicted that neutrophil production would be profoundly more iron-demanding than generation of other white blood cell types. Accordingly in mice, hepcidin-mediated hypoferremia substantially reduced numbers of granulocytes but not monocytes, lymphocytes, or dendritic cells. Neutrophil rebound after anti-Gr-1-induced neutropenia was blunted during hypoferremia but was rescued by supplemental iron. Similarly, hypoferremia markedly inhibited pharmacologically stimulated granulopoiesis mediated by granulocyte colony-stimulating factor and inflammation-induced accumulation of neutrophils in the spleen and peritoneal cavity. Furthermore, hypoferremia specifically altered neutrophil effector functions, suppressing antibacterial mechanisms but enhancing mitochondrial reactive oxygen species-dependent NETosis associated with chronic inflammation. Notably, antagonizing endogenous hepcidin during acute inflammation enhanced production of neutrophils. We propose plasma iron modulates the profile of innate immunity by controlling monocyte-to-neutrophil ratio and neutrophil activity in a therapeutically targetable system.

DOI: https://doi.org/10.1126/sciadv.abq5384
J Am Chem Soc. 2022 Oct 05.

Comparative Photoaffinity Profiling of Omega-3 Signaling Lipid Probes Reveals Prostaglandin Reductase 1 as a Metabolic Hub in Human Macrophages.

Berend Gagestein, Johannes H von Hegedus, Joanneke C Kwekkeboom, Marieke Heijink, Niek Blomberg, Tom van der Wel, Bogdan I Florea, Hans van den Elst, Kim Wals, Herman S Overkleeft, Martin Giera, René E M Toes, Andreea Ioan-Facsinay, Mario van der Stelt.

The fish oil constituent docosahexaenoic acid (DHA, 22:6 n-3) is a signaling lipid with anti-inflammatory properties. The molecular mechanisms underlying the biological effect of DHA are poorly understood. Here, we report the design, synthesis, and application of a complementary pair of bio-orthogonal, photoreactive probes based on the polyunsaturated scaffold DHA and its oxidative metabolite 17-hydroxydocosahexaenoic acid (17-HDHA). In these probes, an alkyne serves as a handle to introduce a fluorescent reporter group or a biotin-affinity tag via copper(I)-catalyzed azide-alkyne cycloaddition. This pair of chemical probes was used to map specific targets of the omega-3 signaling lipids in primary human macrophages. Prostaglandin reductase 1 (PTGR1) was identified as an interaction partner that metabolizes 17-oxo-DHA, an oxidative metabolite of 17-HDHA. 17-oxo-DHA reduced the formation of pro-inflammatory lipids 5-HETE and LTB4 in human macrophages and neutrophils. Our results demonstrate the potential of comparative photoaffinity protein profiling for the discovery of metabolic enzymes of bioactive lipids and highlight the power of chemical proteomics to uncover new biological insights.

DOI: https://doi.org/10.1021/jacs.2c06827
Front Immunol. 2022 ;13 976628

Enforcing GLUT3 expression in CD8+ T cells improves fitness and tumor control by promoting glucose uptake and energy storage.

Elisabetta Cribioli, Greta Maria Paola Giordano Attianese, Pierpaolo Ginefra, Amandine Signorino-Gelo, Romain Vuillefroy de Silly, Nicola Vannini, Christoph Hess, Melita Irving, George Coukos.

  Despite the tremendous success of adoptive T-cell therapies (ACT) in fighting certain hematologic malignancies, not all patients respond, a proportion experience relapse, and effective ACT of most solid tumors remains elusive. In order to improve responses to ACT suppressive barriers in the solid tumor microenvironment (TME) including insufficient nutrient availability must be overcome. Here we explored how enforced expression of the high-affinity glucose transporter GLUT3 impacted tumor-directed T cells. Overexpression of GLUT3 in primary murine CD8+ T cells enhanced glucose uptake and increased glycogen and fatty acid storage, and was associated with increased mitochondrial fitness, reduced ROS levels, higher abundance of the anti-apoptotic protein Mcl-1, and better resistance to stress. Importantly, GLUT3-OT1 T cells conferred superior control of B16-OVA melanoma tumors and, in this same model, significantly improved survival. Moreover, a proportion of treated mice were cured and protected from re-challenge, indicative of long-term T cell persistence and memory formation. Enforcing expression of GLUT3 is thus a promising strategy to improve metabolic fitness and sustaining CD8+ T cell effector function in the context of ACT.

Keywords:  T cell engineering; adoptive cell therapy; glucose; immunotherapy; metabolism; tumor

DOI:  https://doi.org/10.3389/fimmu.2022.976628
Nat Metab. 2022 Oct 06.

Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid clearance.

Lige Leng, Ziqi Yuan, Ruiyuan Pan, Xiao Su, Han Wang, Jin Xue, Kai Zhuang, Ju Gao, Zhenlei Chen, Hui Lin, Wenting Xie, Huifang Li, Zhenyi Chen, Keke Ren, Xiao Zhang, Wenting Wang, Zi-Bing Jin, Shengxi Wu, Xinglong Wang, Zengqiang Yuan, Huaxi Xu, Hei-Man Chow, Jie Zhang.

Microglial cells consume adenosine triphosphate (ATP) during phagocytosis to clear neurotoxic β-amyloid in Alzheimer's disease (AD). However, the contribution of energy metabolism to microglial function in AD remains unclear. Here, we demonstrate that hexokinase 2 (HK2) is elevated in microglia from an AD mouse model (5xFAD) and AD patients. Genetic deletion or pharmacological inhibition of HK2 significantly promotes microglial phagocytosis, lowers the amyloid plaque burden and attenuates cognitive impairment in male AD mice. Notably, the ATP level is dramatically increased in HK2-deficient or inactive microglia, which can be attributed to a marked upregulation in lipoprotein lipase (LPL) expression and subsequent increase in lipid metabolism. We further show that two downstream metabolites of HK2, glucose-6-phosphate and fructose-6-phosphate, can reverse HK2-deficiency-induced upregulation of LPL, thus supporting ATP production and microglial phagocytosis. Our findings uncover a crucial role for HK2 in phagocytosis through regulation of microglial energy metabolism, suggesting a potential therapeutic strategy for AD by targeting HK2.

