bims-imicid 2023-11-05 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023–11–05
thirty papers selected by
Dylan Ryan, University of Cambridge

The Interferon-inducible NAMPT acts as a protein phosphoribosylase to restrict viral infection.
Regulatory T cells shield muscle mitochondria from interferon-γ-mediated damage to promote the beneficial effects of exercise.
Bacterial indole-3-lactic acid affects epithelium-macrophage crosstalk to regulate intestinal homeostasis.
Impaired gut microbiota-mediated short-chain fatty acid production precedes morbidity and mortality in people with HIV.
Ketohexokinase-dependent metabolism of cerebral endogenous fructose in microglia drives diabetes-associated cognitive dysfunction.
The hypoxia-regulated ectonucleotidase CD73 is a host determinant of HIV latency.
PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy.
Unveiling the growing significance of metabolism in modulating immune cell function: exploring mechanisms and implications; a review.
HK2 in microglia and macrophages contribute to the development of neuropathic pain.
1α,25(OH)2D3 ameliorates insulin resistance by alleviating γδ T cell inflammation via enhancing fructose-1,6-bisphosphatase 1 expression.
Dietary leucine supplementation restores T-cell mitochondrial respiration and regulates T-lineage differentiation in denervation-induced sarcopenic mice.
Itaconate inhibits SYK through alkylation and suppresses inflammation against hvKP induced intestinal dysbiosis.
A novel causative role of imbalanced kynurenine pathway in ulcerative colitis: Upregulation of KMO and KYNU promotes intestinal inflammation.
De novo fatty-acid synthesis protects invariant NKT cells from cell death, thereby promoting their homeostasis and pathogenic roles in airway hyperresponsiveness.
Baseline metabolites could predict responders with hepatitis B virus-related liver fibrosis for entecavir or combined with FuzhengHuayu tablet.
Metabolic regulation of microglial phagocytosis: Implications for Alzheimer's disease therapeutics.
Diacylglycerol kinase zeta deficiency attenuates papain-induced type 2 airway inflammation.
Arachidonic acid activates NLRP3 inflammasome in MDSCs via FATP2 to promote post-transplant tumour recurrence in steatotic liver grafts.
Dysregulated CD200-CD200R signaling in early diabetes modulates microglia-mediated retinopathy.
Potential biomarker for diagnosis and therapy of sepsis: Lactylation.
Lachnospiraceae-derived butyrate mediates protection of high fermentable fiber against placental inflammation in gestational diabetes mellitus.
Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors: mechanisms and strategies.
The intersection between bacterial metabolism and innate immunity.
The tryptophan catabolite or kynurenine pathway in autism spectrum disorder; a systematic review and meta-analysis.
The purinergic receptor P2X7 and the NLRP3 inflammasome are druggable host factors required for SARS-CoV-2 infection.
Limitation of amino acid availability by bacterial populations during enhanced colitis in IBD mouse model.
Elevated phospholipids and acylcarnitines C4 and C5 in cerebrospinal fluid distinguish viral CNS infections from autoimmune neuroinflammation.
An obesogenic diet increases atherosclerosis through promoting microbiota dysbiosis-induced gut lymphocyte trafficking into the periphery.
Microbiota-derived tryptophan metabolism: Impacts on health, aging, and disease.
GLUT3 regulates alternative macrophage signaling through a glucose transport-independent role.

bioRxiv. 2023 Oct 16. pii: 2023.10.12.562112. [Epub ahead of print]

The Interferon-inducible NAMPT acts as a protein phosphoribosylase to restrict viral infection.

Shu Zhang, Na Xie, Yongzhen Liu, Chao Qin, Ali Can Savas, Ting-Yu Wang, Shutong Li, Youliang Rao, Alexandra Shambayate, Tsui-Fen Chou, Charles Brenner, Canhua Huang, Pinghui Feng.

As obligate intracellular pathogens, viruses often activate host metabolic enzymes to supply intermediates that support progeny production. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the salvage NAD + synthesis, is an interferon-inducible protein that inhibits the replication of several RNA and DNA viruses with unknown mechanism. Here we report that NAMPT restricts herpes simplex virus 1 (HSV-1) replication via phosphoribosyl-hydrolase activity toward key viral structural proteins, independent of NAD + synthesis. Deep mining of enriched phosphopeptides of HSV-1-infected cells identified phosphoribosylated viral structural proteins, particularly glycoproteins and tegument proteins. Indeed, NAMPT de-phosphoribosylates viral proteins in vitro and in cells. Chimeric and recombinant HSV-1 carrying phosphoribosylation-resistant mutations show that phosphoribosylation promotes the incorporation of structural proteins into HSV-1 virions and subsequent virus entry. Moreover, loss of NAMPT renders mice highly susceptible to HSV-1 infection. The work describes a hidden enzyme activity of a metabolic enzyme in viral infection and host defense, offering a system to interrogate roles of phosphoribosylation in metazoans.

DOI: https://doi.org/10.1101/2023.10.12.562112
Sci Immunol. 2023 Nov 03. 8(89): eadi5377

Regulatory T cells shield muscle mitochondria from interferon-γ-mediated damage to promote the beneficial effects of exercise.

P Kent Langston, Yizhi Sun, Birgitta A Ryback, Amber L Mueller, Bruce M Spiegelman, Christophe Benoist, Diane Mathis.

Exercise enhances physical performance and reduces the risk of many disorders such as cardiovascular disease, type 2 diabetes, dementia, and cancer. Exercise characteristically incites an inflammatory response, notably in skeletal muscles. Although some effector mechanisms have been identified, regulatory elements activated in response to exercise remain obscure. Here, we have addressed the roles of Foxp3+CD4+ regulatory T cells (Tregs) in the healthful activities of exercise via immunologic, transcriptomic, histologic, metabolic, and biochemical analyses of acute and chronic exercise models in mice. Exercise rapidly induced expansion of the muscle Treg compartment, thereby guarding against overexuberant production of interferon-γ and consequent metabolic disruptions, particularly mitochondrial aberrancies. The performance-enhancing effects of exercise training were dampened in the absence of Tregs. Thus, exercise is a natural Treg booster with therapeutic potential in disease and aging contexts.

DOI: https://doi.org/10.1126/sciimmunol.adi5377
Proc Natl Acad Sci U S A. 2023 Nov 07. 120(45): e2309032120

Bacterial indole-3-lactic acid affects epithelium-macrophage crosstalk to regulate intestinal homeostasis.

Kaiyuan Yu, Qianqian Li, Xuan Sun, Xianping Peng, Qiang Tang, Hongyu Chu, Lu Zhou, Bangmao Wang, Zhemin Zhou, Xueqin Deng, Jianming Yang, Junqiang Lv, Ran Liu, Chunhui Miao, Wei Zhao, Zhi Yao, Quan Wang.

  Tryptophan and its derivatives perform a variety of biological functions; however, the role and specific mechanism of many tryptophan derivatives in intestinal inflammation remain largely unclear. Here, we identified that an Escherichia coli strain (Ec-TMU) isolated from the feces of tinidazole-treated individuals, and indole-3-lactic acid (ILA) in its supernatant, decreased the susceptibility of mice to dextran sulfate sodium-induced colitis. Ec-TMU and ILA contribute to the relief of colitis by inhibiting the production of epithelial CCL2/7, thereby reducing the accumulation of inflammatory macrophages in vitro and in vivo. Mechanistically, ILA downregulates glycolysis, NF-κB, and HIF signaling pathways via the aryl hydrocarbon receptor, resulting in decreased CCL2/7 production in epithelial cells. Clinical evidence suggests that the fecal ILA level is negatively correlated with the progression indicator of inflammatory bowel diseases. These results demonstrate that ILA has the potential to regulate intestinal homeostasis by modulating epithelium-macrophage interactions.

