bims-imicid 2022-12-18 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022–12–18
twenty-six papers selected by
Dylan Ryan, University of Cambridge

Activated cholesterol metabolism is integral for innate macrophage responses by amplifying Myd88 signaling.
Consumption of fish oil high-fat diet induces murine hair loss via epidermal fatty acid binding protein in skin macrophages.
Farnesoid X receptor antagonizes macrophage-dependent licensing of effector T lymphocytes and progression of sclerosing cholangitis.
Engineering amino acid uptake or catabolism promotes CAR-T cell adaption to the tumour environment.
Graphene oxide elicits microbiome-dependent type 2 immune responses via the aryl hydrocarbon receptor.
Endogenous drivers of altered immune cell metabolism.
Neutrophil trafficking to the site of infection requires Cpt1a-dependent fatty acid β-oxidation.
Immune Metabolism in TH2 Responses: New Opportunities to Improve Allergy Treatment - Cell Type-Specific Findings (Part 2).
Targeting lactate metabolism for cancer immunotherapy - a matter of precision.
Cystathionine γ-lyase and hydrogen sulfide modulates glucose transporter Glut1 expression via NF-κB and PI3k/Akt in macrophages during inflammation.
SnSe Nanosheets Mimic Lactate Dehydrogenase to Reverse Tumor Acid Microenvironment Metabolism for Enhancement of Tumor Therapy.
Altered lipid metabolism in synovial fibroblasts of individuals at risk of developing rheumatoid arthritis.
Loss of selenoprotein W in murine macrophages alters the hierarchy of selenoprotein expression, redox tone, and mitochondrial functions during inflammation.
Augmented PFKFB3-mediated glycolysis by interferon-γ promotes inflammatory M1 polarization through the JAK2/STAT1 pathway in local vascular inflammation in Takayasu arteritis.
RAGE promotes dysregulation of iron and lipid metabolism in alcoholic liver disease.
GLUT-1/PKM2 loop dysregulation in patients with non-ST-segment elevation myocardial infarction promotes metainflammation.
The mitochondrial UPR regulator ATF5 promotes intestinal barrier function via control of the satiety response.
Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development.
A multi-omics based anti-inflammatory immune signature characterizes long COVID-19 syndrome.
Paraoxonase-2 contributes to promoting lipid metabolism and mitochondrial function via autophagy activation.
Stable isotope tracing in vivo reveals a metabolic bridge linking the microbiota to host histone acetylation.
Modulation of mitochondria by viral proteins.
Tryptophan metabolism can modulate immunologic tolerance in primitive vertebrate lamprey via IDO-kynurenine-AHR pathway.
The rise of viperin: the emerging role of viperin in cancer progression.
Butyrate Ameliorates Intraocular Bacterial Infection by Promoting Autophagy and Attenuating the Inflammatory Response.
Integrated multi-omics of the gastrointestinal microbiome and ruminant host reveals metabolic adaptation underlying early life development.

JCI Insight. 2022 11 22. pii: e138539. [Epub ahead of print]7(22):

Activated cholesterol metabolism is integral for innate macrophage responses by amplifying Myd88 signaling.

Sumio Hayakawa, Atsushi Tamura, Nikita Nikiforov, Hiroyuki Koike, Fujimi Kudo, Yinglan Cheng, Takuro Miyazaki, Marina Kubekina, Tatiana V Kirichenko, Alexander N Orekhov, Nobuhiko Yui, Ichiro Manabe, Yumiko Oishi.

  Recent studies have shown that cellular metabolism is tightly linked to the regulation of immune cells. Here, we show that activation of cholesterol metabolism, involving cholesterol uptake, synthesis, and autophagy/lipophagy, is integral to innate immune responses in macrophages. In particular, cholesterol accumulation within endosomes and lysosomes is a hallmark of the cellular cholesterol dynamics elicited by Toll-like receptor 4 activation and is required for amplification of myeloid differentiation primary response 88 (Myd88) signaling. Mechanistically, Myd88 binds cholesterol via its CLR recognition/interaction amino acid consensus domain, which promotes the protein's self-oligomerization. Moreover, a novel supramolecular compound, polyrotaxane (PRX), inhibited Myd88‑dependent inflammatory macrophage activation by decreasing endolysosomal cholesterol via promotion of cholesterol trafficking and efflux. PRX activated liver X receptor, which led to upregulation of ATP binding cassette transporter A1, thereby promoting cholesterol efflux. PRX also inhibited atherogenesis in Ldlr-/- mice. In humans, cholesterol levels in circulating monocytes correlated positively with the severity of atherosclerosis. These findings demonstrate that dynamic changes in cholesterol metabolism are mechanistically linked to Myd88‑dependent inflammatory programs in macrophages and support the notion that cellular cholesterol metabolism is integral to innate activation of macrophages and is a potential therapeutic and diagnostic target for inflammatory diseases.

Keywords:  Inflammation; Innate immunity; Vascular Biology

DOI:  https://doi.org/10.1172/jci.insight.138539
Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01692-8. [Epub ahead of print]41(11): 111804

Consumption of fish oil high-fat diet induces murine hair loss via epidermal fatty acid binding protein in skin macrophages.

Jiaqing Hao, Rong Jin, Jun Zeng, Yuan Hua, Matthew S Yorek, Lianliang Liu, Anita Mandal, Junling Li, Huaiyu Zheng, Yanwen Sun, Yanmei Yi, Di Yin, Qi Zheng, Xiaohong Li, Chin K Ng, Eric C Rouchka, Nejat K Egilmez, Ali Jabbari, Bing Li.

  Fats are essential in healthy diets, but how dietary fats affect immune cell function and overall health is not well understood. Mimicking human high-fat diets (HFDs), which are rich in different fatty acid (FA) components, we fed mice various HFDs from different fat sources, including fish oil and cocoa butter. Mice consuming the fish oil HFD exhibit a hair-loss phenotype. Further studies show that omega-3 (n-3) FAs in fish oil promote atypical infiltration of CD207- (langerin-) myeloid macrophages in skin dermis, which induce hair loss through elevated TNF-α signaling. Mechanistically, epidermal fatty acid binding protein (E-FABP) is demonstrated to play an essential role in inducing TNF-α-mediated hair loss by activating the n-3 FA/ROS/IL-36 signaling pathway in dermal resident macrophages. Absence of E-FABP abrogates fish oil HFD-induced murine hair loss. Altogether, these findings support a role for E-FABP as a lipid sensor mediating n-3 FA-regulated macrophage function and skin health.

