Acetate Supplementation Research Articles

HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells

Hypoxia is a common feature in various pathophysiological contexts, including tumor microenvironment, and IFN-γ is instrumental for anti-tumor immunity. HIF1α has long been known as a primary regulator of cellular adaptive responses to hypoxia, but its role in IFN-γ induction in hypoxic T cells is unknown. Here, we show that the HIF1α-glycolysis axis controls IFN-γ induction in both human and mouse T cells, activated under hypoxia. Specific deletion of HIF1α in T cells (Hif1α–/–) and glycolytic inhibition suppresses IFN-γ induction. Conversely, HIF1α stabilization by hypoxia and VHL deletion in T cells (Vhl–/–) increases IFN-γ production. Hypoxic Hif1α–/– T cells are less able to kill tumor cells in vitro, and tumor-bearing Hif1α–/– mice are not responsive to immune checkpoint blockade (ICB) therapy in vivo. Mechanistically, loss of HIF1α greatly diminishes glycolytic activity in hypoxic T cells, resulting in depleted intracellular acetyl-CoA and attenuated activation-induced cell death (AICD). Restoration of intracellular acetyl-CoA by acetate supplementation re-engages AICD, rescuing IFN-γ production in hypoxic Hif1α–/– T cells and re-sensitizing Hif1α–/– tumor-bearing mice to ICB. In summary, we identify HIF1α-regulated glycolysis as a key metabolic control of IFN-γ production in hypoxic T cells and ICB response.

Ellagic Acid Reduces Cadmium Exposure-Induced Apoptosis in HT22 Cells via Inhibiting Oxidative Stress and Mitochondrial Dysfunction and Activating Nrf2/HO-1 Pathway.

Exposure to cadmium sulfate (CdSO4) can lead to neurotoxicity. Nevertheless, the precise molecular mechanisms underlying this phenomenon remain unclear, and effective treatment strategies are scarce. This study explored the protective effects of ellagic acid (EA), a natural polyphenolic compound, against CdSO4 exposure-induced neurotoxicity in HT22 cells and the underlying molecular mechanisms. Our findings demonstrated that exposure of HT22 cells to CdSO4 resulted in apoptosis, which was effectively reversed by EA in a dose-dependent manner. EA supplementation also decreased reactive oxygen species (ROS) and mitochondrial ROS production, reduced malondialdehyde (MDA) levels, and restored the activities of superoxide dismutase (SOD) and catalase (CAT). Additionally, EA supplementation at 5-20 μM significantly counteracted Cd-induced the loss of mitochondrial membrane potential and the decrease of ATP and reduced the ratio of Bax/Bcl-2 and cleaved-caspase-3 protein expression. Furthermore, EA supplementation resulted in the upregulation of Nrf2 and HO-1 protein and mRNAs while simultaneously downregulating the phosphorylation of JNK and p38 proteins. The pharmacological inhibition of c-Jun N-terminal kinase (JNK) partially attenuated the activation of the Nrf2/HO-1 pathway induced by CdSO4 and exacerbated its cytotoxic effects. In conclusion, our findings suggest that ethyl acetate (EA) supplementation offers protective effects against CdSO4-induced apoptosis in HT22 cells by inhibiting oxidative stress and activating the Nrf2 signaling pathway. Furthermore, the activation of the JNK pathway appears to play a protective role in CdSO4-induced apoptosis in HT22 cells.

The short-chain fatty acid receptors Gpr41/43 regulate bone mass by promoting adipogenic differentiation of mesenchymal stem cells.

Bone is a dynamic tissue that is constantly remodeled throughout adult life. Recently, it has been shown that bone turnover decreases shortly after food consumption. This process has been linked to the fermentation of non-digestible food ingredients such as inulin by gut microbes, which results in the production of the short-chain fatty acids (SCFAs) acetate, propionate and butyrate. SCFAs exert various metabolic functions, which in part can be explained by activation of G protein-coupled receptors (Gpr) 41 and 43. However, the potential relevance of a SCFA-Gpr41/43 signaling axis for bone metabolism has not been established. The aim of our study is to investigate the role of Gpr41/43 in bone metabolism and osteogenic differentiation of mesenchymal stem cells. For this purpose, we analyzed the skeletal phenotype of wild type controls (WT) and Gpr41/43 double knockout (Gpr41/43 dKO) mice fed either a chow or an inulin-enriched diet. In addition, we isolated bone marrow derived mesenchymal stem cells from WT and Gpr41/43 dKO mice and differentiated them into osteoblasts in the absence or presence of acetate. MicroCT scanning of femoral bones of Gpr41/43 dKO mice revealed a significant increase of trabecular bone volume and trabecular compared to WT controls. Treatment of WT bone marrow-derived osteoblasts with acetate resulted in decreased mineralization and substantial downregulation of bone formation markers such as Phex, Ptgs2 and Col1a1. Notably, this effect was strongly attenuated in differentiated osteoblasts lacking Gpr41/43. Inversely, acetate supplementation resulted in higher levels of adipocyte marker genes including Pparg, Lpl and Adipoq in bone marrow-derived cells from WT mice, an effect blunted in differentiated cells isolated from Gpr41/43 dKO mice. Overall, these data indicate that acetate regulates bone architecture via SCFA-Gpr41/43 signaling by modulating the osteogenic versus adipogenic differentiation of mesenchymal stem cells.