Keywords:  CCL2/7; CCR2; ILA; intestinal homeostasis; macrophage

DOI:  https://doi.org/10.1073/pnas.2309032120
Cell Rep. 2023 Oct 30. pii: S2211-1247(23)01348-7. [Epub ahead of print] 113336

Impaired gut microbiota-mediated short-chain fatty acid production precedes morbidity and mortality in people with HIV.

Irini Sereti, Myrthe L Verburgh, Jacob Gifford, Alice Lo, Anders Boyd, Eveline Verheij, Aswin Verhoeven, Ferdinand W N M Wit, Maarten F Schim van der Loeff, Martin Giera, Neeltje A Kootstra, Peter Reiss, Ivan Vujkovic-Cvijin.

  Antiretroviral therapy (ART) has dramatically lengthened lifespan among people with HIV (PWH), but this population experiences heightened rates of inflammation-related comorbidities. HIV-associated inflammation is linked with an altered microbiome; whether such alterations precede inflammation-related comorbidities or occur as their consequence remains unknown. We find that ART-treated PWH exhibit depletion of gut-resident bacteria that produce short-chain fatty acids (SCFAs)-crucial microbial metabolites with anti-inflammatory properties. Prior reports establish that fecal SCFA concentrations are not depleted in PWH. We find that gut-microbiota-mediated SCFA production capacity is better reflected in serum than in feces and that PWH exhibit reduced serum SCFA, which associates with inflammatory markers. Leveraging stool and serum samples collected prior to comorbidity onset, we find that HIV-specific microbiome alterations precede morbidity and mortality in ART-treated PWH. Among these microbiome alterations, reduced microbiome-mediated conversion of lactate to propionate precedes mortality in PWH. Thus, gut microbial fiber/lactate conversion to SCFAs may modulate HIV-associated comorbidity risk.

Keywords:  CP: Microbiology; HIV; microbiome; short-chain fatty acids

DOI:  https://doi.org/10.1016/j.celrep.2023.113336
Exp Mol Med. 2023 Nov 01.

Ketohexokinase-dependent metabolism of cerebral endogenous fructose in microglia drives diabetes-associated cognitive dysfunction.

Yansong Li, Tao Jiang, Mengyu Du, Shuxuan He, Ning Huang, Bo Cheng, Chaoying Yan, Wenxin Tang, Wei Gao, Hongyan Guo, Qiao Li, Qiang Wang.

Dementia, as an advanced diabetes-associated cognitive dysfunction (DACD), has become the second leading cause of death among diabetes patients. Given that little guidance is currently available to address the DACD process, it is imperative to understand the underlying mechanisms and screen out specific therapeutic targets. The excessive endogenous fructose produced under high glucose conditions can lead to metabolic syndrome and peripheral organ damage. Although generated by the brain, the role of endogenous fructose in the exacerbation of cognitive dysfunction is still unclear. Here, we performed a comprehensive study on leptin receptor-deficient T2DM mice and their littermate m/m mice and revealed that 24-week-old db/db mice had cognitive dysfunction and excessive endogenous fructose metabolism in the hippocampus by multiomics analysis and further experimental validation. We found that the rate-limiting enzyme of fructose metabolism, ketohexokinase, is primarily localized in microglia. It is upregulated in the hippocampus of db/db mice, which enhances mitochondrial damage and reactive oxygen species production by promoting nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) expression and mitochondrial translocation. Inhibiting fructose metabolism via ketohexokinase depletion reduces microglial activation, leading to the restoration of mitochondrial homeostasis, recovery of structural synaptic plasticity, improvement of CA1 pyramidal neuron electrophysiology and alleviation of cognitive dysfunction. Our findings demonstrated that enhanced endogenous fructose metabolism in microglia plays a dominant role in diabetes-associated cognitive dysfunction and could become a potential target for DACD.

DOI: https://doi.org/10.1038/s12276-023-01112-y
Cell Rep. 2023 Oct 31. pii: S2211-1247(23)01297-4. [Epub ahead of print]42(11): 113285

The hypoxia-regulated ectonucleotidase CD73 is a host determinant of HIV latency.

Hannah S Sperber, Kyle A Raymond, Mohamed S Bouzidi, Tongcui Ma, Silvana Valdebenito, Eliseo A Eugenin, Nadia R Roan, Steven G Deeks, Sandra Winning, Joachim Fandrey, Roland Schwarzer, Satish K Pillai.

  Deciphering the mechanisms underlying viral persistence is critical to achieving a cure for human immunodeficiency virus (HIV) infection. Here, we implement a systems approach to discover molecular signatures of HIV latently infected CD4+ T cells, identifying the immunosuppressive, adenosine-producing ectonucleotidase CD73 as a key surface marker of latent cells. Hypoxic conditioning, reflecting the lymphoid tissue microenvironment, increases the frequency of CD73+ CD4+ T cells and promotes HIV latency. Transcriptomic profiles of CD73+ CD4+ T cells favor viral quiescence, immune evasion, and cell survival. CD73+ CD4+ T cells are capable of harboring a functional HIV reservoir and reinitiating productive infection ex vivo. CD73 or adenosine receptor blockade facilitates latent HIV reactivation in vitro, mechanistically linking adenosine signaling to viral quiescence. Finally, tissue imaging of lymph nodes from HIV-infected individuals on antiretroviral therapy reveals spatial association between CD73 expression and HIV persistence in vivo. Our findings warrant development of HIV-cure strategies targeting the hypoxia-CD73-adenosine axis.

Keywords:  CD39; CD73; CP: Immunology; CP: Microbiology; HIV cure; IL-8; adenosine; eradication; hypoxia; lymphoid tissues; persistence; reservoir

DOI:  https://doi.org/10.1016/j.celrep.2023.113285
Nat Metab. 2023 Oct 30.

PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy.

Xuefeng Dou, Qiang Fu, Qilai Long, Shuning Liu, Yejun Zou, Da Fu, Qixia Xu, Zhirui Jiang, Xiaohui Ren, Guilong Zhang, Xiaoling Wei, Qingfeng Li, Judith Campisi, Yuzheng Zhao, Yu Sun.

Senescent cells remain metabolically active, but their metabolic landscape and resulting implications remain underexplored. Here, we report upregulation of pyruvate dehydrogenase kinase 4 (PDK4) upon senescence, particularly in some stromal cell lines. Senescent cells display a PDK4-dependent increase in aerobic glycolysis and enhanced lactate production but maintain mitochondrial respiration and redox activity, thus adopting a special form of metabolic reprogramming. Medium from PDK4+ stromal cells promotes the malignancy of recipient cancer cells in vitro, whereas inhibition of PDK4 causes tumor regression in vivo. We find that lactate promotes reactive oxygen species production via NOX1 to drive the senescence-associated secretory phenotype, whereas PDK4 suppression reduces DNA damage severity and restrains the senescence-associated secretory phenotype. In preclinical trials, PDK4 inhibition alleviates physical dysfunction and prevents age-associated frailty. Together, our study confirms the hypercatabolic nature of senescent cells and reveals a metabolic link between cellular senescence, lactate production, and possibly, age-related pathologies, including but not limited to cancer.

DOI: https://doi.org/10.1038/s42255-023-00912-w
Ann Med Surg (Lond). 2023 Nov;85(11): 5511-5522

Unveiling the growing significance of metabolism in modulating immune cell function: exploring mechanisms and implications; a review.

Nicholas Aderinto, Muili Opeyemi Abdulbasit, Adrien Djabo Eric Tangmi, John Olalekan Okesanya, Jolayemi Mustapha Mubarak.

  Immunometabolism has emerged as a rapidly growing field of research, holding significant promise for personalised medicine and precision immunotherapy. This review explores the intricate relationship between immune function and metabolic processes, emphasising their profound impact on various immune-related disorders. Understanding how metabolic dysregulation contributes to the pathogenesis of these disorders remains a critical research gap. Therefore, this review aims to bridge that gap by examining the key metabolic pathways involved and their specific implications in immune cell function. Key metabolic pathways, including glycolysis, mitochondrial metabolism, fatty acid metabolism, and amino acid metabolism, are discussed in the context of immune cell function. Dysregulation of these pathways can disrupt immune cell activation, differentiation, and overall function, contributing to disease pathogenesis. Understanding these metabolic alterations' molecular mechanisms is essential for developing targeted therapeutic interventions. The review also emphasises the importance of personalised medicine in immune-related disorders. The unique metabolic profiles of individuals can influence treatment outcomes, highlighting the need for tailored approaches. Integrating metabolic profiling into clinical practice can enhance treatment efficacy and improve patient outcomes. Investigating the clinical significance of immunometabolism in diverse disease contexts will facilitate the translation of research findings into clinical practice. Moreover, refining treatment strategies based on individual metabolic profiles will contribute to advancing precision immunotherapy.

Keywords:  immunometabolism; metabolic dysregulation; metabolism

DOI:  https://doi.org/10.1097/MS9.0000000000001308
Glia. 2023 Nov 01.

HK2 in microglia and macrophages contribute to the development of neuropathic pain.

Siyuan Wang, Chao Jiang, Kelei Cao, Run Li, Zhihua Gao, Yue Wang.

  Neuropathic pain is a complex pain condition accompanied by prominent neuroinflammation involving activation of both central and peripheral immune cells. Metabolic switch to glycolysis is an important feature of activated immune cells. Hexokinase 2 (HK2), a key glycolytic enzyme enriched in microglia, has recently been shown important in regulating microglial functions. Whether and how HK2 is involved in neuropathic pain-related neuroinflammation remains unknown. Using a HK2-tdTomato reporter line, we found that HK2 was prominently elevated in spinal microglia. Pharmacological inhibition of HK2 effectively alleviated nerve injury-induced acute mechanical pain. However, selective ablation of Hk2 in microglia reduced microgliosis in the spinal dorsal horn (SDH) with little analgesic effects. Further analyses showed that nerve injury also significantly induced HK2 expression in dorsal root ganglion (DRG) macrophages. Deletion of Hk2 in myeloid cells, including both DRG macrophages and spinal microglia, led to the alleviation of mechanical pain during the first week after injury, along with attenuated microgliosis in the ipsilateral SDH, macrophage proliferation in DRGs, and suppressed inflammatory responses in DRGs. These data suggest that HK2 plays an important role in regulating neuropathic pain-related immune cell responses at acute phase and that HK2 contributes to neuropathic pain onset primarily through peripheral monocytes and DRG macrophages rather than spinal microglia.

Keywords:  hexokinase 2; macrophages; microglia; neuropathic pain

DOI:  https://doi.org/10.1002/glia.24482
Theranostics. 2023 ;13(15): 5290-5304

1α,25(OH)2D3 ameliorates insulin resistance by alleviating γδ T cell inflammation via enhancing fructose-1,6-bisphosphatase 1 expression.

Peng Li, Ke Li, Wenhui Yuan, Yuqi Xu, Ping Li, Ruan Wu, Jingru Han, Zhinan Yin, Ligong Lu, Yunfei Gao.

  Background: Chronic inflammation caused by immune cells is the central link between obesity and insulin resistance. Targeting the inflammatory process is a highly promising method for reversing systemic insulin resistance. Methods: Blood samples were prospectively collected from 68 patients with type 2 diabetes. C57BL/6J mice were fed either a high-fat diet (HFD) or normal chow (NC). We performed phenotypical and functional analyses of immune cells using flow cytometry. Vitamin D receptor (VDR) knockout γδ T cells were constructed using Cas9-gRNA targeted approaches to identify 1α,25(OH)2D3/VDR signaling pathway-mediated transcriptional regulation of fructose-1,6-bisphosphatase (FBP1) in γδ T cells. Results: Serum vitamin D deficiency aggravates inflammation in circulating γδ T cells in type 2 diabetes patients. We defined a critical role for 1α,25(OH)2D3 in regulating glycolysis metabolism, protecting against inflammation, and alleviating insulin resistance. Mechanistically, 1α,25(OH)2D3-VDR promoted FBP1 expression to suppress glycolysis in γδ T cells, thereby inhibiting Akt/p38 MAPK phosphorylation and reducing inflammatory cytokine production. Notably, therapeutic administration of 1α,25(OH)2D3 restrained inflammation in γδ T cells and ameliorated systemic insulin resistance in obese mice. Conclusions: Collectively, these findings show that 1α,25(OH)2D3 plays an important role in maintaining γδ T cell homeostasis by orchestrating metabolic programs, and is a highly promising target for preventing obesity, inflammation, and insulin resistance.

Keywords:  25(OH)2D3; 6-bisphosphatase 1; fructose-1; glycolysis; inflammation; insulin resistance; vitamin 1α; γδ T cell

DOI:  https://doi.org/10.7150/thno.84645
J Nutr Biochem. 2023 Oct 26. pii: S0955-2863(23)00241-3. [Epub ahead of print] 109508

Dietary leucine supplementation restores T-cell mitochondrial respiration and regulates T-lineage differentiation in denervation-induced sarcopenic mice.

Shuang Liu, Marii Mochizuki, Yasuyuki Suzuki, Erika Takemasa, Akiko Yano, Matome Imai, Masaki Mogi.

  With the aim of offsetting immune dysfunction preceded by sarcopenia, the feasibility and efficiency of nutritional leucine supplementation were evaluated using a murine denervation-induced sarcopenia model. Sciatic nerve axotomy caused significant loss of skeletal muscle of the hind limbs and accelerated mitochondrial stress along with suppressed ATP production in spleen-derived T cells. Dietary leucine intake not only ameliorated muscle mass anabolism in a sarcopenic state, but also restored mitochondrial respiratory function, as indicated by elevated levels of basal respiration, maximal respiration, spare respiratory capacity, and ATP production, in T cells, which in turn led to downregulated expression of mTOR and downstream signals, as indicated by the findings of comprehensive transcriptome analysis. Consequentially, this finally resulted in amelioration of the sarcopenia-induced relative Th1/Th17-dominant proinflammatory microenvironment. These results highlight the importance of leucine-promoted metabolic cues in directing T cell fate in a sarcopenic microenvironment. The present study provides insights that particularly help rationalize the design and optimization of leucine supplementation for chronic sarcopenic patients with autoimmune disease.

Keywords:  Leucine; RNA-seq; Sarcopenia; T cell; mitochondria

DOI:  https://doi.org/10.1016/j.jnutbio.2023.109508
Cell Mol Life Sci. 2023 Oct 28. 80(11): 337

Itaconate inhibits SYK through alkylation and suppresses inflammation against hvKP induced intestinal dysbiosis.

Yangguang Li, Yu Xu, Weizhen Li, Jiayang Li, Wenqi Wu, Jiaqi Kang, Haiyang Jiang, Peizhao Liu, Juanhan Liu, Wenbin Gong, Xuanheng Li, Chujun Ni, Mingda Liu, Lijuan Chen, Sicheng Li, Xiuwen Wu, Yun Zhao, Jianan Ren.

  Hypervirulent Klebsiella pneumoniae (hvKP) is a highly lethal opportunistic pathogen that elicits more severe inflammatory responses compared to classical Klebsiella pneumoniae (cKP). In this study, we investigated the interaction between hvKP infection and the anti-inflammatory immune response gene 1 (IRG1)-itaconate axis. Firstly, we demonstrated the activation of the IRG1-itaconate axis induced by hvKP, with a dependency on SYK signaling rather than STING. Importantly, we discovered that exogenous supplementation of itaconate effectively inhibited excessive inflammation by directly inhibiting SYK kinase at the 593 site through alkylation. Furthermore, our study revealed that itaconate effectively suppressed the classical activation phenotype (M1 phenotype) and macrophage cell death induced by hvKP. In vivo experiments demonstrated that itaconate administration mitigated hvKP-induced disturbances in intestinal immunopathology and homeostasis, including the restoration of intestinal barrier integrity and alleviation of dysbiosis in the gut microbiota, ultimately preventing fatal injury. Overall, our study expands the current understanding of the IRG1-itaconate axis in hvKP infection, providing a promising foundation for the development of innovative therapeutic strategies utilizing itaconate for the treatment of hvKP infections.

Keywords:  4-Octyl Itaconate; Dimethyl itaconate; Immunometabolism; Infection; Macrophage

DOI:  https://doi.org/10.1007/s00018-023-04971-w
Biochim Biophys Acta Mol Basis Dis. 2023 Oct 31. pii: S0925-4439(23)00295-8. [Epub ahead of print] 166929

A novel causative role of imbalanced kynurenine pathway in ulcerative colitis: Upregulation of KMO and KYNU promotes intestinal inflammation.

Yingying Shi, Shangjian Luo, Jinyang Zhai, Yingwei Chen.

  The kynurenine pathway (KP) is the principal metabolic route for the essential amino acid tryptophan (TRP). Recent advances have highlighted a pivotal role for several KP metabolites in inflammatory diseases, including ulcerative colitis (UC). However, the alterations of KP enzymes and their functional impact in UC remain poorly defined. Here, we focused on kynurenine 3-monooxygenase (KMO) and kynureninase (KYNU), which serve as critical branching enzymes in the KP. We observed that dextran sodium sulfate (DSS)-induced colitis mice exhibited disturbed TRP metabolism along with KMO and KYNU upregulated. In patients with active UC, both the expression of KMO and KYNU were positively correlated with inflammatory factors TNF-α and IL-1β. Pharmacological blockade of KMO or genetic silencing of KYNU suppressed IL-1β-triggered proinflammatory cytokines expression in intestinal epithelial cells. Furthermore, blockage of KMO by selective inhibitor Ro 61-8048 alleviated the symptom of DSS-induced colitis in mice, accompanied by an expanded NAD+ pool and redox balance restoration. The protective role of Ro 61-8048 may be partly due to its effect on KP regulation, particularly in enhancing kynurenic acid production. In summary, our study provides new evidence for the proinflammatory property of KMO and KYNU in intestinal inflammation, hinting at a promising therapeutic approach in UC through targeting these enzymes.

Keywords:  Kynurenic acid; Kynureninase; Kynurenine 3-monooxygenase; Kynurenine pathway; NAD(+); Ulcerative colitis

DOI:  https://doi.org/10.1016/j.bbadis.2023.166929
Elife. 2023 Nov 02. pii: RP87536. [Epub ahead of print]12

De novo fatty-acid synthesis protects invariant NKT cells from cell death, thereby promoting their homeostasis and pathogenic roles in airway hyperresponsiveness.

Jaemoon Koh, Yeon Duk Woo, Hyun Jung Yoo, Jun-Pyo Choi, Sae Hoon Kim, Yoon-Seok Chang, Kyeong Cheon Jung, Ji Hyung Kim, Yoon Kyung Jeon, Hye Young Kim, Doo Hyun Chung.

  Invariant natural-killer T (iNKT) cells play pathogenic roles in allergic asthma in murine models and possibly also humans. While many studies show that the development and functions of innate and adaptive immune cells depend on their metabolic state, the evidence for this in iNKT cells is very limited. It is also not clear whether such metabolic regulation of iNKT cells could participate in their pathogenic activities in asthma. Here, we showed that acetyl-coA-carboxylase 1 (ACC1)-mediated de novo fatty-acid synthesis is required for the survival of iNKT cells and their deleterious functions in allergic asthma. ACC1, which is a key fatty-acid synthesis enzyme, was highly expressed by lung iNKT cells from WT mice that were developing asthma. Cd4-Cre::Acc1fl/fl mice failed to develop OVA-induced and HDM-induced asthma. Moreover, iNKT cell-deficient mice that were reconstituted with ACC1-deficient iNKT cells failed to develop asthma, unlike when WT iNKT cells were transferred. ACC1 deficiency in iNKT cells associated with reduced expression of fatty acid-binding proteins (FABPs) and peroxisome proliferator-activated receptor (PPAR)γ, but increased glycolytic capacity that promoted iNKT-cell death. Furthermore, circulating iNKT cells from allergic-asthma patients expressed higher ACC1 and PPARG levels than the corresponding cells from non-allergic-asthma patients and healthy individuals. Thus, de novo fatty-acid synthesis prevents iNKT-cell death via an ACC1-FABP-PPARγ axis, which contributes to their homeostasis and their pathogenic roles in allergic asthma.

Keywords:  acetyl-CoA carboxylase 1 (ACC1); allergic asthma; de novo fatty acid synthesis; human; immunology; inflammation; invariant natural killer T cells; mouse

DOI:  https://doi.org/10.7554/eLife.87536
World J Hepatol. 2023 Sep 27. 15(9): 1043-1059

Baseline metabolites could predict responders with hepatitis B virus-related liver fibrosis for entecavir or combined with FuzhengHuayu tablet.

Yun-Kai Dai, Hai-Na Fan, Kai Huang, Xin Sun, Zhi-Min Zhao, Cheng-Hai Liu.

   BACKGROUND: After receiving entecavir or combined with FuzhengHuayu tablet (FZHY) treatment, some sufferers with hepatitis B virus (HBV)-related liver fibrosis could achieve a histological improvement while the others may fail to improve even worsen. Serum metabolomics at baseline in these patients who were effective in treatment remain unclear.
AIM: To explore baseline serum metabolites characteristics in responders.
METHODS: A total of 132 patients with HBV-related liver fibrosis and 18 volunteers as healthy controls were recruited. First, all subjects were divided into training set and validation set. Second, the included patients were subdivided into entecavir responders (E-R), entecavir no-responders (E-N), FZHY + entecavir responders (F-R), and FZHY + entecavir no-responders (F-N) following the pathological histological changes after 48 wk' treatments. Then, Serum samples of all subjects before treatment were tested by high performance liquid chromatography-tandem mass spectrometry (LC-MS) high-performance LC-MS. Data processing was conducted using multivariate principal component analysis and orthogonal partial least squares discriminant analysis. Diagnostic tests of selected differential metabolites were used for Boruta analyses and logistic regression.
RESULTS: As for the intersection about differential metabolic pathways between the groups E-R vs E-N and F-R vs F-N, results showed that 4 pathways including linoleic acid metabolism, aminoacyl-tRNA biosynthesis, cyanoamino acid metabolism, alanine, aspartate and glutamate metabolism were screened out. As for the differential metabolites, these 7 intersected metabolites including hydroxypropionic acid, tyrosine, citric acid, taurochenodeoxycholic acid, benzoic acid, 2-Furoic acid, and propionic acid were selected.
CONCLUSION: Our findings showed that 4 metabolic pathways and 7 differential metabolites had potential usefulness in clinical prediction of the response of entecavir or combined with FZHY on HBV fibrotic liver.