DOI: https://doi.org/10.1038/s42255-022-00643-4
BMB Rep. 2022 Oct 05. pii: 5699. [Epub ahead of print]

The role of immunomodulatory metabolites in shaping the inflammatory response of macrophages.

Doyoung Park, Gyumin Lim, Sung-Jin Yoon, Hyon-Seung Yi, Dong Wook Choi.

Macrophage activation has long been implicated in a myriad of human pathophysiology, particularly in the context of the dysregulated capacities of an unleashing intracellular or/and extracellular inflammatory response. A growing number of studies have functionally coupled the macrophages' inflammatory capacities with dynamic metabolic reprogramming which occurs during activation, albeit the results have been mostly interpreted through classic metabolism point of view; macrophages take advantage of the rewired metabolism as a source of energy and for biosynthetic precursors. However, a specific subset of metabolic products, namely immune-modulatory metabolites, has recently emerged as significant regulatory signals which control inflammatory responses in macrophages and the relevant extracellular milieu. In this review, we introduce recently highlighted the immuno-modulatory metabolites, with the aim of understanding their physiological and pathological relevance in the macrophage inflammatory response.
Front Pharmacol. 2022 ;13 972397

Hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes.

Chao Jin, Bei-Bei Gao, Wen-Jing Zhou, Bao-Jing Zhao, Xing Fang, Chun-Lan Yang, Xiao-Hua Wang, Quan Xia, Ting-Ting Liu.

  Hydroxychloroquine (HCQ) is derivative of the heterocyclic aromatic compound quinoline, which has been used for the treatment of autoimmune diseases. The central purpose of this study was to investigate therapeutic effects and inflammatory immunological molecular mechanism of HCQ in experimental autoimmune hepatitis (AIH). Treatment with HCQ ameliorated hepatic pathologic damage, inflammatory infiltration, while promoted regulatory T cell (Treg) and down-regulated CD8+T cell differentiation in AIH mice induced by S-100 antigen. In vitro, HCQ also suppressed pro-inflammatory cytokine (IFN-γ, TNF-α, and IL-12) secretion, promoted anti-inflammatory cytokine (TGF-β1) secretion. HCQ mainly impaired T cell lipid metabolism but not glycolysis to promote Treg differentiation and function. Mechanistically, HCQ down-regulated GRK2 membrane translocation in T cells, inhibited GRK2-PI3K interaction to reduce the PI3K recruiting to the membrane, followed by suppressing the phosphorylation of PI3K-AKT-mTOR signal. Pretreating T cells with paroxetine, a GRK2 inhibitor, disturbed HCQ effect to T cells. HCQ also reversed the activation of the PI3K-AKT axis by 740 Y-P (PI3K agonist). Meanwhile, HCQ inhibited the PI3K-AKT-mTOR, JAK2-STAT3-SOCS3 and increased the AMPK signals in the liver and T cells of AIH mice. In conclusion, HCQ exhibited specific and potent therapeutic effects on AIH and attendant liver injury, which was attributed to HCQ acted on GRK2 translocation, inhibited metabolism-related PI3K-AKT and inflammation-related JAK2-STAT3 signal in T lymphocytes, thereby modulating lipid metabolism of T cell function to regulate Treg differentiation and function.

Keywords:  G protein-coupled receptor kinase 2; PI3K-AKT axis; autoimmune hepatitis; glycolipid metabolism; hydroxychloroquine; regulatory T cells

DOI:  https://doi.org/10.3389/fphar.2022.972397
Lipids Health Dis. 2022 Oct 06. 21(1): 94

Lipid metabolic features of T cells in the Tumor Microenvironment.

Wanshuang Lou, Chaoju Gong, Zhuoni Ye, Ynayan Hu, Minjing Zhu, Zejun Fang, Huihui Xu.

  The tumor microenvironment (TME) is characterized by discrete changes in metabolic features of cancer and immune cells, with various implications. Cancer cells take up most of the available glucose to support their growth, thereby leaving immune cells with insufficient nutrients to expand. In the relative absence of glucose, T cells switch the metabolic program to lipid-based sources, which is pivotal to T-cell differentiation and activation in nutrient-stressed TME. Although consumption of lipids should provide an alternative energy source to starving T cells, a literature survey has revealed that it may not necessarily lead to antitumor responses. Different subtypes of T cells behave differently in various lipid overload states, which widely depends upon the kind of free fatty acids (FFA) engulfed. Key lipid metabolic genes provide cytotoxic T cells with necessary nutrients for proliferation in the absence of glucose, thereby favoring antitumor immunity, but the same genes cause immune evasion in Tmem and Treg. This review aims to detail the complexity of differential lipid metabolism in distinct subtypes of T cells that drive the antitumor or pro-tumor immunity in specific TME states. We have identified key drug targets related to lipid metabolic rewiring in TME.

Keywords:  CD36; Lipid; PD-L1/2; T-cells; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1186/s12944-022-01705-y
J Steroid Biochem Mol Biol. 2022 Sep 29. pii: S0960-0760(22)00148-0. [Epub ahead of print] 106197

The effects of 1,25(OH)2D3 treatment on metabolic reprogramming and maturation in bone marrow-derived dendritic cells from control and diabetic mice.

Ungue Shin, Hyeyoung You, Ga Young Lee, YeKyoung Son, Sung Nim Han.

  Activated dendritic cells (DCs) undergo significant metabolic reprogramming, which is characterized by an increase in aerobic glycolysis and a concurrent progressive loss of oxidative phosphorylation. The modulation of metabolic reprogramming is believed to be closely related to the function of DCs. Vitamin D has been reported to inhibit the maturation of DCs. DC dysfunction has been reported in diabetic patients, and hyperglycemia is associated with impaired glycolytic metabolism in immune cells. Therefore, vitamin D and diabetes may affect intracellular metabolism, thereby regulating the activity of DCs. We investigated the effect of in vitro treatment of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on metabolic reprogramming and maturation of bone marrow-derived dendritic cells (BMDCs) from diabetic mouse. Six-week-old male C57BLKS/J-m+/m+ mice (CON) and C57BLKS/J-db/db mice (db/db) were fed with a 10% kcal fat diet for seven weeks. BMDCs were generated by culturing bone marrow cells from the mice with rmGM-CSF (20ng/mL) in the absence or presence of 10nM 1,25(OH)2D3. The maturation of BMDCs was induced via lipopolysaccharide (LPS, 50ng/mL) stimulation for 24hours. LPS stimulation induced iNOS protein expression and decreased the mitochondrial respiration, while increased lactate production and the expression of glycolytic pathway-related genes (Glut1 and Pfkfb3) in BMDCs from both CON and db/db groups. In LPS-stimulated mature BMDCs, 1,25(OH)2D3 treatment decreased the expression of surface markers related to immunostimulatory functions (MHC class II, CD80, CD86, and CD40) and production of IL-12p70 in both CON and db/db groups. While the mRNA level of the gene related to glucose uptake (Glut1) was increased in both groups, lactate production was decreased by 1,25(OH)2D3 treatment. mTORC1 activity was suppressed following 1,25(OH)2D3 treatment. Collectively, our findings confirmed that metabolic reprogramming occurred in BMDCs following LPS stimulation. In vitro 1,25(OH)2D3 treatment induced tolerogenic phenotypes by reducing the expression of surface markers, as well as cytokine production. However, no significant difference was observed regarding the effects of 1,25(OH)2D3 treatment on metabolic conversion and maturation of BMDCs between the control and diabetic mice. Additionally, the decreased aerobic glycolysis induced by the 1,25(OH)2D3 treatment appeared to be associated with the diminished maturation of BMDCs, and mTORC1 appears to play a key role in the 1,25(OH)2D3-mediated regulation of glycolysis.

Keywords:  1,25(OH)(2)D(3); aerobic glycolysis; bone marrow-derived dendritic cells; diabetes; mTORC1; metabolic reprogramming

DOI:  https://doi.org/10.1016/j.jsbmb.2022.106197
Nat Commun. 2022 Oct 02. 13(1): 5782

CD36-mediated metabolic crosstalk between tumor cells and macrophages affects liver metastasis.

Ping Yang, Hong Qin, Yiyu Li, Anhua Xiao, Enze Zheng, Han Zeng, Chunxiao Su, Xiaoqing Luo, Qiannan Lu, Meng Liao, Lei Zhao, Li Wei, Zac Varghese, John F Moorhead, Yaxi Chen, Xiong Z Ruan.

Liver metastasis is highly aggressive and treatment-refractory, partly due to macrophage-mediated immune suppression. Understanding the mechanisms leading to functional reprogramming of macrophages in the tumor microenvironment (TME) will benefit cancer immunotherapy. Herein, we find that the scavenger receptor CD36 is upregulated in metastasis-associated macrophages (MAMs) and deletion of CD36 in MAMs attenuates liver metastasis in mice. MAMs contain more lipid droplets and have the unique capability in engulfing tumor cell-derived long-chain fatty acids, which are carried by extracellular vesicles. The lipid-enriched vesicles are preferentially partitioned into macrophages via CD36, that fuel macrophages and trigger their tumor-promoting activities. In patients with liver metastases, high expression of CD36 correlates with protumoral M2-type MAMs infiltration, creating a highly immunosuppressive TME. Collectively, our findings uncover a mechanism by which tumor cells metabolically interact with macrophages in TME, and suggest a therapeutic potential of targeting CD36 as immunotherapy for liver metastasis.

DOI: https://doi.org/10.1038/s41467-022-33349-y
Front Cell Dev Biol. 2022 ;10 1013885

Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy.

Chu Xiao, He Tian, Yujia Zheng, Zhenlin Yang, Shuofeng Li, Tao Fan, Jiachen Xu, Guangyu Bai, Jingjing Liu, Ziqin Deng, Chunxiang Li, Jie He.

  Cancer cells and immune cells all undergo remarkably metabolic reprogramming during the oncogenesis and tumor immunogenic killing processes. The increased dependency on glycolysis is the most typical trait, profoundly involved in the tumor immune microenvironment and cancer immunity regulation. However, how to best utilize glycolytic targets to boost anti-tumor immunity and improve immunotherapies are not fully illustrated. In this review, we describe the glycolytic remodeling of various immune cells within the tumor microenvironment (TME) and the deleterious effects of limited nutrients and acidification derived from enhanced tumor glycolysis on immunological anti-tumor capacity. Moreover, we elucidate the underlying regulatory mechanisms of glycolytic reprogramming, including the crosstalk between metabolic pathways and immune checkpoint signaling. Importantly, we summarize the potential glycolysis-related targets that are expected to improve immunotherapy benefits. Our understanding of metabolic effects on anti-tumor immunity will be instrumental for future therapeutic regimen development.

Keywords:  TME; cancer metabolism; glycolysis; immunity regulation; immunotherapy

DOI:  https://doi.org/10.3389/fcell.2022.1013885
J Biol Chem. 2022 Oct 02. pii: S0021-9258(22)01006-7. [Epub ahead of print] 102562

Isocitrate binds to the itaconic acid-responsive LysR-type transcriptional regulator RipR in Salmonella pathogenesis.

Nayeon Ki, Jinshil Kim, Inseong Jo, Yongseong Hyun, Sangryeol Ryu, Nam-Chul Ha.