Keywords:  CP: Immunology; CP: Metabolism; fatty acid binding protein; fish oil; hair loss; high-fat diet; macrophages

DOI:  https://doi.org/10.1016/j.celrep.2022.111804
Sci Transl Med. 2022 Dec 14. 14(675): eabi4354

Farnesoid X receptor antagonizes macrophage-dependent licensing of effector T lymphocytes and progression of sclerosing cholangitis.

Tiffany Shi, Astha Malik, Annika Yang Vom Hofe, Louis Matuschek, Mary Mullen, Celine S Lages, Ramesh Kudira, Ruchi Singh, Wujuan Zhang, Kenneth D R Setchell, David Hildeman, Chandrashekhar Pasare, Brandee Wagner, Alexander G Miethke.

Immune-mediated bile duct epithelial injury and toxicity of retained hydrophobic bile acids drive disease progression in fibrosing cholangiopathies such as biliary atresia or primary sclerosing cholangitis. Emerging therapies include pharmacological agonists to farnesoid X receptor (FXR), the master regulator of hepatic synthesis, excretion, and intestinal reuptake of bile acids. Unraveling the mechanisms of action of pharmacological FXR agonists in the treatment of sclerosing cholangitis (SC), we found that intestinally restricted FXR activation effectively reduced bile acid pool size but did not improve the SC phenotype in MDR2-/- mice. In contrast, systemic FXR activation not only lowered bile acid synthesis but also suppressed proinflammatory cytokine production by liver-infiltrating inflammatory cells and blocked progression of hepatobiliary injury. The hepatoprotective activity was linked to suppressed production of IL1β and TNFα by hepatic macrophages and inhibition of TH1/TH17 lymphocyte polarization. Deletion of FXR in myeloid cells caused aberrant TH1 and TH17 lymphocyte responses in diethoxycarbonyl-1,4-dihydrocollidine-induced SC and rendered these mice resistant to the anti-inflammatory and liver protective effects of systemic FXR agonist treatment. Pharmacological FXR activation reduced IL1β and IFNγ production by liver- and blood-derived mononuclear cells from patients with fibrosing cholangiopathies. In conclusion, we demonstrate FXR to control the macrophage-TH1/17 axis, which is critically important for the progression of SC. Hepatic macrophages are cellular targets of systemic FXR agonist therapy for cholestatic liver disease.

DOI: https://doi.org/10.1126/scitranslmed.abi4354
Blood Adv. 2022 Dec 15. pii: bloodadvances.2022008272. [Epub ahead of print]

Engineering amino acid uptake or catabolism promotes CAR-T cell adaption to the tumour environment.

Silvia Panetti, Nicola Jane McJannett, Livingstone Fultang, Sarah Booth, Luciana Gneo, Ugo Scarpa, Charles Smith, Ashley Vardon, Lisa Vettore, Celina Whalley, Yi Pan, Csilla Varnai, Hitoshi Endou, Jonathan Barlow, Daniel A Tennant, Andrew D Beggs, Francis Jay Mussai, Carmela De Santo.

Cancer cells take up amino acids from the extracellular space to drive cell proliferation and viability. Similar mechanisms are employed by immune cells. The result is competition between conventional T cells, or indeed CAR-T cells, and tumour cells for limited availability of amino acids within the environment. We demonstrate that T cells can be re-engineered to express SLC7A5 or SLC7A11 transmembrane amino acid transporters alongside chimeric antigen receptors (CAR). Transporter modifications increase CAR-T cell proliferation under low tryptophan or cystine conditions with no loss of CAR cytotoxicity or increased exhaustion. Transcriptomic and phenotypic analysis reveals that downstream, SLC7A5/SLC7A11 modified CAR-T cells upregulate intracellular Arginase expression and activity. In turn we engineer and phenotype a further generation of CAR-T cells which express functional Arginase I/Arginase II enzymes, and have enhanced CAR-T cell proliferation and anti-tumour activity. Thus CAR-T cells can be adapted to the amino acid metabolic microenvironment of cancer, a hitherto recognised but unaddressed barrier to successful CAR-T therapy.

DOI: https://doi.org/10.1182/bloodadvances.2022008272
Nat Nanotechnol. 2022 Dec 12.

Graphene oxide elicits microbiome-dependent type 2 immune responses via the aryl hydrocarbon receptor.

Guotao Peng, Hanna M Sinkko, Harri Alenius, Neus Lozano, Kostas Kostarelos, Lars Bräutigam, Bengt Fadeel.

The gut microbiome produces metabolites that interact with the aryl hydrocarbon receptor (AhR), a key regulator of immune homoeostasis in the gut1,2. Here we show that oral exposure to graphene oxide (GO) modulates the composition of the gut microbiome in adult zebrafish, with significant differences in wild-type versus ahr2-deficient animals. Furthermore, GO was found to elicit AhR-dependent induction of cyp1a and homing of lck+ cells to the gut in germ-free zebrafish larvae when combined with the short-chain fatty acid butyrate. To obtain further insights into the immune responses to GO, we used single-cell RNA sequencing to profile cells from whole germ-free embryos as well as cells enriched for lck. These studies provided evidence for the existence of innate lymphoid cell (ILC)-like cells3 in germ-free zebrafish. Moreover, GO endowed with a 'corona' of microbial butyrate triggered the induction of ILC2-like cells with attributes of regulatory cells. Taken together, this study shows that a nanomaterial can influence the crosstalk between the microbiome and immune system in an AhR-dependent manner.

DOI: https://doi.org/10.1038/s41565-022-01260-8
Exp Biol Med (Maywood). 2022 Dec 13. 15353702221134093

Endogenous drivers of altered immune cell metabolism.

Lianne C Shanley, Hannah K Fitzgerald, Sinead A O'Rourke, Aisling Dunne.

  Dysregulated metabolism has long been recognized as a feature of many metabolic disorders. However, recent studies demonstrating that metabolic reprogramming occurs in immune cells have led to a growing interest in the relationship between metabolic rewiring and immune-mediated disease pathogeneses. It is clear now that immune cell subsets engage in different metabolic pathways depending on their activation and/or maturation state. As a result, it may be possible to modulate metabolic reprogramming for clinical benefit. In this review, we provide an overview of immune cell metabolism with focus on endogenous drivers of metabolic reprogramming given their link to a number of immune-mediated disorders.