Keywords:  Differential metabolites; Entecavir; FuzhengHuayu tablet; Hepatitis B virus-related liver fibrosis; Serum metabolomics; Therapeutic responders

DOI:  https://doi.org/10.4254/wjh.v15.i9.1043
Transl Neurodegener. 2023 Oct 31. 12(1): 48

Metabolic regulation of microglial phagocytosis: Implications for Alzheimer's disease therapeutics.

Izabela Lepiarz-Raba, Ismail Gbadamosi, Roberta Florea, Rosa Chiara Paolicelli, Ali Jawaid.

  Microglia, the resident immune cells of the brain, are increasingly implicated in the regulation of brain health and disease. Microglia perform multiple functions in the central nervous system, including surveillance, phagocytosis and release of a variety of soluble factors. Importantly, a majority of their functions are closely related to changes in their metabolism. This natural inter-dependency between core microglial properties and metabolism offers a unique opportunity to modulate microglial activities via nutritional or metabolic interventions. In this review, we examine the existing scientific literature to synthesize the hypothesis that microglial phagocytosis of amyloid beta (Aβ) aggregates in Alzheimer's disease (AD) can be selectively enhanced via metabolic interventions. We first review the basics of microglial metabolism and the effects of common metabolites, such as glucose, lipids, ketone bodies, glutamine, pyruvate and lactate, on microglial inflammatory and phagocytic properties. Next, we examine the evidence for dysregulation of microglial metabolism in AD. This is followed by a review of in vivo studies on metabolic manipulation of microglial functions to ascertain their therapeutic potential in AD. Finally, we discuss the effects of metabolic factors on microglial phagocytosis of healthy synapses, a pathological process that also contributes to the progression of AD. We conclude by enlisting the current challenges that need to be addressed before strategies to harness microglial phagocytosis to clear pathological protein deposits in AD and other neurodegenerative disorders can be widely adopted.

Keywords:  Alzheimer's disease; Inflammation; Metabolism; Microglia; Neurodegeneration; Phagocytosis

DOI:  https://doi.org/10.1186/s40035-023-00382-w
Cell Immunol. 2023 Oct 30. pii: S0008-8749(23)00119-3. [Epub ahead of print]393-394 104780

Diacylglycerol kinase zeta deficiency attenuates papain-induced type 2 airway inflammation.

Brenal K Singh, Yuichi Yokoyama, Yukinori Tanaka, Dorottya Laczkó, Deepak A Deshpande, Taku Kambayashi.

  Allergic airway diseases are caused by inappropriate immune responses directed against inhaled environmental antigens. We previously reported that the inhibition of diacylglycerol (DAG) kinaseζ (DGKζ),an enzyme that terminates DAG-mediated signaling,protects against T cell-mediated allergic airway inflammation by blocking Th2 cell differentiation.In this study, we tested whether DGKζ deficiency also affects allergic airway disease mediated by type 2 innate lymphoid cells (ILC2)s. DGKζ-deficient mice displayed diminished ILC2 function and reduced papain-induced airway inflammation compared to wildtype mice. Unexpectedly, however, mice with hematopoietic cell-specific deletion ofDGKζ displayed intact airway inflammation upon papain challenge. Rather, bone marrow chimera studies revealed thatDGKζ deficiency in the non-hematopoietic compartment was responsible for the reduction in papain-induced airway inflammation. These data suggest that DGK might represent a novel therapeutic target not only for T cell-dependent but also ILC2-dependent allergic airway inflammation by affecting non-hematopoietic cells.

Keywords:  DGKζ; IL-33; ILC2; Lung; Papain; Type 2 inflammation

DOI:  https://doi.org/10.1016/j.cellimm.2023.104780
JHEP Rep. 2023 Dec;5(12): 100895

Arachidonic acid activates NLRP3 inflammasome in MDSCs via FATP2 to promote post-transplant tumour recurrence in steatotic liver grafts.

Hui Liu, Wai Ho Oscar Yeung, Li Pang, Jiang Liu, Xiao Bing Liu, Kevin Tak Pan Ng, Qingmei Zhang, Wen Qi Qiu, Yueqin Zhu, Tao Ding, Zhe Wang, Ji Ye Zhu, Chung Mau Lo, Kwan Man.

   Background & Aims: The steatotic grafts have been applied in liver transplantation frequently owing to the high incidence of non-alcoholic fatty liver disease. However, fatty livers are vulnerable to graft injury. Myeloid-derived suppressor cell (MDSC) recruitment during liver graft injury promotes tumour recurrence. Lipid metabolism exerts the immunological influence on MDSCs in tumour progression. Here, we aimed to explore the role and mechanism of inflammasome activation in MDSCs induced by lipid metabolism during fatty liver graft injury and the subsequent effects on tumour recurrence.
Methods: MDSC populations and nucleotide-binding oligomerisation domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome levels were investigated in a clinical cohort and a rat liver transplantation model. The mechanism of NLRP3 activation by specific fatty acids was explored in mouse hepatic ischaemia/reperfusion injury (IRI) with tumour recurrence model and in vitro studies.
Results: MDSC populations and NLRP3 levels were increased with higher tumour recurrent rate in patients using steatotic grafts. NLRP3 was upregulated in MDSCs with lipid accumulation post mouse fatty liver IRI. Mechanistically, arachidonic acid was discovered to activate NLRP3 inflammasome in MDSCs through fatty acid transport protein 2 (FATP2), which was identified by screening lipid uptake receptors. The mitochondrial dysfunction with enhanced reactive oxygen species bridged arachidonic acid uptake and NLRP3 activation in MDSCs, which subsequently stimulated CD4+ T cells producing more IL-17 in fatty liver IRI. Blockade of FATP2 inhibited NLRP3 activation in MDSCs, IL-17 production in CD4+ T cells, and the tumour recurrence post fatty liver IRI.
Conclusions: During fatty liver graft injury, arachidonic acid activated NLRP3 inflammasome in MDSCs through FATP2, which subsequently stimulated CD4+ T cells producing IL-17 to promote tumour recurrence post transplantation.
Impact and implications: The high incidence of non-alcoholic fatty liver disease resulted in the frequent application of steatotic donors in liver transplantation. Our data showed that the patients who underwent liver transplantation using fatty grafts experienced higher tumour recurrence. We found that arachidonic acid activated NLRP3 inflammasome in MDSCs through FATP2 during fatty liver graft injury, which led to more IL-17 secretion of CD4+ T cells and promoted tumour recurrence post transplantation. The inflammasome activation by aberrant fatty acid metabolism in MDSCs bridged the acute-phase fatty liver graft injury and liver tumour recurrence.

Keywords:  Inflammasome; Lipid metabolism; MDSC; Steatotic liver graft; Tumour recurrence

DOI:  https://doi.org/10.1016/j.jhepr.2023.100895
Proc Natl Acad Sci U S A. 2023 Nov 07. 120(45): e2308214120

Dysregulated CD200-CD200R signaling in early diabetes modulates microglia-mediated retinopathy.

Charles W Pfeifer, James T Walsh, Andrea Santeford, Joseph B Lin, Wandy L Beatty, Ryo Terao, Yizhou A Liu, Keitaro Hase, Philip A Ruzycki, Rajendra S Apte.

  Diabetic retinopathy (DR) is a neurovascular complication of diabetes. Recent investigations have suggested that early degeneration of the neuroretina may occur prior to the appearance of microvascular changes; however, the mechanisms underlying this neurodegeneration have been elusive. Microglia are the predominant resident immune cell in the retina and adopt dynamic roles in disease. Here, we show that ablation of retinal microglia ameliorates visual dysfunction and neurodegeneration in a type I diabetes mouse model. We also provide evidence of enhanced microglial contact and engulfment of amacrine cells, ultrastructural modifications, and transcriptome changes that drive inflammation and phagocytosis. We show that CD200-CD200R signaling between amacrine cells and microglia is dysregulated during early DR and that targeting CD200R can attenuate high glucose-induced inflammation and phagocytosis in cultured microglia. Last, we demonstrate that targeting CD200R in vivo can prevent visual dysfunction, microglia activation, and retinal inflammation in the diabetic mouse. These studies provide a molecular framework for the pivotal role that microglia play in early DR pathogenesis and identify a potential immunotherapeutic target for treating DR in patients.

Keywords:  diabetes; inflammation; microglia; retina; retinopathy

DOI:  https://doi.org/10.1073/pnas.2308214120
Immun Inflamm Dis. 2023 10;11(10): e1042

Potential biomarker for diagnosis and therapy of sepsis: Lactylation.

ZeXian Sun, Yu Song, Jie Li, Yize Li, YongHao Yu, Xin Wang.

   INTRODUCTION: As a disease that has plagued human health for decades, sepsis has so far had no specific diagnostic or therapeutic indicators. The discovery of lactylation modifications not only uncovered the deep-rooted causes of changing between lactate level and pathophysiology and immunology of sepsis, but also reaffirmed the inevitable link between metabolic reprogramming and epigenetic reprogramming in sepsis. Lactylation modification became a potential marker for diagnosis and guiding the treatment of sepsis.
AIM: In this paper, we will summarize the discovery and regulation of lactylation modifications, discuss the study of lactylation modifications in sepsis, and evaluate their possibility and potential as diagnostic and therapeutic indicators of sepsis.
CONCLUSION: Lactylation modification is directly regulated by glycolysis and lactate, and inhibition of glycolytic pathway-related enzymes can regulate the level of lactylation modification, and more importantly, lactylation modification can act on these enzymes to regulate their functions and feedback regulate the level of glycolysis, this finding provides more ideas for clinical treatment of sepsis. We use "epigenetic modification", "glycolysis", "lactate", "lactylaiton" and "sepsis" as keywords and search the relevant literature through Pubmed and Web of science up to 2023.

Keywords:  epigenetic modification; glycolysis; lactate; lactylation; sepsis

DOI:  https://doi.org/10.1002/iid3.1042
Sci Adv. 2023 Nov 03. 9(44): eadi7337

Lachnospiraceae-derived butyrate mediates protection of high fermentable fiber against placental inflammation in gestational diabetes mellitus.

Shuangbo Huang, Jianzhao Chen, Zhijuan Cui, Kaidi Ma, Deyuan Wu, Jinxi Luo, Fuyong Li, Wenyu Xiong, Sujuan Rao, Quanhang Xiang, Wei Shi, Tongxing Song, Jinping Deng, Yulong Yin, Chengquan Tan.

Inflammation-associated insulin resistance is a key trigger of gestational diabetes mellitus (GDM), but the underlying mechanisms and effective interventions remain unclear. Here, we report the association of placental inflammation (tumor necrosis factor-α) and abnormal maternal glucose metabolism in patients with GDM, and a high fermentable dietary fiber (HFDF; konjac) could reduce GDM development through gut flora-short-chain fatty acid-placental inflammation axis in GDM mouse model. Mechanistically, HFDF increases abundances of Lachnospiraceae and butyrate, reduces placental-derived inflammation by enhancing gut barrier and inhibiting the transfer of bacterial-derived lipopolysaccharide, and ultimately resists high-fat diet-induced insulin resistance. Lachnospiraceae and butyrate have similar anti-GDM and anti-placental inflammation effects, and they can ameliorate placental function and pregnancy outcome effects probably by dampening placental immune dysfunction. These findings demonstrate the involvement of important placental inflammation-related mechanisms in the progression of GDM and the great potential of HFDFs to reduce susceptibility to GDM through gut-flora-placenta axis.

DOI: https://doi.org/10.1126/sciadv.adi7337
Front Med. 2023 Oct 28.

Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors: mechanisms and strategies.

Liming Liao, Huilin Xu, Yuhan Zhao, Xiaofeng Zheng.

  Immunotherapies based on immune checkpoint blockade (ICB) have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade. To date, immune checkpoint inhibitors (ICIs) of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy. Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers, however, a large subset of refractory patients presents poor responsiveness to ICB therapy; and the underlying mechanism remains elusive. Recently, numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment (TME) with various products of metabolism, and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy. Nevertheless, a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance. Here, we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints (CTLA-4, PD-1, and PD-L1) to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.

Keywords:  CTLA-4; PD-1; PD-L1; combined tumor therapeutic strategies; immune checkpoint blockade (ICB); metabolic reprogramming

DOI:  https://doi.org/10.1007/s11684-023-1025-7
J Innate Immun. 2023 Oct 27.

The intersection between bacterial metabolism and innate immunity.

Ivan C Acosta, Francis Alonzo Iii.

BACKGROUND: The innate immune system is the first line of defense against microbial pathogens and is essential for maintaining good health. If pathogens breach innate barriers, the likelihood of infection is significantly increased. Many bacterial pathogens pose a threat to human health on account of their ability to evade innate immunity and survive in growth-restricted environments. These pathogens have evolved sophisticated strategies to obtain nutrients as well as manipulate innate immune responses, resulting in disease or chronic infection.
SUMMARY: The relationship between bacterial metabolism and innate immunity is complex. Although aspects of bacterial metabolism can be beneficial to the host, particularly those related to the microbiota and barrier integrity, others can be harmful. Several bacterial pathogens harness metabolism to evade immune responses and persist during infection. The study of these adaptive traits provides insight into the roles of microbial metabolism in pathogenesis that extend beyond energy balance. This review considers recent studies on bacterial metabolic pathways that promote infection by circumventing several facets of the innate immune system. We also discuss relationships between innate immunity and antibiotics and highlight future directions for research in this field.
KEY MESSAGES: Pathogenic bacteria have a remarkable capacity to harness metabolism to manipulate immune responses and promote pathogenesis. While we are beginning to understand the multifaceted and complex metabolic adaptations that occur during infection, there is still much to uncover with future research.

DOI: https://doi.org/10.1159/000534872
Autism Res. 2023 Nov 01.

The tryptophan catabolite or kynurenine pathway in autism spectrum disorder; a systematic review and meta-analysis.

Abbas F Almulla, Yanin Thipakorn, Chavit Tunvirachaisakul, Michael Maes.

  Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social communication and interaction, as well as rigid and unchanging interests and behaviors. Several studies have reported that activated immune-inflammatory and nitro-oxidative pathways are accompanied by depletion of plasma tryptophan (TRP), increased competing amino acid (CAAs) levels, and activation of the TRP catabolite (TRYCAT) pathway. This study aims to systematically review and meta-analyze data on peripheral TRP, CAAs, TRYCAT pathway activity, and individual TRYCATs, including kynurenine (KYN) and kynurenic acid (KA) levels, in the blood and urine of ASD patients. After extensively searching PubMed, Google Scholar, and SciFinder, a total of 25 full-text papers were included in the analysis, with a total of 6653 participants (3557 people with ASD and 3096 healthy controls). Our results indicate that blood TRP and the TRP/CAAs ratio were not significantly different between ASD patients and controls (standardized mean difference, SMD = -0.227, 95% confidence interval, CI: -0.540; 0.085, and SMD = 0.158, 95% CI: -0.042; 0.359), respectively. The KYN/TRP ratio showed no significant difference between ASD and controls (SMD = 0.001, 95% CI: -0.169; 0.171). Blood KYN and KA levels were not significantly changed in ASD. Moreover, there were no significant differences in urine TRP, KYN, and KA levels between ASD and controls. We could not establish increases in neurotoxic TRYCATs in ASD. In conclusion, this study demonstrates no abnormalities in peripheral blood TRP metabolism, indoleamine 2,3-dioxygenase enzyme (IDO) activity, or TRYCAT production in ASD. Reduced TRP availability and elevated neurotoxic TRYCAT levels are not substantial contributors to ASD's pathophysiology.

Keywords:  autism; indoleamine 2,3-dioxygenase enzyme; inflammation; neuro-immune; oxidative stress

DOI:  https://doi.org/10.1002/aur.3044
Front Immunol. 2023 ;14 1270081

The purinergic receptor P2X7 and the NLRP3 inflammasome are druggable host factors required for SARS-CoV-2 infection.

Déborah Lécuyer, Roberta Nardacci, Désirée Tannous, Emie Gutierrez-Mateyron, Aurélia Deva Nathan, Frédéric Subra, Cristina Di Primio, Paola Quaranta, Vanessa Petit, Clémence Richetta, Ali Mostefa-Kara, Franca Del Nonno, Laura Falasca, Romain Marlin, Pauline Maisonnasse, Julia Delahousse, Juliette Pascaud, Eric Deprez, Marie Naigeon, Nathalie Chaput, Angelo Paci, Véronique Saada, David Ghez, Xavier Mariette, Mario Costa, Mauro Pistello, Awatef Allouch, Olivier Delelis, Mauro Piacentini, Roger Le Grand, Jean-Luc Perfettini.

  Purinergic receptors and NOD-like receptor protein 3 (NLRP3) inflammasome regulate inflammation and viral infection, but their effects on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain poorly understood. Here, we report that the purinergic receptor P2X7 and NLRP3 inflammasome are cellular host factors required for SARS-CoV-2 infection. Lung autopsies from patients with severe coronavirus disease 2019 (COVID-19) reveal that NLRP3 expression is increased in host cellular targets of SARS-CoV-2 including alveolar macrophages, type II pneumocytes and syncytia arising from the fusion of infected macrophages, thus suggesting a potential role of NLRP3 and associated signaling pathways to both inflammation and viral replication. In vitro studies demonstrate that NLRP3-dependent inflammasome activation is detected upon macrophage abortive infection. More importantly, a weak activation of NLRP3 inflammasome is also detected during the early steps of SARS-CoV-2 infection of epithelial cells and promotes the viral replication in these cells. Interestingly, the purinergic receptor P2X7, which is known to control NLRP3 inflammasome activation, also favors the replication of D614G and alpha SARS-CoV-2 variants. Altogether, our results reveal an unexpected relationship between the purinergic receptor P2X7, the NLRP3 inflammasome and the permissiveness to SARS-CoV-2 infection that offers novel opportunities for COVID-19 treatment.

Keywords:  COVID-19; NLRP3; P2X7; SARS-CoV-2; inflammasome

DOI:  https://doi.org/10.3389/fimmu.2023.1270081
mSystems. 2023 Nov 01. e0070323

Limitation of amino acid availability by bacterial populations during enhanced colitis in IBD mouse model.

Tanner G Richie, Leah Heeren, Abigail Kamke, Kourtney Monk, Sophia Pogranichniy, Trey Summers, Hallie Wiechman, Qinghong Ran, Soumyadev Sarkar, Brandon L Plattner, Sonny T M Lee.

  Members of the Enterobacteriaceae and Enterococcus are associated with persistent gut inflammation due to rapid colonization combined with pathogenic tendencies. Here, we investigated the functions of gut microbial populations resulting in persistent gut inflammation. In this study, we utilized the IL-10 knockout mouse model and induced colitis using dextran sulfate sodium (2%) after development. Dams during gestation were provided cefoperazone to induce vertically transmitted dysbiosis in the pups that were monitored in this study. We characterized the dysbiotic gut microbial community and potential crosstalk of these microbes, and host gene expression changes to identify bacterial populations and potential functions that were involved in gut inflammation. We isolated Enterobacteriaceae populations from mice to validate the utilization of sulfur-containing amino acids. Members of Enterobacteriaceae and Enterococcus were highly detected in inflamed mice. Enterobacteriaceae populations containing L-cysteine dioxygenase were strongly correlated with the upregulation of host gene CSAD, responsible for cysteine breakdown. We observed that bacterial isolates from dysbiotic mice displayed increased growth rates when supplemented with L-cysteine, highlighting the use of sulfur metabolism. Our results show that microbial populations use alternate metabolisms and sequester host nutrients for growth, associated with inflammation in the gut.IMPORTANCEInflammatory bowel disease is associated with an increase in Enterobacteriaceae and Enterococcus species; however, the specific mechanisms are unclear. Previous research has reported the associations between microbiota and inflammation, here we investigate potential pathways that specific bacteria populations use to drive gut inflammation. Richie et al. show that these bacterial populations utilize an alternate sulfur metabolism and are tolerant of host-derived immune-response products. These metabolic pathways drive host gut inflammation and fuel over colonization of these pathobionts in the dysbiotic colon. Cultured isolates from dysbiotic mice indicated faster growth supplemented with L-cysteine, showing these microbes can utilize essential host nutrients.

Keywords:  RNA sequencing; amino acid uptake; fecal microbiota transplantation; inflammatory bowel disease; microbial-host interactions; shotgun metagenomics

DOI:  https://doi.org/10.1128/msystems.00703-23
J Transl Med. 2023 Nov 02. 21(1): 776

Elevated phospholipids and acylcarnitines C4 and C5 in cerebrospinal fluid distinguish viral CNS infections from autoimmune neuroinflammation.

Amani Al-Mekhlafi, Fakhar H Waqas, Maike Krueger, Frank Klawonn, Manas K Akmatov, Kirsten Müller-Vahl, Corinna Trebst, Thomas Skripuletz, Martin Stangel, Kurt-Wolfram Sühs, Frank Pessler.