  Macrophages produce itaconic acid in phagosomes in response to bacterial cell wall component lipopolysaccharide (LPS) to eliminate invading pathogenic bacteria. Itaconic acid competitively inhibits the first enzyme of the bacterial glyoxylate cycle. To overcome itaconic acid stress, bacteria employ the bacterial LysR-type transcriptional regulator RipR. However, it remains unknown which molecule activates RipR in bacterial pathogenesis. In this study, we determined the crystal structure of the regulatory domain (RD) of RipR from the intracellular pathogen Salmonella. The RipR RD structure exhibited the typical dimeric arrangement with the putative ligand binding site between the two subdomains. Our isothermal titration calorimetry experiments identified isocitrate as the physiological ligand of RipR, whose intracellular level is increased in response to itaconic acid stress. We further found that 3-phenylpropionic acid significantly decreased the resistance of the bacteria to an itaconic acid challenge. Consistently, the complex structure revealed that the compound is antagonistically bound to the RipR ligand binding site. This study provides the molecular basis of bacterial survival in itaconic acid stress from our immune systems. Further studies are required to reveal biochemical activity, which would elucidate how Salmonella survives in macrophage phagosomes by defending against itaconic acid inhibition of bacterial metabolism.

Keywords:  3-phenylpropionic acid; LysR-type transcriptional regulator; glyoxylate cycle; isocitrate; itaconic acid

DOI:  https://doi.org/10.1016/j.jbc.2022.102562
Front Immunol. 2022 ;13 1010948

Temperature induces metabolic reprogramming in fish during bacterial infection.

Bin Sun, Boguang Sun, Beibei Zhang, Li Sun.

  Water temperature elevation as a consequence of global warming results in increased incidence of bacterial disease, such as edwardsiellosis, in fish farming. Edwardsiellosis is caused by the bacterial pathogen Edwardsiella tarda and affects many farmed fish including flounder (Paralichthys olivaceus). Currently, the effect of temperature on the metabolic response of flounder to E. tarda infection is unclear. In this study, we found that compared to low temperature (15°C), high temperature (23°C) enhanced E. tarda dissemination in flounder tissues. To examine the impact of temperature on the metabolism of flounder induced by E. tarda, comparative metabolomics were performed, which identified a large number of metabolites responsive to E. tarda invasion and temperature alteration. During E. tarda infection, the metabolic profile induced by elevated temperature was mainly featured by extensively decreased amino acids and TCA intermediates such as succinate, a proven immune regulator. Further, 38 potential metabolite markers of temperature effect (MMTE) in association with bacterial infection were identified. When used as exogenous supplements, two of the MMTE, i.e., L-methionine and UDP-glucose, effectively upregulated the expression of pro-inflammatory cytokines and suppressed E. tarda infection in flounder leukocytes. Taken together, the results of this study indicate an important influence of temperature on the metabolism of flounder during bacterial infection, which eventually affects the survivability of the fish.

Keywords:  Edwardsiella; Paralichthys olivaceus; bacterial infection; biomarker; edwardsiellosis; global warming; metabolism; temperature

DOI:  https://doi.org/10.3389/fimmu.2022.1010948
Cell Metab. 2022 Oct 04. pii: S1550-4131(22)00396-5. [Epub ahead of print]34(10): 1422-1424

Dietary sugar lowers immunity and microbiota that protect against metabolic disease.

Han Fang, Fernando F Anhê, Jonathan D Schertzer.

Diet influences intestinal microbiota, inflammation, and metabolism. Kawano et al. show that dietary sugar engaged upper gut innate lymphoid cells to replace segmented filamentous bacteria with a pathobiont. Added sugar worsened early metabolic disease by lowering protective Th17 immunity, thereby promoting intestinal lipid absorption and obesity in high-fat-diet-fed mice.

DOI: https://doi.org/10.1016/j.cmet.2022.09.006
Stem Cell Res Ther. 2022 Oct 04. 13(1): 491

TNFα and IFNγ rapidly activate PI3K-AKT signaling to drive glycolysis that confers mesenchymal stem cells enhanced anti-inflammatory property.

Chenchang Xu, Chao Feng, Peiqing Huang, Yinghong Li, Rui Liu, Chunxiao Liu, Yuyi Han, Lei Chen, Yayun Ding, Changshun Shao, Yufang Shi.

  BACKGROUND: Mesenchymal stem/stromal cells (MSCs) acquire immunosuppressive capacity only in an inflammatory microenvironment. This can be recapitulated in vitro by treating MSCs with inflammatory cytokines TNFα and IFNγ, which induce indoleamine 2,3-dioxygenase (IDO) and TNF-stimulated gene-6 (TSG-6). However, the signaling pathways downstream of the cytokines remain to be elucidated.METHODS: Inflammatory bowel disease (IBD) mouse model was established by subjecting mice to dextran sulfate sodium (DSS) in drinking water for 7 days. Human UC-MSCs were pretreated with TNF-α and IFN-γ for 24 h and were then infused intravenously at day 2 of DSS administration. Colon tissues were collected for length measurement and histopathological examination. The serum level of IL-6 in mice was measured by enzyme-linked immunosorbent assay. Real-time PCR and Western blot were used to examine the mRNA level and protein expression. MSCs overexpressing constitutive active AKT or dominant negative AKT were generated and were analyzed. The glycolysis level of the MSCs was measured using Extracellular Flux Analyzer. 2-NBDG was used to monitor the uptake of glucose by MSCs.
RESULTS: TNFα and IFNγ treatment led to rapid consumption of glucose and metabolic skewing toward glycolysis in MSCs, which was required for the therapeutic efficacy of MSCs on IBD. Blockade of glycolysis in MSCs inhibited the expression of immunomodulatory molecules, IDO and TSG-6, as well as the therapeutic effect on IBD. Moreover, PI3K-AKT signaling axis was rapidly activated and was required for the skewing toward glycolysis induced by TNFα and IFNγ. MSCs expressing dominant negative AKT were compromised in their therapeutic efficacy on IBD.
CONCLUSION: The glycolysis-dependent anti-inflammatory property of MSCs conferred by inflammatory cytokines is mediated by PI3K-AKT signaling pathway.

Keywords:  Anti-inflammation; Glycolysis; IBD; MSCs; PI3K-AKT

DOI:  https://doi.org/10.1186/s13287-022-03178-3
J Virol. 2022 Oct 05. e0082822

Defective Mitochondrial Quality Control during Dengue Infection Contributes to Disease Pathogenesis.

Bharati Singh, Kiran Avula, Shamim Akhtar Sufi, Nahid Parwin, Sayani Das, Mohd Faraz Alam, Subhashish Samantaray, Leelakrishna Bankapalli, Alankrita Rani, Kokavalla Poornima, Biswajita Prusty, Tareni P Mallick, Shubham K Shaw, Hiren Dodia, Shobhitendu Kabi, Trupti T Pagad, Sriprasad Mohanty, Gulam Hussain Syed.

  Mitochondrial fitness is governed by mitochondrial quality control pathways comprising mitochondrial dynamics and mitochondrial-selective autophagy (mitophagy). Disruption of these processes has been implicated in many human diseases, including viral infections. Here, we report a comprehensive analysis of the effect of dengue infection on host mitochondrial homeostasis and its significance in dengue disease pathogenesis. Despite severe mitochondrial stress and injury, we observed that the pathways of mitochondrial quality control and mitochondrial biogenesis are paradoxically downregulated in dengue-infected human liver cells. This leads to the disruption of mitochondrial homeostasis and the onset of cellular injury and necrotic death in the infected cells. Interestingly, dengue promotes global autophagy but selectively disrupts mitochondrial-selective autophagy (mitophagy). Dengue downregulates the expression of PINK1 and Parkin, the two major proteins involved in tagging the damaged mitochondria for elimination through mitophagy. Mitophagy flux assays also suggest that Parkin-independent pathways of mitophagy are also inactive during dengue infection. Dengue infection also disrupts mitochondrial biogenesis by downregulating the master regulators PPARγ and PGC1α. Dengue-infected cells release mitochondrial damage-associated molecular patterns (mtDAMPs) such as mitochondrial DNA into the cytosol and extracellular milieu. Furthermore, the challenge of naive immune cells with culture supernatants from dengue-infected liver cells was sufficient to trigger proinflammatory signaling. In correlation with our in vitro observations, dengue patients have high levels of cell-free mitochondrial DNA in their blood in proportion to the degree of thrombocytopenia. Overall, our study shows how defective mitochondrial homeostasis in dengue-infected liver cells can drive dengue disease pathogenesis. IMPORTANCE Many viruses target host cell mitochondria to create a microenvironment conducive to viral dissemination. Dengue virus also exploits host cell mitochondria to facilitate its viral life cycle. Dengue infection of liver cells leads to severe mitochondrial injury and inhibition of proteins that regulate mitochondrial quality control and biogenesis, thereby disrupting mitochondrial homeostasis. A defect in mitochondrial quality control leads to the accumulation of damaged mitochondria and promotes cellular injury. This leads to the release of mitochondrial damage-associated molecular patterns (mt-DAMPs) into the cell cytoplasm and extracellular milieu. These mt-DAMPs activate the naive immune cells and trigger proinflammatory signaling, leading to the release of cytokines and chemokines, which may trigger systemic inflammation and contribute to dengue disease pathogenesis. In correlation with this, we observed high levels of cell-free mitochondrial DNA in dengue patient blood. This study provides insight into how the disruption of mitochondrial quality control in dengue-infected cells can trigger inflammation and drive dengue disease pathogenesis.

Keywords:  autophagy; dengue virus; inflammation; mitochondria; mitochondrial homeostasis; mitochondrial quality control; mitophagy; mt-DNA; necrosis

DOI:  https://doi.org/10.1128/jvi.00828-22
Allergy. 2022 Oct 01.

Metabolic regulation by prostaglandin E2 impairs lung group 2 innate lymphoid cell responses.

Calum T Robb, You Zhou, Jennifer M Felton, Birong Zhang, Marie Goepp, Privjyot Jheeta, Danielle J Smyth, Rodger Duffin, Sonja Vermeren, Richard M Breyer, Shuh Narumiya, Henry J McSorley, Rick M Maizels, Jürgen K J Schwarze, Adriano G Rossi, Chengcan Yao.

  BACKGROUND: Group 2 innate lymphoid cells (ILC2s) play a critical role in asthma pathogenesis. Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is associated with reduced signaling via EP2, a receptor for prostaglandin E2 (PGE2 ). However, the respective roles for the PGE2 receptors EP2 and EP4 (both share same downstream signaling) in the regulation of lung ILC2 responses has yet been deciphered.METHODS: The roles of PGE2 receptors EP2 and EP4 on ILC2-mediated lung inflammation were investigated using genetically modified mouse lines and pharmacological approaches in IL-33-induced lung allergy model. The effects of PGE2 receptors and downstream signals on ILC2 metabolic activation and effector function were examined using in vitro cell cultures.
RESULTS: Deficiency of EP2 rather than EP4 augments IL-33-induced mouse lung ILC2 responses and eosinophilic inflammation in vivo. In contrast, exogenous agonism of EP4 and EP2 or inhibition of phosphodiesterase markedly restricts IL-33-induced lung ILC2 responses. Mechanistically, PGE2 directly suppresses IL-33-dependent ILC2 activation through the EP2/EP4-cAMP pathway, which downregulates STAT5 and MYC pathway gene expression and ILC2 energy metabolism. Blocking glycolysis diminishes IL-33-dependent ILC2 responses in mice where endogenous PG synthesis or EP2 signaling is blocked but not in mice with intact PGE2 -EP2 signaling.
CONCLUSION: We have defined a mechanism for optimal suppression of mouse lung ILC2 responses by endogenous PGE2 -EP2 signaling which underpins the clinical findings of defective EP2 signaling in patients with NERD. Our findings also indicate that exogenously targeting the PGE2 -EP4-cAMP and energy metabolic pathways may provide novel opportunities for treating ILC2-initiated lung inflammation in asthma and NERD.

Keywords:  EP2; EP4; Group 2 innate lymphoid cell (ILC2); NSAID-exacerbated respiratory disease (NERD); cellular metabolism; lung allergy; prostaglandin E2 (PGE2)

DOI:  https://doi.org/10.1111/all.15541
MedComm (2020). 2022 Dec;3(4): e178

Potential mechanisms by which impaired ketogenesis links metabolism to T-cell dysfunction in patients with severe COVID-19.

Bin Wang, Lei Zhang, Fangfang Zhou, Long Zhang.

DOI: https://doi.org/10.1002/mco2.178
Gastroenterology. 2022 Sep 29. pii: S0016-5085(22)01150-7. [Epub ahead of print]

Unfermented β-fructan fibers fuel inflammation in select inflammatory bowel disease patients.

Heather K Armstrong, Michael Bording-Jorgensen, Deanna M Santer, Zhengxiao Zhang, Rosica Valcheva, Aja M Rieger, Justin Sung-Ho Kim, Stephanie I Dijk, Ramsha Mahmood, Olamide Ogungbola, Juan Jovel, France Moreau, Hayley Gorman, Robyn Dickner, Jeremy Jerasi, Inderdeep K Mander, Dawson Lafleur, Christopher Cheng, Alexandra Petrova, Terri-Lyn Jeanson, Andrew Mason, Consolato M Sergi, Arie Levine, Kris Chadee, David Armstrong, Sarah Rauscher, Charles N Bernstein, Matthew W Carroll, Hien Q Huynh, Jens Walter, Karen L Madsen, Levinus A Dieleman, Eytan Wine.

  BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD) are impacted by dietary factors, including non-digestible carbohydrates (fibers), which are fermented by colonic microbes. Fibers are overall beneficial but not all fibers are alike and some IBD patients report intolerance to fiber consumption. Given reproducible evidence of reduced fiber-fermenting microbes in IBD patients, we hypothesized that fibers remain intact in select patients with reduced fiber-fermenting microbes and can then bind host cell receptors, subsequently promoting gut inflammation.METHODS: Colonic biopsies cultured ex vivo and cell lines in vitro were incubated with oligofructose (5g/L), or fermentation supernatants (24hr anaerobic fermentation) and immune responses (cytokine secretion [ELISA/MSD] and expression [qPCR]) were assessed. Influence of microbiota in mediating host response was examined and taxonomic classification of microbiota was conducted with Kraken2 and metabolic profiling by HUMAnN2, using R software.
RESULTS: Unfermented dietary β-fructan fibers induced pro-inflammatory cytokines in a subset of IBD intestinal biopsies cultured ex vivo, and immune cells (including peripheral blood mononuclear cells). Results were validated in an adult IBD randomized controlled trial examining β-fructan supplementation. The pro-inflammatory response to intact β-fructan required activation of the NLRP3 and TLR2 pathways. Fermentation of β-fructans by human gut whole-microbiota cultures reduced the pro-inflammatory response, but only when microbes were collected from non-IBD or inactive IBD patients. Fiber-induced immune responses correlated with microbe functions, luminal metabolites, and dietary fiber avoidance.
CONCLUSION: While fibers are typically beneficial in individuals with normal microbial fermentative potential, some dietary fibers have detrimental effects in select patients with active IBD who lack fermentative microbe activities.

Keywords:  Dietary fibers; IBD; fermentation; microbiome

DOI:  https://doi.org/10.1053/j.gastro.2022.09.034
Cell Immunol. 2022 Sep 09. pii: S0008-8749(22)00128-9. [Epub ahead of print]381 104603

BAFF antagonism via the BAFF receptor 3 binding site attenuates BAFF 60-mer-induced classical NF-κB signaling and metabolic reprogramming of B cells.

Melissa D Lempicki, Saikat Paul, Vlad Serbulea, Clint M Upchurch, Srabani Sahu, Jake A Gray, Gorav Ailawadi, Brandon L Garcia, Coleen A McNamara, Norbert Leitinger, Akshaya K Meher.

  Human recombinant B cell activating factor (BAFF) is secreted as 3-mers, which can associate to form 60-mers in culture supernatants. However, the presence of BAFF multimers in humans is still debated and it is incompletely understood how BAFF multimers activate the B cells. Here, we demonstrate that BAFF can exist as 60-mers or higher order multimers in human plasma. In vitro, BAFF 60-mer strongly induced the transcriptome of B cells which was partly attenuated by antagonism using a soluble fragment of BAFF receptor 3. Furthermore, compared to BAFF 3-mer, BAFF 60-mer strongly induced a transient classical and prolonged alternate NF-κB signaling, glucose oxidation by both aerobic glycolysis and oxidative phosphorylation, and succinate utilization by mitochondria. BAFF antagonism selectively attenuated classical NF-κB signaling and glucose oxidation. Altogether, our results suggest critical roles of BAFF 60-mer and its BAFF receptor 3 binding site in hyperactivation of B cells.

Keywords:  B cell activation; BAFF multimers; Metabolic reprogramming; NF-κB signaling; Transcriptomics

DOI:  https://doi.org/10.1016/j.cellimm.2022.104603
Anim Nutr. 2022 Dec;11 87-101

Metabolomic and transcriptomic study to understand changes in metabolic and immune responses in steers under heat stress.

Jun Sik Eom, Da Som Park, Sang Jin Lee, Bon-Hee Gu, Shin Ja Lee, Sang-Suk Lee, Seon-Ho Kim, Byeong-Woo Kim, Sung Sill Lee, Myunghoo Kim.

  Heat stress (HS) damages livestock by adversely affecting physiological and immunological functions. However, fundamental understanding of the metabolic and immunological mechanisms in animals under HS remains elusive, particularly in steers. To understand the changes on metabolic and immune responses in steers under HS condition, we performed RNA-sequencing and proton nuclear magnetic resonance spectroscopy-based metabolomics on HS-free (THI value: 64.92 ± 0.56) and HS-exposed (THI value: 79.13 ± 0.56) Jersey steer (n = 8, body weight: 559.67 ± 32.72 kg). This study clarifies the metabolic changes in 3 biofluids (rumen fluid, serum, and urine) and the immune responses observed in the peripheral blood mononuclear cells of HS-exposed steers. This integrated approach allowed the discovery of HS-sensitive metabolic and immunological pathways. The metabolomic analysis indicated that HS-exposed steers showed potential HS biomarkers such as isocitrate, formate, creatine, and riboflavin (P < 0.05). Among them, there were several integrative metabolic pathways between rumen fluid and serum. Furthermore, HS altered mRNA expression and immune-related signaling pathways. A meta-analysis revealed that HS decreased riboflavin metabolism and the expression of glyoxylate and dicarboxylate metabolism-related genes. Moreover, metabolic pathways, such as the hypoxia-inducible factor-1 signaling pathway, were downregulated in immune cells by HS (P < 0.05). These findings, along with the datasets of pathways and phenotypic differences as potential biomarkers in steers, can support more in-depth research to elucidate the inter-related metabolic and immunological pathways. This would help suggest new strategies to ameliorate the effects of HS, including disease susceptibility and metabolic disorders, in Jersey steers.

Keywords:  Heat stress; Immunity; Jersey steer; Metabolism; Metabolome; Transcriptome

DOI:  https://doi.org/10.1016/j.aninu.2022.06.012
Life Sci. 2022 Oct 04. pii: S0024-3205(22)00731-7. [Epub ahead of print] 121031

Choline kinase: An underappreciated rheumatoid arthritis therapeutic target.

Ann Miriam Jose, Mahaboobkhan Rasool.

  Choline kinase (ChoK) has been well documented as a major enzyme involved in the anomalous cellular lipid metabolic profile of chronic inflammatory disorders. However, new research has now been unveiled that helps us to better understand how changes in lipid metabolism influence the transformational phenotype, drug resistance, and antiapoptotic characteristics of invasive cells, leading to rheumatoid arthritis (RA) disease progression. It is still unknown how ChoK modulates the lipid metabolic aberrations that may promote altered cell phenotype and functionality in RA. Herein, we review the current understanding of ChoK's role in altered metabolism in diverse cell types involved in RA progression, and for the first time, we take a step forward to complete the puzzle and summarise striking facts that link choline metabolism to its transformed phenotype, in order to postulate ChoK as a robust therapeutic target in RA. This review forms a foundation on which ChoK can be tackled as a potential biomarker, opening doors for RA diagnosis and prognosis. It frameworks several ChoK inhibitors that rewire the lipid metabolic profile in the inflammatory disease landscape and envisages its being translated to clinics.

Keywords:  Choline kinase; Inflammatory diseases; Lymphocytes; Rheumatoid arthritis; Synovial lining cells

DOI:  https://doi.org/10.1016/j.lfs.2022.121031
Food Funct. 2022 Oct 05.

Succinate communicates pro-inflammatory signals to the host and regulates bile acid enterohepatic metabolism in a pig model.

Xuan Li, Yuting Ren, Guowen Huang, Ruofan Zhang, Yanan Zhang, Weiyun Zhu, Kaifan Yu.

Succinate is produced by both the host and microbiota with pleiotropic functions in the modulation of intestinal inflammation and metabolic homeostasis, but the mechanisms remain elusive. This study aimed to determine whether dietary succinate influences the intestinal inflammatory response and to analyze the possible mechanisms by which succinate regulates enterohepatic metabolism. Sixteen growing barrows were randomly assigned to two groups, fed with a basal diet that consisted of a typical commercial diet or fed with a basal diet supplemented with 1% sodium succinate. Our data showed that dietary succinate activated the expression of succinate receptor 1 (SUCNR1) and increased the concentrations of pro-inflammatory cytokines in the intestine. Dietary succinate inhibited the expression levels of the ileal Farnesol X receptor (FXR) and its target genes, promoted hepatic bile acid secretion, and altered the bile acid metabolic profile. Then, we demonstrated that the pro-inflammatory cytokines triggered by succinate disrupted the ability of bile acids to activate FXR and fibroblast growth factor 19. Furthermore, dietary succinate reduced the abundance of bile-salt hydrolase enriched bacteria in the ileum. Taken together, dietary succinate activated the pro-inflammatory response via SUCNR1 in the intestine, and the pro-inflammatory cytokines induced by succinate blocked the activation of FXR and its target genes and disturbed bile acid enterohepatic circulation.

DOI: https://doi.org/10.1039/d2fo01958b
Front Physiol. 2022 ;13 997358

Mitochondrial fatty acid β-oxidation is important for normal osteoclast formation in growing female mice.

Priyanka Kushwaha, Nathalie S Alekos, Soohyun P Kim, Zhu Li, Michael J Wolfgang, Ryan C Riddle.

  Skeletal remodeling is an energy demanding process that is linked to nutrient availability and the levels of metabolic hormones. While recent studies have examined the metabolic requirements of bone formation by osteoblasts, much less is known about the energetic requirements of bone resorption by osteoclasts. The abundance of mitochondria in mature osteoclasts suggests that the production of an acidified micro-environment conducive to the ionization of hydroxyapatite, secretion of matrix-degrading enzymes, and motility during resorption requires significant energetic capacity. To investigate the contribution of mitochondrial long chain fatty acid β-oxidation to osteoclast development, we disrupted the expression of carnitine palmitoyltransferase-2 (Cpt2) in myeloid-lineage cells. Fatty acid oxidation increases dramatically in bone marrow cultures stimulated with RANKL and M-CSF and microCT analysis revealed that the genetic inhibition of long chain fatty acid oxidation in osteoclasts significantly increases trabecular bone volume in female mice secondary to reduced osteoclast numbers. In line with these data, osteoclast precursors isolated from Cpt2 mutants exhibit reduced capacity to form large-multinucleated osteoclasts, which was not rescued by exogenous glucose or pyruvate, and signs of an energetic stress response. Together, our data demonstrate that mitochondrial long chain fatty acid oxidation by the osteoclast is required for normal bone resorption as its inhibition produces an intrinsic defect in osteoclast formation.

Keywords:  CPT2; bone; glucose; lipid metabolism; osteoclast

DOI:  https://doi.org/10.3389/fphys.2022.997358
Cancer Discov. 2022 Oct 05. 12(10): 2237-2239

GOT2: An Unexpected Mediator of Immunosuppression in Pancreatic Cancer.

Zeribe C Nwosu, Marina Pasca di Magliano.

In this issue, Abrego and colleagues describe an unexpected role for the mitochondrial enzyme glutamic-oxaloacetic transaminase (GOT2) in pancreatic cancer, whereby it acts as a nuclear fatty acid transporter binding to and activating the PPARδ nuclear receptor. In turn, the GOT2-PPARδaxis drives immunosuppression by suppressing T cell-mediated antitumor immunity. See related article by Abrego et al., p. 2414 (3).

DOI: https://doi.org/10.1158/2159-8290.CD-22-0845
Gut Microbes. 2022 Jan-Dec;14(1):14(1): 2127456

Bifidobacterium spp. and their metabolite lactate protect against acute pancreatitis via inhibition of pancreatic and systemic inflammatory responses.

Han Li, Jinyan Xie, Xiuliu Guo, Guilian Yang, Bin Cai, Jingtianyi Liu, Mengjia Yue, Yixin Tang, Gan Wang, Shuxian Chen, Jialin Guo, Xuchen Qi, Donghai Wang, Huijun Zheng, Wei Liu, Hong Yu, Chunfeng Wang, Shu Jeffrey Zhu, Feng Guo.

  Severe acute pancreatitis (SAP) is a critical illness characterized by a severe systemic inflammatory response resulting in persistent multiple organ failure and sepsis. The intestinal microbiome is increasingly appreciated to play a crucial role in modulation of AP disease outcome, but limited information is available about the identity and mechanism of action for specific commensal bacteria involved in AP-associated inflammation. Here we show that Bifidobacteria, particularly B. animalis, can protect against AP by regulating pancreatic and systemic inflammation in germ-free (GF) and oral antibiotic-treated (Abx) mouse models. Colonization by B. animalis and administration of its metabolite lactate protected Abx and GF mice from AP by reducing serum amylase concentration, ameliorating pancreatic lesions and improving survival rate after retrograde injection of sodium taurocholate. B. animalis relieved macrophage-associated local and systemic inflammation of AP in a TLR4/MyD88- and NLRP3/Caspase1-dependent manner through its metabolite lactate. Supporting our findings from the mouse study, clinical AP patients exhibited a decreased fecal abundance of Bifidobacteria that was inversely correlated with the severity of systemic inflammatory responses. These results may shed light on the heterogeneity of clinical outcomes and drive the development of more efficacious therapeutic interventions for AP, and potentially for other inflammatory disorders.

Keywords:  Bifidobacterium; immunomodulation; lactate; macrophages; microbial metabolite; pancreatic and systemic inflammation

DOI:  https://doi.org/10.1080/19490976.2022.2127456
Front Microbiol. 2022 ;13 976406

Potential of gut-derived short-chain fatty acids to control enteric pathogens.

Ziyang Zhan, Hao Tang, Ying Zhang, Xinxiang Huang, Min Xu.

  Short-chain fatty acids (SCFAs) are a very important group of metabolites located in the gut that play a crucial role in the regulation of gut function and pathogen resistance. Since many enteric pathogens respond differently to various SCFAs, substantial efforts have been made to understand the regulatory effects of SCFA types on enteric pathogens. The application of protein post-translational modifications (PTMs) in bacterial research provides a new perspective for studying the regulation of enteric pathogens by different SCFAs. Existing evidence suggests that the SCFAs acetate, propionate, and butyrate influence bacterial processes by extensively promoting the acylation of key bacterial proteins. SCFAs can also prevent the invasion of pathogenic bacteria by regulating the barrier function and immune status of the host gut. In this review, we describe the mechanisms by which different SCFAs modulate the pathogenicity of enteric pathogens from multiple perspectives. We also explore some recent findings on how enteric pathogens counteract SCFA inhibition. Lastly, we discuss the prospects and limitations of applying SCFAs to control enteric pathogens.

Keywords:  acetate; butyrate; enteric pathogens; post-translational modifications; propionate; short-chain fatty acids

DOI:  https://doi.org/10.3389/fmicb.2022.976406
World J Virol. 2022 Sep 25. 11(5): 237-251

Association of COVID-19 with hepatic metabolic dysfunction.

Ramesh Kumar, Vijay Kumar, Rahul Arya, Utpal Anand, Rajeev Nayan Priyadarshi.

  The coronavirus disease 2019 (COVID-19) pandemic continues to be a global problem with over 438 million cases reported so far. Although it mostly affects the respiratory system, the involvement of extrapulmonary organs, including the liver, is not uncommon. Since the beginning of the pandemic, metabolic com-orbidities, such as obesity, diabetes, hypertension, and dyslipidemia, have been identified as poor prognostic indicators. Subsequent metabolic and lipidomic studies have identified several metabolic dysfunctions in patients with COVID-19. The metabolic alterations appear to be linked to the course of the disease and inflammatory reaction in the body. The liver is an important organ with high metabolic activity, and a significant proportion of COVID-19 patients have metabolic comorbidities; thus, this factor could play a key role in orchestrating systemic metabolic changes during infection. Evidence suggests that metabolic dysregulation in COVID-19 has both short- and long-term metabolic implications. Furthermore, COVID-19 has adverse associations with metabolic-associated fatty liver disease. Due to the ensuing effects on the renin-angiotensin-aldosterone system and ammonia metabolism, COVID-19 can have significant implications in patients with advanced chronic liver disease. A thorough understanding of COVID-19-associated metabolic dysfunction could lead to the identification of important plasma biomarkers and novel treatment targets. In this review, we discuss the current understanding of metabolic dysfunction in COVID-19, focusing on the liver and exploring the underlying mechanistic pathogenesis and clinical implications.

Keywords:  COVID-19; Coronavirus; Hepatic dysfunction; Metabolic inflammation; Metabolic syndrome; Metabolism

DOI:  https://doi.org/10.5501/wjv.v11.i5.237