Effects of L-leucine and sodium acetate on milk protein synthesis under heat stress conditions in bovine mammary epithelial cells in vitro

It is widely known that heat stress (HS) has negative effects on dairy cows, such as a reduction in milk production and milk protein. However, there has been no research yet on the effects of HS at the bovine mammary epithelial cells (MAC-T) level and the function of L-leucine (LEU) and sodium acetate (ACE) in reducing HS. In this study, we evaluated the negative effects of HS at various temperatures on MAC-T and verified whether LEU and ACE are effective at reducing HS and increasing protein synthesis. An experiment was conducted by dividing MAC-T into three groups: 39 °C, 41 °C, and 43 °C. In the case of LEU and ACE supplementation experiments, the cells were supplemented with 0, 0.45, 0.9, 1.8, and 3.6 mM of LEU and ACE to reach the differentiation medium. It was observed that under HS at 41 °C, HSP70, BAX, and eIF4EBP1 gene expression were increased, whereas Bcl-2, eIF4E, and PRKAA1 gene expression were decreased. When 1.8 mM of LEU was added under HS at 41 °C, it suppressed apoptosis by reducing the gene expression of HSP70 and controlling the gene expression of apoptosis-related genes such as BAX and Bcl-2. Additionally, mTOR, P-mTOR, and β-casein proteins were increased. In the case of 0.9 mM of ACE, it was found to decrease the gene expression of HSP70 and BAX and increase the amount of β-casein protein synthesis. Simultaneous supplementation of LEU and ACE has been shown to reduce HS, inhibit apoptosis, and increase β-casein protein expression. In summary, HS at 41 °C began to have a negative effect on MAC-T, while LEU and ACE reduced HS and inhibited apoptosis, alleviating cell damage and effectively increasing β-casein protein synthesis. The results suggest that LEU and ACE have the potential to reduce HS and promote protein synthesis under HS conditions in MAC-T.

Effect of NH4Cl supplementation on growth, photosynthesis, and triacylglycerol content in Chlamydomonas reinhardtii under mixotrophic cultivation.

Ammonium chloride (NH4Cl) is one of the nitrogen sources for microalgal cultivation. An excessive amounts of NH4Cl are toxic for microalgae. However, combining mixotrophic conditions and excessive quantities of NH4Cl positively affects microalgal biomass and lipid production. In this study, we investigated the impact of NH4Cl on the growth, biomass, and triglyceride (TAG) content of the green microalga Chlamydomonas reinhardtii especially under mixotrophic conditions. Under photoautotrophic conditions (without organic carbon supplementation), adding 25 mM NH4Cl had no significant effect on microalgal growth or TAG content. However, under mixotrophic condition (with acetate supplementation), NH4Cl interfered with microalgal growth while inducing TAG content. To explore these effects further, we conducted a two-step cultivation process and found that NH4Cl reduced microalgal growth, but induced total lipid and TAG content, especially after 4-day cultivation. The photosynthesis performances showed that NH4Cl completely inhibited oxygen evolution on day 4. However, NH4Cl slightly reduced the Fv/Fm ratio indicating that the NH4Cl supplementation directly affects microalgal photosynthesis. To investigate the TAG induction effect by NH4Cl, we compared the protein expression profiles of microalgae grown mixotrophically with and without 25 mM NH4Cl using a proteomics approach. This analysis identified 1782 proteins, with putative acetate uptake transporter GFY5 and acyl-coenzyme A oxidase being overexpressed in the NH4Cl-treated group. These findings suggested that NH4Cl supplementation may stimulate acetate utilization and fatty acid synthesis pathways in microalgae cells. Our study indicated that NH4Cl supplementation can induce microalgal biomass and lipid production, particularly when combined with mixotrophic conditions.