   BACKGROUND: Viral and autoimmune encephalitis may present with similar symptoms, but require different treatments. Thus, there is a need for biomarkers to improve diagnosis and understanding of pathogenesis. We hypothesized that virus-host cell interactions lead to different changes in central nervous system (CNS) metabolism than autoimmune processes and searched for metabolite biomarkers in cerebrospinal fluid (CSF) to distinguish between the two conditions.
METHODS: We applied a targeted metabolomic/lipidomic analysis to CSF samples from patients with viral CNS infections (n = 34; due to herpes simplex virus [n = 9], varicella zoster virus [n = 15], enteroviruses [n = 10]), autoimmune neuroinflammation (n = 25; autoimmune anti-NMDA-receptor encephalitis [n = 8], multiple sclerosis [n = 17), and non-inflamed controls (n = 31; Gilles de la Tourette syndrome [n = 20], Bell's palsy with normal CSF cell count [n = 11]). 85 metabolites passed quality screening and were evaluated as biomarkers. Standard diagnostic CSF parameters were assessed for comparison.
RESULTS: Of the standard CSF parameters, the best biomarkers were: CSF cell count for viral infections vs. controls (area under the ROC curve, AUC = 0.93), Q-albumin for viral infections vs. autoimmune neuroinflammation (AUC = 0.86), and IgG index for autoimmune neuroinflammation vs. controls (AUC = 0.90). Concentrations of 2 metabolites differed significantly (p < 0.05) between autoimmune neuroinflammation and controls, with proline being the best biomarker (AUC = 0.77). In contrast, concentrations of 67 metabolites were significantly higher in viral infections than controls, with SM.C16.0 being the best biomarker (AUC = 0.94). Concentrations of 68 metabolites were significantly higher in viral infections than in autoimmune neuroinflammation, and the 10 most accurate metabolite biomarkers (AUC = 0.89-0.93) were substantially better than Q-albumin (AUC = 0.86). These biomarkers comprised six phosphatidylcholines (AUC = 0.89-0.92), two sphingomyelins (AUC = 0.89, 0.91), and acylcarnitines isobutyrylcarnitine (C4, AUC = 0.92) and isovalerylcarnitine (C5, AUC = 0.93). Elevated C4 and C5 concentrations suggested dysfunctional mitochondrial β-oxidation and correlated only moderately with CSF cell count (Spearman ρ = 0.41 and 0.44), indicating that their increase is not primarily driven by inflammation.
CONCLUSIONS: Changes in CNS metabolism differ substantially between viral CNS infections and autoimmune neuroinflammation and reveal CSF metabolites as pathophysiologically relevant diagnostic biomarkers for the differentiation between the two conditions. In viral CNS infections, the observed higher concentrations of free phospholipids are consistent with disruption of host cell membranes, whereas the elevated short-chain acylcarnitines likely reflect compromised mitochondrial homeostasis and energy generation.

Keywords:  Autoimmunity; Biomarkers; Cell membrane; Central nervous system; Encephalitis; Enterovirus; Fatty acid oxidation; Glycerophospholipids; Herpes simplex virus; Infection; Isobutyrylcarnitine; Isovalerylcarnitine; Lecithin; Lysophosphatidylcholine; Meningitis; Metabolism; Mitochondria; Phosphatidylcholine; Phospholipid; Sphingomyelin; Varicella zoster virus; n-methyl-D-aspartate receptor

DOI:  https://doi.org/10.1186/s12967-023-04637-y
Cell Rep. 2023 Oct 27. pii: S2211-1247(23)01362-1. [Epub ahead of print]42(11): 113350

An obesogenic diet increases atherosclerosis through promoting microbiota dysbiosis-induced gut lymphocyte trafficking into the periphery.

Ludivine Laurans, Nirmala Mouttoulingam, Mouna Chajadine, Aonghus Lavelle, Marc Diedisheim, Emilie Bacquer, Laura Creusot, Nadine Suffee, Bruno Esposito, Nada Joe Melhem, Wilfried Le Goff, Yacine Haddad, Jean-Louis Paul, Dominique Rainteau, Alain Tedgui, Hafid Ait-Oufella, Laurence Zitvogel, Harry Sokol, Soraya Taleb.

  Although high-fat diet (HFD)-induced gut microbiota dysbiosis is known to affect atherosclerosis, the underlying mechanisms remain to be fully explored. Here, we show that the progression of atherosclerosis depends on a gut microbiota shaped by an HFD but not a high-cholesterol (HC) diet and, more particularly, on low fiber (LF) intake. Mechanistically, gut lymphoid cells impacted by HFD- or LF-induced microbiota dysbiosis highly proliferate in mesenteric lymph nodes (MLNs) and migrate from MLNs to the periphery, which fuels T cell accumulation within atherosclerotic plaques. This is associated with the induction of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) within plaques and the presence of enterotropic lymphocytes expressing β7 integrin. MLN resection or lymphocyte deficiency abrogates the pro-atherogenic effects of a microbiota shaped by LF. Our study shows a pathological link between a diet-shaped microbiota, gut immune cells, and atherosclerosis, suggesting that a diet-modulated microbiome might be a suitable therapeutic target to prevent atherosclerosis.

Keywords:  CP: Immunology; CP: Metabolism; atherosclerosis; high-fat diet; low fiber; microbiota

DOI:  https://doi.org/10.1016/j.celrep.2023.113350
Exp Gerontol. 2023 Oct 26. pii: S0531-5565(23)00240-1. [Epub ahead of print] 112319

Microbiota-derived tryptophan metabolism: Impacts on health, aging, and disease.

Sonu Kumar Gupta, Sagar Vyavahare, Ian L Duchesne Blanes, Ford Berger, Carlos Isales, Sadanand Fulzele.

  The intricate interplay between gut microbiota and the host is pivotal in maintaining homeostasis and health. Dietary tryptophan (TRP) metabolism initiates a cascade of essential endogenous metabolites, including kynurenine, kynurenic acid, serotonin, and melatonin, as well as microbiota-derived Trp metabolites like tryptamine, indole propionic acid (IPA), and other indole derivatives. Notably, tryptamine and IPA, among the indole metabolites, exert crucial roles in modulating immune, metabolic, and neuronal responses at both local and distant sites. Additionally, these metabolites demonstrate potent antioxidant and anti-inflammatory activities. The levels of microbiota-derived TRP metabolites are intricately linked to the gut microbiota's health, which, in turn, can be influenced by age-related changes. This review aims to comprehensively summarize the cellular and molecular impacts of tryptamine and IPA on health and aging-related complications. Furthermore, we explore the levels of tryptamine and IPA and their corresponding bacteria in select diseased conditions, shedding light on their potential significance as biomarkers and therapeutic targets.

Keywords:  Aging; Disease; Gut microbiota; IPA; Tryptamine; Tryptophan

DOI:  https://doi.org/10.1016/j.exger.2023.112319
J Clin Invest. 2023 Nov 01. pii: e174540. [Epub ahead of print]133(21):

GLUT3 regulates alternative macrophage signaling through a glucose transport-independent role.

Peng Zhang, Jason Miska, Amy B Heimberger.

Macrophages are key mediators of innate immunity whose functional state can be regulated by glucose transporters. Although abundantly expressed in macrophages, the specific function of GLUT3, an isoform of facilitative glucose transporters, has not been clearly established. In this issue of the JCI, Dong-Min Yu and colleagues identify an alternative role for GLUT3 in promoting M2 macrophage polarization. The authors demonstrated that GLUT3 was upregulated upon M2 stimulation and was required for efficient alternative macrophage polarization and function. They further showed that GLUT3-induced M2 polarization was independent of glucose transport and functioned through Ras-mediated regulation of IL-4R endocytosis and IL-4/STAT6 activation. These findings may guide the development of macrophage-targeted treatments.

DOI: https://doi.org/10.1172/JCI174540