Keywords:  Immunometabolism; cellular respiration; damage or disease-associated molecular patterns; metabolic reprogramming

DOI:  https://doi.org/10.1177/15353702221134093
Commun Biol. 2022 Dec 13. 5(1): 1366

Neutrophil trafficking to the site of infection requires Cpt1a-dependent fatty acid β-oxidation.

Ly Pham, Padmini Komalavilas, Alex M Eddie, Timothy E Thayer, Dalton L Greenwood, Ken H Liu, Jaclyn Weinberg, Andrew Patterson, Joshua P Fessel, Kelli L Boyd, Jenny C Schafer, Jamie L Kuck, Aaron C Shaver, David K Flaherty, Brittany K Matlock, Christiaan D M Wijers, C Henrique Serezani, Dean P Jones, Evan L Brittain, Jeffrey C Rathmell, Michael J Noto.

Cellular metabolism influences immune cell function, with mitochondrial fatty acid β-oxidation and oxidative phosphorylation required for multiple immune cell phenotypes. Carnitine palmitoyltransferase 1a (Cpt1a) is considered the rate-limiting enzyme for mitochondrial metabolism of long-chain fatty acids, and Cpt1a deficiency is associated with infant mortality and infection risk. This study was undertaken to test the hypothesis that impairment in Cpt1a-dependent fatty acid oxidation results in increased susceptibility to infection. Screening the Cpt1a gene for common variants predicted to affect protein function revealed allele rs2229738_T, which was associated with pneumonia risk in a targeted human phenome association study. Pharmacologic inhibition of Cpt1a increases mortality and impairs control of the infection in a murine model of bacterial pneumonia. Susceptibility to pneumonia is associated with blunted neutrophilic responses in mice and humans that result from impaired neutrophil trafficking to the site of infection. Chemotaxis responsible for neutrophil trafficking requires Cpt1a-dependent mitochondrial fatty acid oxidation for amplification of chemoattractant signals. These findings identify Cpt1a as a potential host determinant of infection susceptibility and demonstrate a requirement for mitochondrial fatty acid oxidation in neutrophil biology.

DOI: https://doi.org/10.1038/s42003-022-04339-z
Curr Allergy Asthma Rep. 2022 Dec 15.

Immune Metabolism in TH2 Responses: New Opportunities to Improve Allergy Treatment - Cell Type-Specific Findings (Part 2).

Y-J Lin, A Goretzki, H Rainer, J Zimmermann, Stefan Schülke.

   PURPOSE OF REVIEW: Over the last years, we have learned that the metabolic phenotype of immune cells is closely connected to the cell's effector function. Understanding these changes will allow us to better understand allergic disease pathology and improve allergy treatment by modulating immune metabolic pathways. As part two of a two-article series, this review reports on the recent studies investigating the metabolism of the cell types involved in allergies and discusses the initial application of these discoveries in allergy treatment.
RECENT FINDINGS: The cell types involved in allergic reactions display pronounced and highly specific metabolic changes (here discussed for epithelial cells, APCs, ILC2s, mast cells, eosinophils, and Th2 cells). Currently, the first drugs targeting metabolic pathways are tested for their potential to improve allergy treatment. Immune-metabolic changes observed in allergy so far are complex and depend on the investigated disease and cell type. However, our increased understanding of the underlying principles has pointed to several promising target molecules that are now being investigated to improve allergy treatment.

Keywords:  APC; Allergy; Fatty acid oxidation; ILC2; Immune metabolism; Immunotherapy; Oxidative phosphorylation; Th2; Warburg

DOI:  https://doi.org/10.1007/s11882-022-01058-7
Semin Cancer Biol. 2022 Dec 07. pii: S1044-579X(22)00255-3. [Epub ahead of print]88 32-45

Targeting lactate metabolism for cancer immunotherapy - a matter of precision.

Christoph Heuser, Kathrin Renner, Marina Kreutz, Luca Gattinoni.

  Immune checkpoint inhibitors and adoptive T cell therapies have been valuable additions to the toolbox in the fight against cancer. These treatments have profoundly increased the number of patients with a realistic perspective toward a return to a cancer-free life. Yet, in a number of patients and tumor entities, cancer immunotherapies have been ineffective so far. In solid tumors, immune exclusion and the immunosuppressive tumor microenvironment represent substantial roadblocks to successful therapeutic outcomes. A major contributing factor to the depressed anti-tumor activity of immune cells in tumors is the harsh metabolic environment. Hypoxia, nutrient competition with tumor and stromal cells, and accumulating noxious waste products, including lactic acid, pose massive constraints to anti-tumor immune cells. Numerous strategies are being developed to exploit the metabolic vulnerabilities of tumor cells in the hope that these would also alleviate metabolism-inflicted immune suppression. While promising in principle, especially in combination with immunotherapies, these strategies need to be scrutinized for their effect on tumor-fighting immune cells, which share some of their key metabolic properties with tumor cells. Here, we provide an overview of strategies that seek to tackle lactate metabolism in tumor or immune cells to unleash anti-tumor immune responses, thereby opening therapeutic options for patients whose tumors are currently not treatable.

Keywords:  Acidification; Adoptive cell transfer; Checkpoint inhibition; Glycolysis; Immunotherapy; Lactate; Metabolism

DOI:  https://doi.org/10.1016/j.semcancer.2022.12.001
PLoS One. 2022 ;17(12): e0278910

Cystathionine γ-lyase and hydrogen sulfide modulates glucose transporter Glut1 expression via NF-κB and PI3k/Akt in macrophages during inflammation.

Alex Cornwell, Samantha Fedotova, Sara Cowan, Alireza Badiei.

Macrophages play a crucial role in inflammation, a defense mechanism of the innate immune system. Metabolic function powered by glucose transporter isoform 1 (Glut1) is necessary for macrophage activity during inflammation. The present study investigated the roles of cystathionine-γ-lyase (CSE) and its byproduct, hydrogen sulfide (H2S), in macrophage glucose metabolism to explore the mechanism by which H2S acts as an inflammatory regulator in lipopolysaccharide- (LPS) induced macrophages. Our results demonstrated that LPS-treated macrophages increased Glut1 expression. LPS-induced Glut1 expression is regulated via nuclear factor (NF)-κB activation and is associated with phosphatidylinositol-3-kinase PI3k activation. Small interfering (si) RNA-mediated silencing of CSE decreased the LPS-induced NF-κB activation and Glut1 expression, suggesting a role for H2S in metabolic function in macrophages during pro-inflammatory response. Confoundingly, treatment with GYY4137, an H2S-donor molecule, also displayed inhibitory effects upon LPS-induced NF-κB activation and Glut1 expression. Moreover, GYY4137 treatment increased Akt activation, suggesting a role in promoting resolution of inflammation. Our study provides evidence that the source of H2S, either endogenous (via CSE) or exogenous (via GYY4137), supports or inhibits the LPS-induced NF-κB activity and Glut1 expression, respectively. Therefore, H2S may influence metabolic programming in immune cells to alter glucose substrate availability that impacts the immune response.

DOI: https://doi.org/10.1371/journal.pone.0278910
Molecules. 2022 Dec 05. pii: 8552. [Epub ahead of print]27(23):

SnSe Nanosheets Mimic Lactate Dehydrogenase to Reverse Tumor Acid Microenvironment Metabolism for Enhancement of Tumor Therapy.

Heng Wang, Beilei Wang, Jie Jiang, Yi Wu, Anning Song, Xiaoyu Wang, Chenlu Yao, Huaxing Dai, Jialu Xu, Yue Zhang, Qingle Ma, Fang Xu, Ruibin Li, Chao Wang.

  The acidic tumor microenvironment (TME) is unfriendly to the activity and function of immune cells in the TME. Here, we report inorganic nanozymes (i.e., SnSe NSs) that mimic the catalytic activity of lactate dehydrogenase to degrade lactate to pyruvate, contributing to the metabolic treatment of tumors. As found in this study, SnSe NSs successfully decreased lactate levels in cells and tumors, as well as reduced tumor acidity. This is associated with activation of the immune response of T cells, thus alleviating the immunosuppressive environment of the TME. More importantly, the nanozyme successfully inhibited tumor growth in mutilate mouse tumor models. Thus, SnSe NSs show a promising result in lactate depletion and tumor suppression, which exemplifies its potential strategy in targeting lactate for metabolic therapy.

Keywords:  lactate; nanozyme; tumor acidity; tumor microenvironment

DOI:  https://doi.org/10.3390/molecules27238552
J Autoimmun. 2022 Dec 10. pii: S0896-8411(22)00182-2. [Epub ahead of print]134 102974

Altered lipid metabolism in synovial fibroblasts of individuals at risk of developing rheumatoid arthritis.

T A de Jong, J F Semmelink, S W Denis, M G H van de Sande, R H L Houtkooper, L G M van Baarsen.

   OBJECTIVE: Fibroblast-like synoviocytes (FLS) can augment the inflammatory process observed in synovium of patients with rheumatoid arthritis (RA). A recent transcriptomic study in synovial biopsies revealed changes in metabolic pathways before disease onset in absence of synovial tissue inflammation. This raises the question whether alterations in cellular metabolism in tissue resident FLS underlie disease pathogenesis.
MATERIALS AND METHODS: To study this, we compared the metabolic profile of FLS isolated from synovial biopsies from individuals with arthralgia who were autoantibody positive but without any evidence of arthritis (RA-risk individuals, n = 6) with FLS from patients with RA (n = 6), osteoarthritis (OA, n = 6) and seronegative controls (n = 6). After synovial digestion, FLS were cultured in vitro and cellular metabolism was assessed using quantitative PCR, flow cytometry, XFe96 Seahorse Analyzer and tritium-labelled oleate oxidation assays.
RESULTS: Real-time metabolic profiling revealed that basal (p < 0.0001) and maximum mitochondrial respiration (p = 0.0024) were significantly lower in RA FLS compared with control FLS. In all donors, basal respiration was largely dependent on fatty acid oxidation while glucose was only highly used by FLS from RA patients. Moreover, we showed that RA-risk and RA FLS are less metabolically flexible. Strikingly, mitochondrial fatty acid β-oxidation was significantly impaired in RA-risk (p = 0.001) and RA FLS (p < 0.0001) compared with control FLS.
CONCLUSION: Overall, this study showed several metabolic alterations in FLS even in absence of synovial inflammation, suggesting that these alterations already start before clinical manifestation of disease and may drive disease pathogenesis.

Keywords:  Fibroblast-like synoviocytes (FLS); Metabolic alteration; RA-Risk individuals; Rheumatoid arthritis (RA); β-Oxidation

DOI:  https://doi.org/10.1016/j.jaut.2022.102974
Redox Biol. 2022 Dec 08. pii: S2213-2317(22)00343-3. [Epub ahead of print]59 102571

Loss of selenoprotein W in murine macrophages alters the hierarchy of selenoprotein expression, redox tone, and mitochondrial functions during inflammation.

Sougat Misra, Tai-Jung Lee, Aswathy Sebastian, John McGuigan, Chang Liao, Imhoi Koo, Andrew D Patterson, Randall M Rossi, Molly A Hall, Istvan Albert, K Sandeep Prabhu.

  Macrophages play a pivotal role in mediating inflammation and subsequent resolution of inflammation. The availability of selenium as a micronutrient and the subsequent biosynthesis of selenoproteins, containing the 21st amino acid selenocysteine (Sec), are important for the physiological functions of macrophages. Selenoproteins regulate the redox tone in macrophages during inflammation, the early onset of which involves oxidative burst of reactive oxygen and nitrogen species. SELENOW is a highly expressed selenoprotein in bone marrow-derived macrophages (BMDMs). Beyond its described general role as a thiol and peroxide reductase and as an interacting partner for 14-3-3 proteins, its cellular functions, particularly in macrophages, remain largely unknown. In this study, we utilized Selenow knock-out (KO) murine bone marrow-derived macrophages (BMDMs) to address the role of SELENOW in inflammation following stimulation with bacterial endotoxin lipopolysaccharide (LPS). RNAseq-based temporal analyses of expression of selenoproteins and the Sec incorporation machinery genes suggested no major differences in the selenium utilization pathway in the Selenow KO BMDMs compared to their wild-type counterparts. However, selective enrichment of oxidative stress-related selenoproteins and increased ROS in Selenow-/- BMDMs indicated anomalies in redox homeostasis associated with hierarchical expression of selenoproteins. Selenow-/- BMDMs also exhibited reduced expression of arginase-1, a key enzyme associated with anti-inflammatory (M2) phenotype necessary to resolve inflammation, along with a significant decrease in efferocytosis of neutrophils that triggers pathways of resolution. Parallel targeted metabolomics analysis also confirmed an impairment in arginine metabolism in Selenow-/- BMDMs. Furthermore, Selenow-/- BMDMs lacked the ability to enhance characteristic glycolytic metabolism during inflammation. Instead, these macrophages atypically relied on oxidative phosphorylation for energy production when glucose was used as an energy source. These findings suggest that SELENOW expression in macrophages may have important implications on cellular redox processes and bioenergetics during inflammation and its resolution.