Comparative analysis of sulfur-driven autotrophic denitrification for pilot-scale application: Pollutant removal performance and metagenomic function

Two parallel pilot-scale reactors were operated to investigate pollutant removal performance and metabolic pathways in elemental sulfur-driven autotrophic denitrification (SDAD) process under low temperature and after addition of external electron donors. The results showed that low temperature slightly inhibited SDAD (average total nitrogen removal of ∼4.7 mg L−1) while supplement of sodium thiosulfate (stage 2) and sodium acetate (stage 3) enhanced denitrification and secretion of extracellular polymeric substances (EPS), leading to the average removal rate of 0.75 and 1.01 kg N m−3 d−1, respectively with over twice higher total EPS. Correspondingly, nitrogen and sulfur related microbial metabolisms especially nitrite reductase and nitric oxide reductase encoding were promoted by genera including Thermomonas and Thiobacillus. The variations revealed that extra sodium acetate improved denitrification and enriched more SDAD-related microorganisms compared with sodium thiosulfate, which potentially catalyzed the refinement of practical strategies for optimizing denitrification in low carbon to nitrogen ratio wastewater treatment.

Different Short-Chain Fatty Acids Unequally Modulate Intestinal Homeostasis and Reverse Obesity-Related Symptoms in Lead-Exposed High-Fat Diet Mice.

Our previous study showed that heavy metal lead (Pb) exposure exacerbates high-fat-diet (HFD)-induced metabolic damage and significantly depletes the gut microbiota-derived metabolite short-chain fatty acid (SCFA) levels. However, it remains unclear whether SCFA is a key metabolite involved in accelerating adverse consequences after Pb exposure. In this study, we explored the effects of exogenous supplementation of acetate, propionate, and butyrate on a metabolic disorder model in Pb-exposed HFD mice. We found that three SCFA interventions attenuated glycolipid metabolism disorders and liver damage, with butyrate performing the best effects in improving obesity-related symptoms. All three SCFA promoted the abundance of Muribaculaceae and Muribaculum, acetate specifically enriched Christensenellaceae, Blautia, and Ruminococcus, and butyrate specifically enriched Parasutterella, Rikenella, Prevotellaceae_UCG-001, and Bacteroides, which contributed to the positive promotion of SCFA production forming a virtuous cycle. Besides, butyrate inhibited Gram-negative bacteria Escherichia-Shigella. All of these events alleviated the intestinal Th17/Treg imbalance and inflammatory response through crosstalk between the G protein-coupled receptor (GPR)/histone deacetylase 3 (HDAC3) and lipopolysaccharide (LPS)/toll-like receptors 4 (TLR4)/nuclear factor κ-B (NF-κB) pathways and ultimately improved the intestinal barrier function. SCFA further upregulated the monocarboxylate transporter 1 (MCT1) and GPR43/adenosine 5'-monophosphate-activated protein kinase (AMPK) pathways to inhibit hepatic lipid accumulation. Overall, SCFA, especially butyrate, is an effective modulator to improve metabolic disorders in obese individuals exposed to heavy metals by targeting gut microecology.

Escherichia coli Nissle 1917 Protects against Sepsis-Induced Intestinal Damage by Regulating the SCFA/GPRs Signaling Pathway.

This study explores whether Escherichia coli Nissle 1917 (EcN) can preserve the integrity of the intestinal barrier by modulating the metabolism pathway of short-chain fatty acids (SCFAs) in a C57BL/6J mouse model of lipopolysaccharide (LPS)-induced acute enteritis and a model of a Caco-2 monolayer. The study involved establishing a septic shock model in mice through lipopolysaccharide (LPS) injection. Clinical scores and intestinal permeability were meticulously documented. Immunofluorescence was utilized to localize the tight junction proteins. A quantitative real-time polymerase chain reaction (qRT-PCR) was employed to assess the expression of G protein-coupled receptors (GPRs) signaling. Additionally, the supplement of acetate and butyrate with Caco-2 monolayers to elucidate the potential of EcN in augmenting the intestinal barrier primarily via the modulation of SCFAs and qRT-PCR was performed to detect the expression of tight junction proteins and the activation of the GPRs protein signaling pathway. EcN mitigated the clinical symptoms and reduced intestinal permeability in the colon of LPS-induced mice. It also enhanced the production of SCFAs in the gut and upregulated the expression of SCFA receptor proteins GPR41 and GPR43 in the colon tissue. Our findings reveal that EcN activates the SCFA/GPRs pathway, thereby preserving intestinal barrier function and alleviating inflammation in a mouse sepsis model.

Dose-dependent effect of megestrol acetate supplementation in cancer patients with anorexia-cachexia syndrome: A meta-analysis.

There is inconsistent evidence relating to the effects of megestrol acetate (MA) supplementation on cancer patients suffering from anorexia-cachexia syndrome. This review aimed to examine the dose-response effect of MA supplementation in patients with cancer-associated anorexia/cachexia. Relevant keywords were searched in PubMed, Scopus and ISI Web of Science from inception to June 2023 for randomized controlled trials (RCTs) examining the effect of MA on pathologies in patients with cancer-associated cachexia. Our primary outcomes were changes in body weight and appetite. However, fatigue and quality of life were secondary outcomes. The mean difference (MD) and 95% confidence interval (95% CI) were estimated using the random-effects method. Thirteen trials comprising 1229 participants (mean age 60years) were identified. The results of our highest versus lowest analysis revealed that MA supplementation was not associated with any increase in body weight (MD: 0.64kg, 95% CI [-0.11, 1.38], P=0.093, I2=69.1%; GRADE=very low certainty). Twelve trials, including 14 effect sizes derived from 1369 patients (intervention=689, control=680), provided data on the effect of MA on body weight. Subgroup analyses showed a significant increase in body weight following short-term intervention (≤8weeks) and a combination of radiation/chemotherapy as concurrent treatment. A linear dose-response meta-analysis indicated that each 200mg/day increment in MA consumption had a significant increase in weight gain (MD: 0.44; 95% CI [0.13, 0.74], P=0.005; I2=97.1%); however, the magnitude of the effect was small. MA administration significantly affected the quality of life based on pooled effect sizes (MD: 1.15, 95% CI [0.76, 1.54], P<0.001, I2=0%; n=2 RCTs including 176 patients; GRADE=very low certainty). However, no significant effect of MA supplementation was observed on appetite (MD: 0.29, 95% CI [-0.05, 0.64], P=0.096, I2=18.3%; n=3 RCTs including 163 patients; GRADE=very low certainty) and fatigue (MD: 0.14, 95% CI [-0.09, 0.36], P=0.236, I2=0%; n=2 RCTs including 300 patients; GRADE=very low certainty). With very low certainty of the evidence, MA supplementation may not lead to a significantly increased weight gain and other outcomes.

Acetyl-CoA metabolism maintains histone acetylation for syncytialization of human placental trophoblast stem cells

During pregnancy, placental-fetal nutrient allocation is crucial for fetal and maternal health. However, the regulatory mechanisms for nutrient metabolism and allocation in placental trophoblasts have remained unclear. Here, we used human first-trimester placenta samples and human trophoblast stem cells (hTSCs) to discover that glucose metabolism is highly active in hTSCs and cytotrophoblasts, but during syncytialization, it decreases to basal levels, remaining necessary for fueling acetyl-CoA and differentiation potential. Acetate supplementation could rescue syncytiotrophoblast fusion from glycolysis deficiency by replenishing acetyl-CoA and maintaining histone acetylation, thus rescuing the activation of syncytialization genes. Even brief glycolysis deficiency could permanently inhibit differentiation potential and promote inflammation, which could also be permanently rescued by brief acetate supplementation invivo. These results suggest that hTSCs retain only basal glycolytic acetyl-CoA metabolism during syncytialization to regulate cell fates via nutrient-responsive histone acetylation, with implications for our understanding of the balance between placental and fetal nutrition.

Supplementation of sodium acetate improves the growth performance and intestinal health of rabbits through Wnt/β-catenin signaling pathway.

Acetic acid, which is one of the most abundant short-chain fatty acids (SCFA) in rabbits' cecum, has been reported to play an important function during various physiological metabolic processes. The present study was conducted to elucidate the effects of sodium acetate on growth performance and intestinal health by evaluating feed intake and efficiency, diarrhea score, serum and cecum metabolites, cecal pH and SCFA, histological staining, nutritional composition of meat and gene expression profile of cecum in rabbits. As a result of sodium acetate supplement, the feed conversion ratio, diarrhea score, and diameter of muscle fiber were significantly decreased (P < 0.05). Additionally, dietary sodium acetate significantly increased in total area of muscle fibers and content of crude ash (P < 0.05). Dietary sodium acetate significantly increased serum glucose, total bile acid, and total cholesterol levels and decreased amylase, lipase, and tCO2 content (P < 0.05). Further examination suggested that sodium acetate supplementation enhanced the micro-environment of cecum, evidenced by significantly increased levels of total antioxidant capacity, total superoxide dismutase, and glutathione peroxidase, and decreased pH and amylase levels (P < 0.05). According to transcriptome sequencing of cecal tissues, differentially expressed genes were predominantly enriched in cell cycle, ABC transporters, and chemokine signaling pathways. Sodium acetate was further suggested to stimulate the proliferation and migration of rabbits' cecum epithelial cells by activating Wnt/β-catenin pathway both in vivo and in vitro. In conclusion, dietary sodium acetate supplementation improved growth performance and intestinal health in rabbits.

Gut microbiota mediates ambient PM2.5 exposure-induced abnormal glucose metabolism via short-chain fatty acids

PM2.5 exposure has been found to cause gut dysbiosis and impair glucose homeostasis in human and animals, yet their underlying biological connection remain unclear. In the present study, we aim to investigate the biological significance of gut microbiota in PM2.5-induced glucose metabolic abnormalities. Our results showed that microbiota depletion by antibiotics treatment significantly alleviated PM2.5-induced glucose intolerance and insulin resistance, as indicated by the intraperitoneal glucose tolerance test, glucose-induced insulin secretion, insulin tolerance test, insulin-induced phosphorylation levels of Akt and GSK-3β in insulin sensitive tissues. In addition, faecal microbiota transplantation (FMT) from PM2.5-exposed donor mice successfully remodeled the glucose metabolism abnormalities in recipient mice, while the transplantation of autoclaved faecal materials did not. Faecal microbiota analysis demonstrated that the composition and alpha diversity of the gut bacterial community were altered by PM2.5 exposure and in FMT recipient mice. Furthermore, short-chain fatty acids levels analysis showed that the circulating acetate was significantly decreased in PM2.5-exposed donor and FMT recipient mice, and supplementation of sodium acetate for 3 months successfully improved the glucose metabolism abnormalities induced by PM2.5 exposure. These results indicate that manipulating gut microbiota or its metabolites could be a potential strategy for preventing the adverse health effects of ambient PM2.5.

Acetate derived from the intestinal tract has a critical role in maintaining skeletal muscle mass and strength in mice.

Acetate is a short-chain fatty acid (SCFA) that is produced by microbiota in the intestinal tract. It is an important nutrient for the intestinal epithelium, but also has a high plasma concentration and is used in the various tissues. Acetate is involved in endurance exercise, but its role in resistance exercise remains unclear. To investigate this, mice were administered either multiple antibiotics with and without oral acetate supplementation or fed a low-fiber diet. Antibiotic treatment for 2 weeks significantly reduced grip strength and the cross-sectional area (CSA) of muscle fiber compared with the control group. Intestinal concentrations of SCFAs were reduced in the antibiotic-treated group. Oral administration of acetate with antibiotics prevented antibiotic-induced weakness of skeletal muscle and reduced CSA of muscle fiber. Similarly, a low-fiber diet for 1 year significantly reduced the CSA of muscle fiber and fecal and plasma acetate concentrations. To investigate the role of acetate as an energy source, acetyl-CoA synthase 2 knockout mice were used. These mice had a shorter lifespan, reduced skeletal muscle mass and smaller CSA of muscle fiber than their wild type littermates. In conclusion, acetate derived from the intestinal microbiome can contribute to maintaining skeletal muscle performance.

Acetate Alleviates Gut Microbiota Depletion-Induced Retardation of Skeletal Muscle Growth and Development in Young Mice.

The normal growth and development of skeletal muscle is essential for the health of the body. The regulation of skeletal muscle by intestinal microorganisms and their metabolites has been continuously demonstrated. Acetate is the predominant short-chain fatty acids synthesized by gut microbiota through the fermentation of dietary fiber; however, the underlying molecular mechanisms governing the interaction between acetate and skeletal muscle during the rapid growth stage remains to be further elucidated. Herein, specific pathogen-free (SPF) mice, germ-free (GF) mice, and germ-free mice supplemented with sodium acetate (GS) were used to evaluate the effects of acetate on the skeletal muscle growth and development of young mice with gut microbiota deficiency. We found that the concentration of serum acetate, body mass gain, succinate dehydrogenase activity, and expression of the myogenesis maker gene of skeletal muscle in the GS group were higher than those in the GF group, following sodium acetate supplementation. Furthermore, the transcriptome analysis revealed that acetate activated the biological processes that regulate skeletal muscle growth and development in the GF group, which are otherwise inhibited due to a gut microbiota deficiency. The in vitro experiment showed that acetate up-regulated Gm16062 to promote skeletal muscle cell differentiation. Overall, our findings proved that acetate promotes skeletal muscle growth and development in young mice via increasing Gm16062 expression.

Acetate reprogrammes tumour metabolism and promotes PD-L1 expression and immune evasion by upregulating c-Myc.

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.

346. Therapeutic Potential of the Oral Supplementation of Gut Metabolite Acetate in Mitigating Traumatic Stress-Induced Impairments in Male Rats

346. