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Cell Metabolism Mar 2024The brain and gut are intricately connected and respond to various stimuli. Stress-induced brain-gut communication is implicated in the pathogenesis and relapse of gut...
The brain and gut are intricately connected and respond to various stimuli. Stress-induced brain-gut communication is implicated in the pathogenesis and relapse of gut disorders. The mechanism that relays psychological stress to the intestinal epithelium, resulting in maladaptation, remains poorly understood. Here, we describe a stress-responsive brain-to-gut metabolic axis that impairs intestinal stem cell (ISC) lineage commitment. Psychological stress-triggered sympathetic output enriches gut commensal Lactobacillus murinus, increasing the production of indole-3-acetate (IAA), which contributes to a transferrable loss of intestinal secretory cells. Bacterial IAA disrupts ISC mitochondrial bioenergetics and thereby prevents secretory lineage commitment in a cell-intrinsic manner. Oral α-ketoglutarate supplementation bolsters ISC differentiation and confers resilience to stress-triggered intestinal epithelial injury. We confirm that fecal IAA is higher in patients with mental distress and is correlated with gut dysfunction. These findings uncover a microbe-mediated brain-gut pathway that could be therapeutically targeted for stress-driven gut-brain comorbidities.
Topics: Humans; Cell Lineage; Gastrointestinal Microbiome; Stress, Psychological; Acetates; Indoles
PubMed: 38266651
DOI: 10.1016/j.cmet.2023.12.026 -
Transplant International : Official... 2023Despite advances in monitoring and treatment, cytomegalovirus (CMV) infections remain one of the most common complications after solid organ transplantation (SOT). CMV... (Review)
Review
Despite advances in monitoring and treatment, cytomegalovirus (CMV) infections remain one of the most common complications after solid organ transplantation (SOT). CMV infection may fail to respond to standard first- and second-line antiviral therapies with or without the presence of antiviral resistance to these therapies. This failure to respond after 14 days of appropriate treatment is referred to as "resistant/refractory CMV." Limited data on refractory CMV without antiviral resistance are available. Reported rates of resistant CMV are up to 18% in SOT recipients treated for CMV. Therapeutic options for treating these infections are limited due to the toxicity of the agent used or transplant-related complications. This is often the challenge with conventional agents such as ganciclovir, foscarnet and cidofovir. Recent introduction of new CMV agents including maribavir and letermovir as well as the use of adoptive T cell therapy may improve the outcome of these difficult-to-treat infections in SOT recipients. In this expert review, we focus on new treatment options for resistant/refractory CMV infection and disease in SOT recipients, with an emphasis on maribavir, letermovir, and adoptive T cell therapy.
Topics: Humans; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Acetates; Ganciclovir
PubMed: 37901297
DOI: 10.3389/ti.2023.11785 -
Nature Cancer Oct 2023Acetate metabolism is an important metabolic pathway in many cancers and is controlled by acetyl-CoA synthetase 2 (ACSS2), an enzyme that catalyzes the conversion of...
Acetate metabolism is an important metabolic pathway in many cancers and is controlled by acetyl-CoA synthetase 2 (ACSS2), an enzyme that catalyzes the conversion of acetate to acetyl-CoA. While the metabolic role of ACSS2 in cancer is well described, the consequences of blocking tumor acetate metabolism on the tumor microenvironment and antitumor immunity are unknown. We demonstrate that blocking ACSS2, switches cancer cells from acetate consumers to producers of acetate thereby freeing acetate for tumor-infiltrating lymphocytes to use as a fuel source. We show that acetate supplementation metabolically bolsters T-cell effector functions and proliferation. Targeting ACSS2 with CRISPR-Cas9 guides or a small-molecule inhibitor promotes an antitumor immune response and enhances the efficacy of chemotherapy in preclinical breast cancer models. We propose a paradigm for targeting acetate metabolism in cancer in which inhibition of ACSS2 dually acts to impair tumor cell metabolism and potentiate antitumor immunity.
Topics: Humans; Female; Breast Neoplasms; Acetyl Coenzyme A; Cell Line, Tumor; Acetates; T-Lymphocytes; Immunologic Factors; Tumor Microenvironment
PubMed: 37723305
DOI: 10.1038/s43018-023-00636-6 -
Nature Metabolism May 2024Acetate, a precursor of acetyl-CoA, is instrumental in energy production, lipid synthesis and protein acetylation. However, whether acetate reprogrammes tumour...
Acetate, a precursor of acetyl-CoA, is instrumental in energy production, lipid synthesis and protein acetylation. However, whether acetate reprogrammes tumour metabolism and plays a role in tumour immune evasion remains unclear. Here, we show that acetate is the most abundant short-chain fatty acid in human non-small cell lung cancer tissues, with increased tumour-enriched acetate uptake. Acetate-derived acetyl-CoA induces c-Myc acetylation, which is mediated by the moonlighting function of the metabolic enzyme dihydrolipoamide S-acetyltransferase. Acetylated c-Myc increases its stability and subsequent transcription of the genes encoding programmed death-ligand 1, glycolytic enzymes, monocarboxylate transporter 1 and cell cycle accelerators. Dietary acetate supplementation promotes tumour growth and inhibits CD8 T cell infiltration, whereas disruption of acetate uptake inhibits immune evasion, which increases the efficacy of anti-PD-1-based therapy. These findings highlight a critical role of acetate promoting tumour growth beyond its metabolic role as a carbon source by reprogramming tumour metabolism and immune evasion, and underscore the potential of controlling acetate metabolism to curb tumour growth and improve the response to immune checkpoint blockade therapy.
Topics: B7-H1 Antigen; Humans; Acetates; Proto-Oncogene Proteins c-myc; Animals; Mice; Immune Evasion; Carcinoma, Non-Small-Cell Lung; Up-Regulation; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Acetylation; Lung Neoplasms; Acetyl Coenzyme A; Tumor Escape
PubMed: 38702440
DOI: 10.1038/s42255-024-01037-4 -
Drugs Feb 2024Etrasimod (VELSIPITY™) is an orally available, small-molecule selective sphingosine-1-phosphate (S1P) receptor modulator being developed by Pfizer for the treatment of... (Review)
Review
Etrasimod (VELSIPITY™) is an orally available, small-molecule selective sphingosine-1-phosphate (S1P) receptor modulator being developed by Pfizer for the treatment of ulcerative colitis and other immune-mediated inflammatory disorders. Etrasimod is selective for S1P receptor subtypes S1P, S1P and S1P while having minimal activity on S1P and no activity on S1P. Etrasimod received its first approval, in the USA, in October 2023 for the treatment of moderately to severely active ulcerative colitis in adults. Subsequently, the European Medicines Agency adopted a positive opinion in December 2023, recommending the granting of marketing authorisation for etrasimod for the treatment of patients aged ≥ 16 years with moderately to severely active ulcerative colitis who have had an inadequate response, lost response, or were intolerant to either conventional therapy, or a biological agent. Etrasimod is also under regulatory review for the treatment of ulcerative colitis in several other countries. Clinical development of etrasimod for use in the treatment of Crohn's disease, atopic dermatitis, eosinophilic oesophagitis and alopecia areata is ongoing worldwide. This article summarises the milestones in the development of etrasimod leading to this first approval for the treatment of ulcerative colitis in adults.
Topics: Adult; Humans; Colitis, Ulcerative; Crohn Disease; Acetates; Indoles
PubMed: 38388871
DOI: 10.1007/s40265-024-01997-7 -
Circulation Research Jan 2024T cells are central to the immune responses contributing to hypertension. LGMN (legumain) is highly expressed in T cells; however, its role in the pathogenesis of...
BACKGROUND
T cells are central to the immune responses contributing to hypertension. LGMN (legumain) is highly expressed in T cells; however, its role in the pathogenesis of hypertension remains unclear.
METHODS
Peripheral blood samples were collected from patients with hypertension, and cluster of differentiation (CD)4+ T cells were sorted for gene expression and Western blotting analysis. TLGMNKO (T cell-specific LGMN-knockout) mice (Lgmn/CD4), regulatory T cell (Treg)-specific LGMN-knockout mice (Lgmn/Foxp3), and RR-11a (LGMN inhibitor)-treated C57BL/6 mice were infused with Ang II (angiotensin II) or deoxycorticosterone acetate/salt to establish hypertensive animal models. Flow cytometry, 4-dimensional label-free proteomics, coimmunoprecipitation, Treg suppression, and in vivo Treg depletion or adoptive transfer were used to delineate the functional importance of T-cell LGMN in hypertension development.
RESULTS
LGMN mRNA expression was increased in CD4+ T cells isolated from hypertensive patients and mice, was positively correlated with both systolic and diastolic blood pressure, and was negatively correlated with serum IL (interleukin)-10 levels. TLGMNKO mice exhibited reduced Ang II-induced or deoxycorticosterone acetate/salt-induced hypertension and target organ damage relative to wild-type (WT) mice. Genetic and pharmacological inhibition of LGMN blocked Ang II-induced or deoxycorticosterone acetate/salt-induced immunoinhibitory Treg reduction in the kidneys and blood. Anti-CD25 antibody depletion of Tregs abolished the protective effects against Ang II-induced hypertension in TLGMNKO mice, and LGMN deletion in Tregs prevented Ang II-induced hypertension in mice. Mechanistically, endogenous LGMN impaired Treg differentiation and function by directly interacting with and facilitating the degradation of TRAF6 (tumor necrosis factor receptor-associated factor 6) via chaperone-mediated autophagy, thereby inhibiting NF-κB (nuclear factor kappa B) activation. Adoptive transfer of LGMN-deficient Tregs reversed Ang II-induced hypertension, whereas depletion of TRAF6 in LGMN-deficient Tregs blocked the protective effects.
CONCLUSIONS
LGMN deficiency in T cells prevents hypertension and its complications by promoting Treg differentiation and function. Specifically targeting LGMN in Tregs may be an innovative approach for hypertension treatment.
Topics: Animals; Humans; Mice; Acetates; Angiotensin II; CD4-Positive T-Lymphocytes; Desoxycorticosterone; Hypertension; Mice, Inbred C57BL; Mice, Knockout; T-Lymphocytes, Regulatory; TNF Receptor-Associated Factor 6
PubMed: 38047378
DOI: 10.1161/CIRCRESAHA.123.322835 -
American Journal of Health-system... Sep 2023
Topics: Humans; Antifungal Agents; Echinocandins; Acetates
PubMed: 37471252
DOI: 10.1093/ajhp/zxad144 -
International Journal of Toxicology Aug 2024The Expert Panel for Cosmetic Ingredient Safety reviewed newly available studies since their original assessment in 1982 and a previous re-review in 2002, along with... (Review)
Review
The Expert Panel for Cosmetic Ingredient Safety reviewed newly available studies since their original assessment in 1982 and a previous re-review in 2002, along with updated information regarding product types and concentrations of use. Considering this information, the Panel confirmed that Laneth-9 Acetate and Laneth-10 Acetate are safe for topical application to humans in the present practices of use and concentration as described in this report.
Topics: Humans; Cosmetics; Animals; Acetates; Consumer Product Safety
PubMed: 38653732
DOI: 10.1177/10915818241249398 -
Proceedings of the National Academy of... Dec 2023Mild or transient dietary restriction (DR) improves many aspects of health and aging. Emerging evidence from us and others has demonstrated that DR also optimizes the...
Mild or transient dietary restriction (DR) improves many aspects of health and aging. Emerging evidence from us and others has demonstrated that DR also optimizes the development and quality of immune responses. However, the factors and mechanisms involved remain to be elucidated. Here, we propose that DR-induced optimization of immunological memory requires a complex cascade of events involving memory T cells, the intestinal microbiota, and myeloid cells. Our findings suggest that DR enhances the ability of memory T cells to recruit and activate myeloid cells in the context of a secondary infection. Concomitantly, DR promotes the expansion of commensal Bifidobacteria within the large intestine, which produce the short-chain fatty acid acetate. Acetate conditioning of the myeloid compartment during DR enhances the capacity of these cells to kill pathogens. Enhanced host protection during DR is compromised when Bifidobacteria expansion is prevented, indicating that microbiota configuration and function play an important role in determining immune responsiveness to this dietary intervention. Altogether, our study supports the idea that DR induces both memory T cells and the gut microbiota to produce distinct factors that converge on myeloid cells to promote optimal pathogen control. These findings suggest that nutritional cues can promote adaptation and co-operation between multiple immune cells and the gut microbiota, which synergize to optimize immunity and protect the collective metaorganism.
Topics: Microbiota; Gastrointestinal Microbiome; Fatty Acids, Volatile; Acetates
PubMed: 38011570
DOI: 10.1073/pnas.2304905120 -
Nature Cell Biology Apr 2024The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic...
The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP-seq and RNA-seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We identified acetate/ACSS2-mediated acetylation of SP1 at the lysine 19 residue that increased SP1 protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2-SP1-SAT1 axis diminished the tumour burden in mouse models. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2-SP1-SAT1 axis.
Topics: Animals; Mice; Cancer-Associated Fibroblasts; Cell Line, Tumor; Acetates; Pancreatic Neoplasms; Polyamines; Tumor Microenvironment
PubMed: 38429478
DOI: 10.1038/s41556-024-01372-4