Keywords:  Arginase; Energy metabolism; Glycolysis; Krebs cycle; Metabolism; Mitochondrial respiration; Reactive oxygen species; Resolution; Sik2

DOI:  https://doi.org/10.1016/j.redox.2022.102571
Arthritis Res Ther. 2022 12 12. 24(1): 266

Augmented PFKFB3-mediated glycolysis by interferon-γ promotes inflammatory M1 polarization through the JAK2/STAT1 pathway in local vascular inflammation in Takayasu arteritis.

Rongyi Chen, Jinghua Wang, Xiaojuan Dai, Sifan Wu, Qingrong Huang, Lindi Jiang, Xiufang Kong.

   BACKGROUND: Takayasu arteritis (TAK) is characterized by pro-inflammatory M1 macrophage infiltration and increased interferon (IFN)-γ expression in vascular lesions. IFN-γ is a key cytokine involved in M1 polarization. Macrophage polarization is accompanied by metabolic changes. However, the metabolic regulation mechanism of IFN-γ in M1 macrophage polarization in TAK remains unclear.
METHODS: Immunohistochemistry and immunofluorescence were employed to observe the expression of IFN-γ, PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, the rate-limiting enzyme in glycolysis), and macrophage surface markers in the vascular tissue. Monocyte-derived macrophages from patients with TAK were cultured to examine the role of PFKFB3 in IFN-γ-induced M1 macrophage polarization. Seahorse analysis was used to detect the alterations in glucose metabolism during this process. Quantitative reverse transcription PCR, flow cytometry, and western blot were used to confirm the phenotypes of macrophages and related signaling pathways.
RESULTS: In the vascular adventitia of patients with TAK, an increase in PFKFB3 accompanied by IFN-γ expression was observed in M1 macrophages. In vitro, IFN-γ successfully induced macrophage differentiation into the M1 phenotype, which was manifested as an increase in CD80 and HLA-DR markers and the pro-inflammatory cytokines IL-6 and TNF-α. During this process, PFKFB3 expression and glycolysis levels were significantly increased. However, glycolysis and M1 polarization induced by IFN-γ were suppressed by a PFKFB3 inhibitor. In addition, JAK2/STAT1 phosphorylation was also enhanced in macrophages stimulated by IFN-γ. The effects of IFN-γ on macrophages, including the expression of PFKFB3, glycolysis, and M1 polarization, were also inhibited by the JAK inhibitor tofacitinib or STAT1 inhibitor fludarabine.
CONCLUSION: PFKFB3-mediated glycolysis promotes IFN-γ-induced M1 polarization through the JAK2/STAT1 signaling pathway, indicating that PFKFB3 plays an important role in M1 polarization mediated by IFN-γ; thus, PFKFB3 is a potential intervention target in TAK.

Keywords:  Glucose metabolism; Inflammation; Interferon-γ; Macrophage; Takayasu arteritis

DOI:  https://doi.org/10.1186/s13075-022-02960-1
Redox Biol. 2022 Dec 01. pii: S2213-2317(22)00331-7. [Epub ahead of print]59 102559

RAGE promotes dysregulation of iron and lipid metabolism in alcoholic liver disease.

Yunjia Li, Mengchen Qin, Weichao Zhong, Chang Liu, Guanghui Deng, Menghan Yang, Junjie Li, Haixin Ye, Hao Shi, Chaofeng Wu, Haiyan Lin, Yuyao Chen, Shaohui Huang, Chuying Zhou, Zhiping Lv, Lei Gao.

  Alcoholic liver disease (ALD) is associated with hepatic inflammatory activation and iron overload. The receptor for advanced glycation end products (RAGE) is an important metabolic mediator during the development of ALD. The aim of this study was to determine the effect of RAGE on iron homeostasis in ALD. We found increased circulating transferrin, hepcidin and ferritin in ALD patients and positively correlated with RAGE level. RAGE knockout (RAGE-/-) and wild-type mice were subjected to chronic alcoholic feeding for 6 weeks to induce ALD, and RAGE inhibitor, iron chelator or lipid peroxidation inhibitor were administered. We showed that chronic alcohol administration triggered hepatic steatosis, inflammation, and oxidative stress, which were eliminated by deficiency or inhibition of RAGE. Surprisingly, pathways of hepatic iron metabolism were significantly altered, including increased iron uptake (Tf/TfR) and storage (Ferritin), as well as decreased iron export (FPN1/Hepcidin). In vitro experiments confirmed that RAGE had different effects on the mechanism of iron metabolism of hepatocytes and macrophages respectively. In conclusion, our data revealed preclinical evidence for RAGE inhibition as an effective intervention for alleviating alcohol-induced liver injury.

Keywords:  Inflammation; Iron metabolism; Lipid peroxidation; Macrophages; Oxidative stress; RAGE

DOI:  https://doi.org/10.1016/j.redox.2022.102559
Cardiovasc Res. 2022 Dec 13. pii: cvac184. [Epub ahead of print]

GLUT-1/PKM2 loop dysregulation in patients with non-ST-segment elevation myocardial infarction promotes metainflammation.

Francesco Canonico, Daniela Pedicino, Anna Severino, Ramona Vinci, Davide Flego, Eugenia Pisano, Alessia d'Aiello, Pellegrino Ciampi, Myriana Ponzo, Alice Bonanni, Astrid De Ciutiis, Sara Russo, Marianna Di Sario, Giulia Angelini, Piotr Szczepaniak, Alfonso Baldi, Boguslaw Kapelak, Karol Wierzbicki, Rocco A Montone, Domenico D'Amario, Massimo Massetti, Tomasz J Guzik, Filippo Crea, Giovanna Liuzzo.

   AIM: The functional capacity of the immune cells is strongly dependent on their metabolic state and inflammatory responses are characterized by a greater use of glucose in immune cells. This study is aimed to establish the role of glucose metabolism and its players [glucose transporter-1 (GLUT-1) and pyruvate kinase isozyme M2 (PKM2)] in the dysregulation of adaptive immunity and inflammation observed in patients with non-ST-segment elevation myocardial infarction (NSTEMI).
METHODS AND RESULTS: We enrolled 248 patients allocated to three groups: NSTEMI patients, chronic coronary syndromes (CCS) patients, healthy subjects (HS). NSTEMI patients showed higher expression of GLUT-1 and an enhanced glucose uptake in T cells as compared to CCS patients (p < 0.0001; p = 0.0101, respectively) and HS (p = 0.0071; p = 0.0122, respectively). PKM2 had a prevalent nuclear localization in T lymphocytes in NSTEMI (p = 0.0005 for nuclear versus cytoplasm localization), while in CCS and HS was equally distributed in both compartments. In addition, the nuclear fraction of PKM2 was significantly higher in NSTEMI compared to HS (p = 0.0023). In NSTEMI patients, treatment with Shikonin and Fasentin, which inhibits PKM2 enzyme activity and GLUT-1 mediated glucose internalization, respectively, led to a significant reduction in GLUT-1 expression along with the downregulation of pro-inflammatory cytokine expression.
CONCLUSIONS: NSTEMI patients exhibit dysregulation of the GLUT-1/PKM2 metabolic loop characterized by nuclear translocation of PKM2, where it acts as a transcription regulator of pro-inflammatory genes. This detrimental loop might represent a new therapeutic target for personalized medicine.

Keywords:  Acute Coronary Syndromes; Adaptive immunity; GLUT-1; Immuno-metabolism; Metainflammation; PKM2; Precision Medicine

DOI:  https://doi.org/10.1093/cvr/cvac184
Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01677-1. [Epub ahead of print]41(11): 111789

The mitochondrial UPR regulator ATF5 promotes intestinal barrier function via control of the satiety response.

Douja Chamseddine, Siraje A Mahmud, Aundrea K Westfall, Todd A Castoe, Rance E Berg, Mark W Pellegrino.

  Organisms use several strategies to mitigate mitochondrial stress, including the activation of the mitochondrial unfolded protein response (UPRmt). The UPRmt in Caenorhabditis elegans, regulated by the transcription factor ATFS-1, expands on this recovery program by inducing an antimicrobial response against pathogens that target mitochondrial function. Here, we show that the mammalian ortholog of ATFS-1, ATF5, protects the host during infection with enteric pathogens but, unexpectedly, by maintaining the integrity of the intestinal barrier. Intriguingly, ATF5 supports intestinal barrier function by promoting a satiety response that prevents obesity and associated hyperglycemia. This consequently averts dysregulated glucose metabolism that is detrimental to barrier function. Mechanistically, we show that intestinal ATF5 stimulates the satiety response by transcriptionally regulating the gastrointestinal peptide hormone cholecystokinin, which promotes the secretion of the hormone leptin. We propose that ATF5 protects the host from enteric pathogens by promoting intestinal barrier function through a satiety-response-mediated metabolic control mechanism.

Keywords:  ATF5; CP: Metabolism; CP: Molecular biology; UPR(mt); cholecystokinin; colitis; epithelial barrier; host-pathogen interaction; hyperglycemia; leptin; mitochondria; satiety

DOI:  https://doi.org/10.1016/j.celrep.2022.111789
Immunity. 2022 Dec 09. pii: S1074-7613(22)00603-3. [Epub ahead of print]

Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development.

Xiaochen Wang, Qifeng He, Chuanli Zhou, Yueyuan Xu, Danhui Liu, Naoto Fujiwara, Naoto Kubota, Arielle Click, Polly Henderson, Janiece Vancil, Cesia Ammi Marquez, Ganesh Gunasekaran, Myron E Schwartz, Parissa Tabrizian, Umut Sarpel, Maria Isabel Fiel, Yarui Diao, Beicheng Sun, Yujin Hoshida, Shuang Liang, Zhenyu Zhong.

  Obesity-induced chronic liver inflammation is a hallmark of nonalcoholic steatohepatitis (NASH)-an aggressive form of nonalcoholic fatty liver disease. However, it remains unclear how such a low-grade, yet persistent, inflammation is sustained in the liver. Here, we show that the macrophage phagocytic receptor TREM2, induced by hepatocyte-derived sphingosine-1-phosphate, was required for efferocytosis of lipid-laden apoptotic hepatocytes and thereby maintained liver immune homeostasis. However, prolonged hypernutrition led to the production of proinflammatory cytokines TNF and IL-1β in the liver to induce TREM2 shedding through ADAM17-dependent proteolytic cleavage. Loss of TREM2 resulted in aberrant accumulation of dying hepatocytes, thereby further augmenting proinflammatory cytokine production. This ultimately precipitated a vicious cycle that licensed chronic inflammation to drive simple steatosis transition to NASH. Therefore, impaired macrophage efferocytosis is a previously unrecognized key pathogenic event that enables chronic liver inflammation in obesity. Blocking TREM2 cleavage to restore efferocytosis may represent an effective strategy to treat NASH.

Keywords:  TREM2; chronic inflammation; efferocytosis; nonalcoholic steatohepatitis; proinflammatory cytokines

DOI:  https://doi.org/10.1016/j.immuni.2022.11.013
iScience. 2023 Jan 20. 26(1): 105717

A multi-omics based anti-inflammatory immune signature characterizes long COVID-19 syndrome.

Johannes J Kovarik, Andrea Bileck, Gerhard Hagn, Samuel M Meier-Menches, Tobias Frey, Anna Kaempf, Marlene Hollenstein, Tarik Shoumariyeh, Lukas Skos, Birgit Reiter, Marlene C Gerner, Andreas Spannbauer, Ena Hasimbegovic, Doreen Schmidl, Gerhard Garhöfer, Mariann Gyöngyösi, Klaus G Schmetterer, Christopher Gerner.

  To investigate long COVID-19 syndrome (LCS) pathophysiology, we performed an exploratory study with blood plasma derived from three groups: 1) healthy vaccinated individuals without SARS-CoV-2 exposure; 2) asymptomatic recovered patients at least three months after SARS-CoV-2 infection and; 3) symptomatic patients at least 3 months after SARS-CoV-2 infection with chronic fatigue syndrome or similar symptoms, here designated as patients with long COVID-19 syndrome (LCS). Multiplex cytokine profiling indicated slightly elevated pro-inflammatory cytokine levels in recovered individuals in contrast to patients with LCS. Plasma proteomics demonstrated low levels of acute phase proteins and macrophage-derived secreted proteins in LCS. High levels of anti-inflammatory oxylipins including omega-3 fatty acids in LCS were detected by eicosadomics, whereas targeted metabolic profiling indicated high levels of anti-inflammatory osmolytes taurine and hypaphorine, but low amino acid and triglyceride levels and deregulated acylcarnitines. A model considering alternatively polarized macrophages as a major contributor to these molecular alterations is presented.

Keywords:  Immunology; immune response; omics

DOI:  https://doi.org/10.1016/j.isci.2022.105717
Sci Rep. 2022 Dec 12. 12(1): 21483

Paraoxonase-2 contributes to promoting lipid metabolism and mitochondrial function via autophagy activation.

Gu-Choul Shin, Hyeong Min Lee, Nayeon Kim, Sang-Ku Yoo, Hyung Soon Park, Leo Sungwong Choi, Kwang Pyo Kim, Ah-Ra Lee, Sang-Uk Seo, Kyun-Hwan Kim.

Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent immuno-metabolic disease that can progress to hepatic cirrhosis and cancer. NAFLD pathogenesis is extremely complex and is characterized by oxidative stress, impaired mitochondrial function and lipid metabolism, and cellular inflammation. Thus, in-depth research on its underlying mechanisms and subsequent investigation into a potential drug target that has overarching effects on these features will help in the discovery of effective treatments for NAFLD. Our study examines the role of endogenous paraoxonase-2 (PON2), a membrane protein with reported antioxidant activity, in an in vitro cell model of NAFLD. We found that the hepatic loss of PON2 activity aggravated steatosis and oxidative stress under lipotoxic conditions, and our transcriptome analysis revealed that the loss of PON2 disrupts the activation of numerous functional pathways closely related to NAFLD pathogenesis, including mitochondrial respiratory capacity, lipid metabolism, and hepatic fibrosis and inflammation. We found that PON2 promoted the activation of the autophagy pathway, specifically the mitophagy cargo sequestration, which could potentially aid PON2 in alleviating oxidative stress, mitochondrial dysfunction, lipid accumulation, and inflammation. These results provide a mechanistic foundation for the prospect of PON2 as a drug target, leading to the development of novel therapeutics for NAFLD.

DOI: https://doi.org/10.1038/s41598-022-25802-1
Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01697-7. [Epub ahead of print]41(11): 111809

Stable isotope tracing in vivo reveals a metabolic bridge linking the microbiota to host histone acetylation.

Peder J Lund, Leah A Gates, Marylene Leboeuf, Sarah A Smith, Lillian Chau, Mariana Lopes, Elliot S Friedman, Yedidya Saiman, Min Soo Kim, Clarissa A Shoffler, Christopher Petucci, C David Allis, Gary D Wu, Benjamin A Garcia.

  The gut microbiota influences acetylation on host histones by fermenting dietary fiber into butyrate. Although butyrate could promote histone acetylation by inhibiting histone deacetylases, it may also undergo oxidation to acetyl-coenzyme A (CoA), a necessary cofactor for histone acetyltransferases. Here, we find that epithelial cells from germ-free mice harbor a loss of histone H4 acetylation across the genome except at promoter regions. Using stable isotope tracing in vivo with 13C-labeled fiber, we demonstrate that the microbiota supplies carbon for histone acetylation. Subsequent metabolomic profiling revealed hundreds of labeled molecules and supported a microbial contribution to host fatty acid metabolism, which declined in response to colitis and correlated with reduced expression of genes involved in fatty acid oxidation. These results illuminate the flow of carbon from the diet to the host via the microbiota, disruptions to which may affect energy homeostasis in the distal gut and contribute to the development of colitis.

Keywords:  CP: Microbiology; colitis; epigenetics; fatty acid metabolism; histone acetylation; host-microbiota interactions

DOI:  https://doi.org/10.1016/j.celrep.2022.111809
Life Sci. 2022 Dec 13. pii: S0024-3205(22)00971-7. [Epub ahead of print] 121271

Modulation of mitochondria by viral proteins.

Reshu Saxena, Priyanka Sharma, Sandeep Kumar, Niteshkumar Agrawal, Sumit Kumar Sharma, Amit Awasthi.

  Mitochondria are dynamic cellular organelles with diverse functions including energy production, calcium homeostasis, apoptosis, host innate immune signaling, and disease progression. Several viral proteins specifically target mitochondria to subvert host defense as mitochondria stand out as the most suitable target for the invading viruses. They have acquired the capability to control apoptosis, metabolic state, and evade immune responses in host cells, by targeting mitochondria. In this way, the viruses successfully allow the spread of viral progeny and thus the infection. Viruses employ their proteins to alter mitochondrial dynamics and their specific functions by a modulation of membrane potential, reactive oxygen species, calcium homeostasis, and mitochondrial bioenergetics to help them achieve a state of persistent infection. A better understanding of such viral proteins and their impact on mitochondrial forms and functions is the main focus of this review. We also attempt to emphasize the importance of exploring the role of mitochondria in the context of SARS-CoV2 pathogenesis and identify host-virus protein interactions.

Keywords:  Mitochondria; SARS-CoV2; Viral proteins; Viruses

DOI:  https://doi.org/10.1016/j.lfs.2022.121271
Fish Shellfish Immunol. 2022 Dec 12. pii: S1050-4648(22)00825-7. [Epub ahead of print]132 108485

Tryptophan metabolism can modulate immunologic tolerance in primitive vertebrate lamprey via IDO-kynurenine-AHR pathway.

Xuyuan Duan, Yimu Luan, Yaocen Wang, Xiuli Wang, Peng Su, Qingwei Li, Yue Pang, Jingyi He, Meng Gou.

  Tryptophan is mainly degraded through kynurenine pathway (KP) in vertebrates which is closely related to the nerve and depression, while the studies on immunity is still limited. This study aims to explore the functions of tryptophan in the innate immunity of primitive vertebrate lamprey. MTT (3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide) assay showed that tryptophan had no obvious effect on cell viability. Tryptophan was transported into leukocytes and degraded via the KP after tryptophan supplement. Tryptophan treatment (T1x and T2x) failed to alter the total antioxidant capacity regardless of stimulation and exposure time. Real-time quantitative PCR and western blotting results revealed that tryptophan was not only able to reduce the expression of pro-inflammatory factors Lj-TNF-α, Lj-IL1β and Lj-NF-κB, but also to upregulate the expression of anti-inflammatory factor Lj-TGF-β independent of stimulation and time. In addition, tryptophan can exert immune tolerance function by inhibiting TLR-MyD88 and promoting (Indoleamine 2, 3-Dioxygenase) IDO-kynurenine-AHR (aryl hydrocarbon receptor) pathways. This study provides a new understanding for tryptophan-kynurenine metabolism and mechanism of immune tolerance function in primitive vertebrate lamprey.

Keywords:  Immunosuppression; Innate immunity; Lampetra japonicum; Tryptophan; Tryptophan-kynurenine pathway

DOI:  https://doi.org/10.1016/j.fsi.2022.108485
J Clin Invest. 2022 Dec 15. pii: e165907. [Epub ahead of print]132(24):

The rise of viperin: the emerging role of viperin in cancer progression.

Alyssa G Weinstein, Inês Godet, Daniele M Gilkes.

Viperin, an IFN-regulated gene product, is known to inhibit fatty acid β-oxidation in the mitochondria, which enhances glycolysis and lipogenesis during viral infections. Yet, its role in altering the phenotype of cancer cells has not been established. In this issue of the JCI, Choi, Kim, and co-authors report on a role of viperin in regulating metabolic alterations in cancer cells. The authors showed a correlation between clinical outcomes and viperin expression levels in multiple cancer tissues and proposed that viperin expression was upregulated in the tumor microenvironment via the JAK/STAT and PI3K/AKT/mTOR/HIF-1α pathways. Functionally, viperin increased lipogenesis and glycolysis in cancer cells by inhibiting fatty acid β-oxidation. Viperin expression also enhanced cancer stem cell properties, ultimately promoting tumor initiation in murine models. This study proposes a protumorigenic role for viperin and identifies HIF-1α as a transcription factor that increases viperin expression under serum starvation and hypoxia.

DOI: https://doi.org/10.1172/JCI165907
Infect Immun. 2022 Dec 14. e0025222

Butyrate Ameliorates Intraocular Bacterial Infection by Promoting Autophagy and Attenuating the Inflammatory Response.

Sukhvinder Singh, Pawan Kumar Singh, Ashok Kumar.

  Despite an important link between the gut and ocular health, the role of the gut-eye axis remains elusive in ocular infections. In this study, we investigated the role of butyrate, a gut microbial metabolite, in the pathobiology of intraocular bacterial (Staphylococcus aureus) infection, endophthalmitis. We found that intravitreal administration of butyrate derivatives, sodium butyrate (NaB), or phenylbutyrate (PBA) reduced intraocular bacterial growth and retinal inflammatory response. The ocular tissue architecture and retinal function were preserved in butyrate-treated eyes. In cultured mouse bone marrow-derived macrophages (BMDMs) and human retinal Müller glia, NaB or PBA treatment reduced S. aureus-induced inflammatory response by inhibiting NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. However, in vivo data showed NLRP3-independent effects of butyrate. The butyrate-treated mouse retina and cells exhibited induced expression of antimicrobial molecules CRAMP (LL37) and S100A7/A8, resulting in increased bacterial phagocytosis and killing. Moreover, butyrate treatment enhanced AMP-activated protein kinase (AMPK)-dependent autophagy and promoted the co-localization of CRAMP in autophagosomes, indicating autophagy-mediated bacterial killing. Furthermore, pharmacological inhibition of autophagy in mice revealed its role in butyrate-mediated protection. Finally, butyrate exhibited synergy with antibiotic in promoting endophthalmitis resolution. Collectively, our study demonstrated the protective mechanisms of butyrate in ameliorating bacterial endophthalmitis. Therefore, butyrate derivatives could be explored as immunomodulatory and anti-bacterial therapeutics to improve visual outcomes in ocular bacterial infections.

Keywords:  AMPK; Staphylococcus aureus; autophagy; butyrate; endophthalmitis; eye; inflammation; innate immunity; retina

DOI:  https://doi.org/10.1128/iai.00252-22
Microbiome. 2022 Dec 12. 10(1): 222

Integrated multi-omics of the gastrointestinal microbiome and ruminant host reveals metabolic adaptation underlying early life development.

Xiaoting Yan, Huazhe Si, Yuhang Zhu, Songze Li, Yu Han, Hanlu Liu, Rui Du, Phillip B Pope, Qiang Qiu, Zhipeng Li.

   BACKGROUND: The gastrointestinal tract (GIT) microbiome of ruminants and its metabolic repercussions vastly influence host metabolism and growth. However, a complete understanding of the bidirectional interactions that occur across the host-microbiome axis remains elusive, particularly during the critical development stages at early life. Here, we present an integrative multi-omics approach that simultaneously resolved the taxonomic and functional attributes of microbiota from five GIT regions as well as the metabolic features of the liver, muscle, urine, and serum in sika deer (Cervus nippon) across three key early life stages.
RESULTS: Within the host, analysis of metabolites over time in serum, urine, and muscle (longissimus lumborum) showed that changes in the fatty acid profile were concurrent with gains in body weight. Additional host transcriptomic and metabolomic analysis revealed that fatty acid β-oxidation and metabolism of tryptophan and branched chain amino acids play important roles in regulating hepatic metabolism. Across the varying regions of the GIT, we demonstrated that a complex and variable community of bacteria, viruses, and archaea colonized the GIT soon after birth, whereas microbial succession was driven by the cooperative networks of hub populations. Furthermore, GIT volatile fatty acid concentrations were marked by increased microbial metabolic pathway abundances linked to mannose (rumen) and amino acids (colon) metabolism. Significant functional shifts were also revealed across varying GIT tissues, which were dominated by host fatty acid metabolism associated with reactive oxygen species in the rumen epithelium, and the intensive immune response in both small and large intestine. Finally, we reveal a possible contributing role of necroptosis and apoptosis in enhancing ileum and colon epithelium development, respectively.
CONCLUSIONS: Our findings provide a comprehensive view for the involved mechanisms in the context of GIT microbiome and ruminant metabolic growth at early life. Video Abstract.

Keywords:  Butyrate; Cooperation; Early life; Fatty acid metabolism; Immune response; Ontogeny; Region- and stage-specific development

DOI:  https://doi.org/10.1186/s40168-022-01396-8