bims-imicid 2024-07-21 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–07–21
seventeen papers selected by
Dylan Ryan, University of Cambridge

Metabolic reprogramming and dysregulated IL-17 production impairs CD4 T cell function post sepsis.
Mitochondrial Fatty Acid Synthesis and Mecr Regulate CD4+ T Cell Function and Oxidative Metabolism.
Fatty acid oxidation in immune function.
Therapeutic targeting of immunometabolism reveals a critical reliance on hexokinase 2 dosage for microglial activation and Alzheimer's progression.
MicroRNA-mediated metabolic regulation of immune cells in cancer: an updated review.
Gut commensal metabolite rhamnose promotes macrophages phagocytosis by activating SLC12A4 and protects against sepsis in mice.
Fatty acid synthesis promotes inflammasome activation through NLRP3 palmitoylation.
Mitochondrial perturbations in low-protein-diet-fed mice are associated with altered neutrophil development and effector functions.
Bruton's tyrosine kinase (BTK) inhibitors alter blood glucose and insulin in obese mice but reduce inflammation independent of BTK.
Antibiotic-driven dysbiosis in early life disrupts indole-3-propionic acid production and exacerbates allergic airway inflammation in adulthood.
Sphinganine recruits TLR4 adaptors in macrophages and promotes inflammation in murine models of sepsis and melanoma.
Sphingosine 1-phosphate combining with S1PR4 promotes regulatory T cell differentiation related to FAO through Nrf2/PPARα.
Dietary Fiber-Derived Microbial Butyrate Suppresses ILC2-Dependent Airway Inflammation in COPD.
Alterations in tryptophan metabolism and de novo NAD+ biosynthesis within the microbiota-gut-brain axis in chronic intestinal inflammation.
Mitochondrial perturbation in the intestine causes microbiota-dependent injury and gene signatures discriminative of inflammatory disease.
Metabolic insights into HIV/TB co-infection: an untargeted urinary metabolomics approach.
Mice live longer when inflammation-boosting protein is blocked.

iScience. 2024 Jul 19. 27(7): 110114

Metabolic reprogramming and dysregulated IL-17 production impairs CD4 T cell function post sepsis.

Patricia A Assis, Ronald M Allen, Matthew A Schaller, Steven L Kunkel, Jennifer R Bermick.

  Sepsis survivors are at high risk for infection-related rehospitalization and mortality for years following the resolution of the acute septic event. These infection-causing microorganisms generally do not cause disease in immunocompetent hosts, suggesting that the post-septic immune response is compromised. Given the importance of CD4 T cells in the development of long-lasting protective immunity, we analyzed their post-septic function. Here we showed that sepsis induced chronic increased and non-specific production of IL-17 by CD4 T cells, resulting in the inability to mount an effective immune response to a secondary pneumonia challenge. Altered cell function was associated with metabolic reprogramming, characterized by mitochondrial dysfunction and increased glycolysis. This metabolic reprogramming began during the acute septic event and persisted long after sepsis had resolved. Our findings reveal cell metabolism as a potential therapeutic target. Given the critical role of cell metabolism in the physiological and pathophysiological processes of immune cells, these findings reveal a potential new therapeutic target to help mitigate sepsis survivors' susceptibility to secondary infections.

Keywords:  Components of the immune system; Immunology; Molecular biology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2024.110114
bioRxiv. 2024 Jul 11. pii: 2024.07.08.602554. [Epub ahead of print]

Mitochondrial Fatty Acid Synthesis and Mecr Regulate CD4+ T Cell Function and Oxidative Metabolism.

KayLee K Steiner, Arissa C Young, Andrew R Patterson, Erin Q Jennings, Channing Chi, Zaid Hatem, Darren Heintzman, Ayaka Sugiura, Emily N Arner, Allison E Sewell, Matthew Z Madden, Richmond Okparaugo, Emilia V Fallman, Katherine Gibson-Corley, Kelsey Voss, Denis Mogilenko, Jeffrey Rathmell.

Lipid metabolism is fundamental to CD4+ T cell metabolism yet remains poorly understood across subsets. Therefore, we performed targeted in vivo CRISPR/Cas9 screens to identify lipid-associated genes essential for T cell subset functions. These screens established mitochondrial fatty acid synthesis (mtFAS) genes Mecr, Mcat and Oxsm as highly impactful. Of these, the inborn error of metabolism gene Mecr was most dynamically regulated. Effector and memory T cells were reduced in Mecrfl/fl; Cd4cre mice, and MECR was required for activated CD4+ T cells to efficiently proliferate, differentiate, and survive. Mecr-deficient T cells also had decreased mitochondrial respiration, reduced TCA intermediates, and accumulated intracellular iron, which contributed to cell death and sensitivity to ferroptosis. Importantly, Mecr-deficient T cells exhibited fitness disadvantages in inflammatory, tumor, and infection models. mtFAS and MECR thus play important roles in activated T cells and may provide targets to modulate immune functions in inflammatory diseases. The immunological state of MECR- and mtFAS-deficient patients may also be compromised.

DOI: https://doi.org/10.1101/2024.07.08.602554
Front Immunol. 2024 ;15 1420336

Fatty acid oxidation in immune function.

Felicia Kemp, Erica L Braverman, Craig A Byersdorfer.

  Cellular metabolism is a crucial determinant of immune cell fate and function. Extensive studies have demonstrated that metabolic decisions influence immune cell activation, differentiation, and cellular capacity, in the process impacting an organism's ability to stave off infection or recover from injury. Conversely, metabolic dysregulation can contribute to the severity of multiple disease conditions including autoimmunity, alloimmunity, and cancer. Emerging data also demonstrate that metabolic cues and profiles can influence the success or failure of adoptive cellular therapies. Importantly, immunometabolism is not one size fits all; and different immune cell types, and even subdivisions within distinct cell populations utilize different metabolic pathways to optimize function. Metabolic preference can also change depending on the microenvironment in which cells are activated. For this reason, understanding the metabolic requirements of different subsets of immune cells is critical to therapeutically modulating different disease states or maximizing cellular function for downstream applications. Fatty acid oxidation (FAO), in particular, plays multiple roles in immune cells, providing both pro- and anti-inflammatory effects. Herein, we review the major metabolic pathways available to immune cells, then focus more closely on the role of FAO in different immune cell subsets. Understanding how and why FAO is utilized by different immune cells will allow for the design of optimal therapeutic interventions targeting this pathway.

Keywords:  adoptive cellular therapies; fatty acid oxidation (FAO); immune cell differentiation; immunometabolism; metabolic adaptation; metabolic dysregulation

DOI:  https://doi.org/10.3389/fimmu.2024.1420336
Cell Rep. 2024 Jul 11. pii: S2211-1247(24)00817-9. [Epub ahead of print]43(7): 114488

Therapeutic targeting of immunometabolism reveals a critical reliance on hexokinase 2 dosage for microglial activation and Alzheimer's progression.

Juan F Codocedo, Claudia Mera-Reina, Peter Bor-Chian Lin, Paul B Fallen, Shweta S Puntambekar, Brad T Casali, Nur Jury-Garfe, Pablo Martinez, Cristian A Lasagna-Reeves, Gary E Landreth.

  Neuroinflammation is a prominent feature of Alzheimer's disease (AD). Activated microglia undergo a reprogramming of cellular metabolism necessary to power their cellular activities during disease. Thus, selective targeting of microglial immunometabolism might be of therapeutic benefit for treating AD. In the AD brain, the levels of microglial hexokinase 2 (HK2), an enzyme that supports inflammatory responses by promoting glycolysis, are significantly increased. In addition, HK2 displays non-metabolic activities that extend its inflammatory role beyond glycolysis. The antagonism of HK2 affects microglial phenotypes and disease progression in a gene-dose-dependent manner. HK2 complete loss fails to improve pathology by exacerbating inflammation, while its haploinsufficiency reduces pathology in 5xFAD mice. We propose that the partial antagonism of HK2 is effective in slowing disease progression by modulating NF-κB signaling through its cytosolic target, IKBα. The complete loss of HK2 affects additional inflammatory mechanisms related to mitochondrial dysfunction.

Keywords:  Alzheimer’s disease; CP: Metabolism; CP: Neuroscience; NF-κB; amyloid; hexokinase 2; inflammation; lonidamine; microglia; mitochondria

DOI:  https://doi.org/10.1016/j.celrep.2024.114488
Front Immunol. 2024 ;15 1424909

MicroRNA-mediated metabolic regulation of immune cells in cancer: an updated review.

Sepideh Chowdary Khameneh, Sara Razi, Ramin Lashanizadegan, Sanaz Akbari, Masoud Sayaf, Karimeh Haghani, Salar Bakhtiyari.

  The study of immunometabolism, which examines how immune cells regulate their metabolism to maintain optimal performance, has become an important area of focus in cancer immunology. Recent advancements in this field have highlighted the intricate connection between metabolism and immune cell function, emphasizing the need for further research. MicroRNAs (miRNAs) have gained attention for their ability to post-transcriptionally regulate gene expression and impact various biological processes, including immune function and cancer progression. While the role of miRNAs in immunometabolism is still being explored, recent studies have demonstrated their significant influence on the metabolic activity of immune cells, such as macrophages, T cells, B cells, and dendritic cells, particularly in cancer contexts. Disrupted immune cell metabolism is a hallmark of cancer progression, and miRNAs have been linked to this process. Understanding the precise impact of miRNAs on immune cell metabolism in cancer is essential for the development of immunotherapeutic approaches. Targeting miRNAs may hold potential for creating groundbreaking cancer immunotherapies to reshape the tumor environment and improve treatment outcomes. In summary, the recognition of miRNAs as key regulators of immune cell metabolism across various cancers offers promising potential for refining cancer immunotherapies. Further investigation into how miRNAs affect immune cell metabolism could identify novel therapeutic targets and lead to the development of innovative cancer immunotherapies.

Keywords:  cancer; immune cells; immunotherapy; metabolic regulation; microRNAs (miRNAs)

DOI:  https://doi.org/10.3389/fimmu.2024.1424909
Acta Pharm Sin B. 2024 Jul;14(7): 3068-3085

Gut commensal metabolite rhamnose promotes macrophages phagocytosis by activating SLC12A4 and protects against sepsis in mice.

Dongping Li, Rongjuan Wei, Xianglong Zhang, Shenhai Gong, Meijuan Wan, Fangzhao Wang, Jiaxin Li, Meiling Chen, Ruofan Liu, Yantong Wan, Yinghao Hong, Zhenhua Zeng, Peng Gu, Zhang Wang, Kutty Selva Nandakumar, Yong Jiang, Hongwei Zhou, Peng Chen.

  Sepsis progression is significantly associated with the disruption of gut eubiosis. However, the modulatory mechanisms of gut microbiota operating during sepsis are still unclear. Herein, we investigated how gut commensals impact sepsis development in a pre-clinical model. Cecal ligation and puncture (CLP) surgery was used to establish polymicrobial sepsis in mice. Mice depleted of gut microbiota by an antibiotic cocktail (ABX) exhibited a significantly higher level of mortality than controls. As determined by metabolomics analysis, ABX treatment has depleted many metabolites, and subsequent supplementation with l-rhamnose (rhamnose, Rha), a bacterial carbohydrate metabolite, exerted profound immunomodulatory properties with a significant enhancement in macrophage phagocytosis, which in turn improved organ damage and mortality. Mechanistically, rhamnose binds directly to and activates the solute carrier family 12 (potassium-chloride symporter), member 4 (SLC12A4) in macrophages and promotes phagocytosis by activating the small G-proteins, Ras-related C3 botulinum toxin substrate1 (Rac1) and cell division control protein 42 homolog (Cdc42). Interestingly, rhamnose has enhanced the phagocytosis capacity of macrophages from sepsis patients. In conclusion, by identifying SLC12A4 as the host interacting protein, we disclosed that the gut commensal metabolite rhamnose is a functional molecular that could promote the phagocytosis capacity of macrophages and protect the host against sepsis.

Keywords:  GTP-Cdc42; GTP-Rac1; Gut microbiota; Macrophage; Phagocytosis; Rhamnose; SLC12A4; Sepsis

DOI:  https://doi.org/10.1016/j.apsb.2024.03.025
Cell Rep. 2024 Jul 17. pii: S2211-1247(24)00845-3. [Epub ahead of print]43(8): 114516

Fatty acid synthesis promotes inflammasome activation through NLRP3 palmitoylation.

Stuart Leishman, Najd M Aljadeed, Liyunhe Qian, Shamshad Cockcroft, Jacques Behmoaras, Paras K Anand.

  Despite its significance, the role of lipid metabolism in NLRP3 inflammasome remains elusive. Here, we reveal a critical role for fatty acid synthase (FASN) in NLRP3 inflammasome activation. We demonstrate that pharmacological or genetic depletion of FASN dampens NLRP3 activation in primary mouse and human macrophages and in mice. This disruption in NLRP3 activation is contingent upon FASN activity. Accordingly, abolishing cellular palmitoylation, a post-translational modification in which the FASN product palmitate is reversibly conjugated to cysteine residues of target proteins, blunts inflammasome signaling. Correspondingly, an acyl-biotin exchange assay corroborated NLRP3 palmitoylation. Mechanistically, Toll-like receptor (TLR) ligation introduces palmitoylation at NLRP3 Cys898, permitting NLRP3 translocation to dispersed trans-Golgi network (dTGN) vesicles, the site of inflammasome assembly, upon NLRP3 activation. Accordingly, the NLRP3 Cys898 mutant exhibits reduced palmitoylation, limited translocation to the dTGN compartment, and diminished inflammasome activation. These results underscore mechanistic insights through which lipid metabolism licenses NLRP3 inflammasome assembly and activation.

Keywords:  CP: Immunology; CP: Metabolism; FASN; NLRP3; SREBP1; immunometabolism; inflammasome; lipid biosynthesis; lipid metabolism; palmitoylation; pyroptosis; trans Golgi network

DOI:  https://doi.org/10.1016/j.celrep.2024.114516
Cell Rep. 2024 Jul 18. pii: S2211-1247(24)00822-2. [Epub ahead of print]43(8): 114493

Mitochondrial perturbations in low-protein-diet-fed mice are associated with altered neutrophil development and effector functions.

Mehakpreet K Thind, Emiliano Miraglia, Catriona Ling, Meraj A Khan, Aida Glembocki, Celine Bourdon, YueYing ChenMi, Nades Palaniyar, Michael Glogauer, Robert H J Bandsma, Amber Farooqui.

  Severe malnutrition is associated with infections, namely lower respiratory tract infections (LRTIs), diarrhea, and sepsis, and underlies the high risk of morbidity and mortality in children under 5 years of age. Dysregulations in neutrophil responses in the acute phase of infection are speculated to underlie these severe adverse outcomes; however, very little is known about their biology in this context. Here, in a lipopolysaccharide-challenged low-protein diet (LPD) mouse model, as a model of malnutrition, we show that protein deficiency disrupts neutrophil mitochondrial dynamics and ATP generation to obstruct the neutrophil differentiation cascade. This promotes the accumulation of atypical immature neutrophils that are incapable of optimal antimicrobial response and, in turn, exacerbate systemic pathogen spread and the permeability of the alveolocapillary membrane with the resultant lung damage. Thus, this perturbed response may contribute to higher mortality risk in malnutrition. We also offer a nutritional therapeutic strategy, nicotinamide, to boost neutrophil-mediated immunity in LPD-fed mice.

Keywords:  CP: Immunology; CP: Microbiology; cellular metabolism; development and functions; immunometabolism; low-protein diet; malnutrition; neutrophils

DOI:  https://doi.org/10.1016/j.celrep.2024.114493
Am J Physiol Endocrinol Metab. 2024 Jul 17.

Bruton's tyrosine kinase (BTK) inhibitors alter blood glucose and insulin in obese mice but reduce inflammation independent of BTK.

Darryl Y Chan, Nicole G Barra, Han Fang, Rodrigo Rodrigues E-Lacerda, Jonathan D Schertzer.

  Obesity is associated with metabolic inflammation, which can contribute to insulin resistance, higher blood glucose and higher insulin indicative of prediabetes progression. The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a metabolic danger sensor implicated in metabolic inflammation. Many features of metabolic disease can activate of the NLRP3 inflammasome; however, it is not yet clear which upstream trigger to target, and there are no clinically approved NLRP3 inflammasome inhibitors for metabolic disease. Bruton's tyrosine kinase (BTK) mediates activation of the NLRP3 inflammasome. Ibrutinib is the most-studied pharmacological inhibitor of BTK and it can improve blood glucose control in obese mice. However, inhibitors of tyrosine kinases are permissive, and it is unknown if BTK inhibitors require BTK to alter endocrine control of metabolism or metabolic inflammation. We tested whether ibrutinib and acalabrutinib, a new generation BTK inhibitor with higher selectivity, require BTK to inhibit the NLRP3 inflammasome, metabolic inflammation and blood glucose in obese mice. Chronic ibrutinib administration lowered fasting blood glucose and improved glycemia, while acalabrutinib increased blood insulin levels and increased markers of insulin resistance in high-fat fed CBA/J mice with intact Btk. These metabolic effects of BTK inhibitors were absent in CBA/CaHN-Btkxid/J mice with mutant Btk. However, ibrutinib and acalabrutinib reduced NF-κB activity pro-inflammatory gene expression and NLRP3 inflammasome activation in macrophages with and without functional BTK. These data highlight the BTK inhibitors can have divergent effect on metabolism and separate effects on metabolic inflammation that can occur independently of actions on BTK.

Keywords:  Acalabrutinib; Bruton's tyrosine kinase; Glucose control; Ibrutinib; Metabolic inflammation

DOI:  https://doi.org/10.1152/ajpendo.00205.2024
Immunity. 2024 Jul 06. pii: S1074-7613(24)00316-9. [Epub ahead of print]

Antibiotic-driven dysbiosis in early life disrupts indole-3-propionic acid production and exacerbates allergic airway inflammation in adulthood.

Olaf Perdijk, Alana Butler, Matthew Macowan, Roxanne Chatzis, Edyta Bulanda, Rhiannon D Grant, Nicola L Harris, Tomasz P Wypych, Benjamin J Marsland.

  Antibiotic use in early life disrupts microbial colonization and increases the risk of developing allergies and asthma. We report that mice given antibiotics in early life (EL-Abx), but not in adulthood, were more susceptible to house dust mite (HDM)-induced allergic airway inflammation. This susceptibility was maintained even after normalization of the gut microbiome. EL-Abx decreased systemic levels of indole-3-propionic acid (IPA), which induced long-term changes to cellular stress, metabolism, and mitochondrial respiration in the lung epithelium. IPA reduced mitochondrial respiration and superoxide production and altered chemokine and cytokine production. Consequently, early-life IPA supplementation protected EL-Abx mice against exacerbated HDM-induced allergic airway inflammation in adulthood. These results reveal a mechanism through which EL-Abx can predispose the lung to allergic airway inflammation and highlight a possible preventative approach to mitigate the detrimental consequences of EL-Abx.

Keywords:  airway epithelial cells; allergy; antibiotics; early life; gut-lung axis; indole-3-propionic acid; metabolites; microbiota; redox balance; window of opportunity

DOI:  https://doi.org/10.1016/j.immuni.2024.06.010
Nat Commun. 2024 Jul 18. 15(1): 6067

Sphinganine recruits TLR4 adaptors in macrophages and promotes inflammation in murine models of sepsis and melanoma.

Marvin Hering, Alaa Madi, Roger Sandhoff, Sicong Ma, Jingxia Wu, Alessa Mieg, Karsten Richter, Kerstin Mohr, Nora Knabe, Diana Stichling, Gernot Poschet, Felix Bestvater, Larissa Frank, Jochen Utikal, Viktor Umansky, Guoliang Cui.

After recognizing its ligand lipopolysaccharide, Toll-like receptor 4 (TLR4) recruits adaptor proteins to the cell membrane, thereby initiating downstream signaling and triggering inflammation. Whether this recruitment of adaptor proteins is dependent solely on protein-protein interactions is unknown. Here, we report that the sphingolipid sphinganine physically interacts with the adaptor proteins MyD88 and TIRAP and promotes MyD88 recruitment in macrophages. Myeloid cell-specific deficiency in serine palmitoyltransferase long chain base subunit 2, which encodes the key enzyme catalyzing sphingolipid biosynthesis, decreases the membrane recruitment of MyD88 and inhibits inflammatory responses in in vitro bone marrow-derived macrophage and in vivo sepsis models. In a melanoma mouse model, serine palmitoyltransferase long chain base subunit 2 deficiency decreases anti-tumor myeloid cell responses and increases tumor growth. Therefore, sphinganine biosynthesis is required for the initiation of TLR4 signal transduction and serves as a checkpoint for macrophage pattern recognition in sepsis and melanoma mouse models.

DOI: https://doi.org/10.1038/s41467-024-50341-w
Scand J Immunol. 2023 Dec;98(6): e13322

Sphingosine 1-phosphate combining with S1PR4 promotes regulatory T cell differentiation related to FAO through Nrf2/PPARα.

Rui Feng, Chuang Liu, Zilin Cui, Zirong Liu, Yamin Zhang.

  Metabolism and metabolic processes have long been considered to shape the tumour immunosuppressive microenvironment. Recent research has demonstrated that T regulatory cells (Tregs) display high rates of fatty acid oxidation (FAO) and a relatively low rate of glycolysis. Sphingosine 1-phosphate (S1P), which is a G protein signalling activator involved in immune regulation and FAO modulation, has been implicated in Treg differentiation. However, the precise relation between Treg differentiation and S1P remains unclear. In this study, we isolated naïve CD4+ T cells from the spleens of 6-8-week-old BALB/c mice using magnetic bead sorting, which was used in our study for Treg differentiation. S1P stimulation was performed during Treg differentiation. We examined the oxygen consumption and palmitic acid metabolism of the differentiated Tregs and evaluated the expression levels of various proteins, including Nrf2, CPT1A, Glut1, ACC1 and PPARα, through Western blotting. Our results demonstrate that S1P promotes Treg differentiation and enhances FAO, and that the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and peroxisome proliferator-activated receptor α (PPARα) is upregulated. Furthermore, Nrf2 or PPARα knockdown dampened the Treg differentiation and FAO that were promoted by S1P, confirming that S1P can bind with S1PR4 to promote Treg differentiation through the Nrf2/PPARα signalling pathway, which may be related to FAO facilitation.

Keywords:  differentiation; fatty acid oxidation; nuclear factor (erythroid‐derived 2)‐like 2; regulatory T cell; sphingosine 1‐phosphate

DOI:  https://doi.org/10.1111/sji.13322
Mediators Inflamm. 2024 ;2024 6263447

Dietary Fiber-Derived Microbial Butyrate Suppresses ILC2-Dependent Airway Inflammation in COPD.

Min Jiang, Jing Wang, Zheng Li, Dan Xu, Jing Jing, Fengsen Li, Jianbing Ding, Qifeng Li.

Group 2 innate lymphoid cells (ILC2) strongly modulate COPD pathogenesis. However, the significance of microbiota in ILC2s remains unelucidated. Herein, we investigated the immunomodulatory role of short-chain fatty acids (SCFAs) in regulating ILC2-associated airway inflammation and explores its associated mechanism in COPD. In particular, we assessed the SCFA-mediated regulation of survival, proliferation, and cytokine production in lung sorted ILC2s. To elucidate butyrate action in ILC2-driven inflammatory response in COPD models, we administered butyrate to BALB/c mice via drinking water. We revealed that SCFAs, especially butyrate, derived from dietary fiber fermentation by gut microbiota inhibited pulmonary ILC2 functions and suppressed both IL-13 and IL-5 synthesis by murine ILC2s. Using in vivo and in vitro experimentation, we validated that butyrate significantly ameliorated ILC2-induced inflammation. We further demonstrated that butyrate suppressed ILC2 proliferation and GATA3 expression. Additionally, butyrate potentially utilized histone deacetylase (HDAC) inhibition to enhance NFIL3 promoter acetylation, thereby augmenting its expression, which eventually inhibited cytokine production in ILC2s. Taken together, the aforementioned evidences demonstrated a previously unrecognized role of microbial-derived SCFAs on pulmonary ILC2s in COPD. Moreover, our evidences suggest that metabolomics and gut microbiota modulation may prevent lung inflammation of COPD.

DOI: https://doi.org/10.1155/2024/6263447
Front Med (Lausanne). 2024 ;11 1379335

Alterations in tryptophan metabolism and de novo NAD+ biosynthesis within the microbiota-gut-brain axis in chronic intestinal inflammation.

Jeannie Devereaux, Ainsley M Robinson, Rhian Stavely, Majid Davidson, Narges Dargahi, Ramya Ephraim, Dimitros Kiatos, Vasso Apostolopoulos, Kulmira Nurgali.

   Background: Inflammatory bowel disease is an incurable and idiopathic disease characterized by recurrent gastrointestinal tract inflammation. Tryptophan metabolism in mammalian cells and some gut microbes comprise intricate chemical networks facilitated by catalytic enzymes that affect the downstream metabolic pathways of de novo nicotinamide adenine dinucleotide (NAD+) synthesis. It is hypothesized that a correlation exists between tryptophan de novo NAD+ synthesis and chronic intestinal inflammation.
Methods: Transcriptome analysis was performed using high-throughput sequencing of mRNA extracted from the distal colon and brain tissue of Winnie mice with spontaneous chronic colitis and C57BL/6 littermates. Metabolites were assessed using ultra-fast liquid chromatography to determine differences in concentrations of tryptophan metabolites. To evaluate the relative abundance of gut microbial genera involved in tryptophan and nicotinamide metabolism, we performed 16S rRNA gene amplicon sequencing of fecal samples from C57BL/6 and Winnie mice.
Results: Tryptophan and nicotinamide metabolism-associated gene expression was altered in distal colons and brains of Winnie mice with chronic intestinal inflammation. Changes in these metabolic pathways were reflected by increases in colon tryptophan metabolites and decreases in brain tryptophan metabolites in Winnie mice. Furthermore, dysbiosis of gut microbiota involved in tryptophan and nicotinamide metabolism was evident in fecal samples from Winnie mice. Our findings shed light on the physiological alterations in tryptophan metabolism, specifically, its diversion from the serotonergic pathway toward the kynurenine pathway and consequential effects on de novo NAD+ synthesis in chronic intestinal inflammation.
Conclusion: The results of this study reveal differential expression of tryptophan and nicotinamide metabolism-associated genes in the distal colon and brain in Winnie mice with chronic intestinal inflammation. These data provide evidence supporting the role of tryptophan metabolism and de novo NAD+ synthesis in IBD pathophysiology.

Keywords:  chronic intestinal inflammation; colitis; gut-brain axis; inflammatory bowel disease; microbiota; nicotinamide metabolism; tryptophan metabolism

DOI:  https://doi.org/10.3389/fmed.2024.1379335
Cell Host Microbe. 2024 Jul 10. pii: S1931-3128(24)00231-2. [Epub ahead of print]

Mitochondrial perturbation in the intestine causes microbiota-dependent injury and gene signatures discriminative of inflammatory disease.

Elisabeth Urbauer, Doriane Aguanno, Nora Mindermann, Hélène Omer, Amira Metwaly, Tina Krammel, Tim Faro, Marianne Remke, Sandra Reitmeier, Stefanie Bärthel, Johannes Kersting, Zihua Huang, Feng Xian, Manuela Schmidt, Dieter Saur, Samuel Huber, Bärbel Stecher, Markus List, David Gómez-Varela, Katja Steiger, Matthieu Allez, Eva Rath, Dirk Haller.

  Mitochondrial dysfunction is associated with inflammatory bowel diseases (IBDs). To understand how microbial-metabolic circuits contribute to intestinal injury, we disrupt mitochondrial function in the epithelium by deleting the mitochondrial chaperone, heat shock protein 60 (Hsp60Δ/ΔIEC). This metabolic perturbation causes self-resolving tissue injury. Regeneration is disrupted in the absence of the aryl hydrocarbon receptor (Hsp60Δ/ΔIEC;AhR-/-) involved in intestinal homeostasis or inflammatory regulator interleukin (IL)-10 (Hsp60Δ/ΔIEC;Il10-/-), causing IBD-like pathology. Injury is absent in the distal colon of germ-free (GF) Hsp60Δ/ΔIEC mice, highlighting bacterial control of metabolic injury. Colonizing GF Hsp60Δ/ΔIEC mice with the synthetic community OMM12 reveals expansion of metabolically flexible Bacteroides, and B. caecimuris mono-colonization recapitulates the injury. Transcriptional profiling of the metabolically impaired epithelium reveals gene signatures involved in oxidative stress (Ido1, Nos2, Duox2). These signatures are observed in samples from Crohn's disease patients, distinguishing active from inactive inflammation. Thus, mitochondrial perturbation of the epithelium causes microbiota-dependent injury with discriminative inflammatory gene profiles relevant for IBD.

Keywords:  Bacteroides; IBD; cell stress; heat shock protein 60; inflammation; intestinal epithelial cells; metabolic injury; microbiome; mitochondrial dysfunction; unfolded protein response

DOI:  https://doi.org/10.1016/j.chom.2024.06.013
Metabolomics. 2024 Jul 16. 20(4): 78

Metabolic insights into HIV/TB co-infection: an untargeted urinary metabolomics approach.

Cara Olivier, Laneke Luies.

   INTRODUCTION: Amid the global health crisis, HIV/TB co-infection presents significant challenges, amplifying the burden on patients and healthcare systems alike. Metabolomics offers an innovative window into the metabolic disruptions caused by co-infection, potentially improving diagnosis and treatment monitoring.
AIM: This study uses untargeted metabolomics to investigate the urinary metabolic signature of HIV/TB co-infection, enhancing understanding of the metabolic interplay between these infections.
METHODS: Urine samples from South African adults, categorised into four groups - healthy controls, TB-positive, HIV-positive, and HIV/TB co-infected - were analysed using GCxGC-TOFMS. Metabolites showing significant differences among groups were identified through Kruskal-Wallis and Wilcoxon rank sum tests.
RESULTS: Various metabolites (n = 23) were modulated across the spectrum of health and disease states represented in the cohorts. The metabolomic profiles reflect a pronounced disruption in biochemical pathways involved in energy production, amino acid metabolism, gut microbiome, and the immune response, suggesting a bidirectional exacerbation between HIV and TB. While both diseases independently perturb the host's metabolism, their co-infection leads to a unique metabolic phenotype, indicative of an intricate interplay rather than a simple additive effect.
CONCLUSION: Metabolic profiling revealed a unique metabolic landscape shaped by HIV/TB co-infection. The findings highlight the potential of urinary differential metabolites for co-infection, offering a non-invasive tool for enhancing diagnostic precision and tailoring therapeutic interventions. Future research should focus on expanding sample sizes and integrating longitudinal analyses to build upon these foundational insights, paving the way for metabolomic applications in combating these concurrent pandemics.

Keywords:  Co-infection; GC-MS; HIV; Metabolomics; TB; Urine

DOI:  https://doi.org/10.1007/s11306-024-02148-5
Nature. 2024 Jul 17.

Mice live longer when inflammation-boosting protein is blocked.

Heidi Ledford.



Keywords:  Ageing; Immunology; Metabolism

DOI:  https://doi.org/10.1038/d41586-024-02298-5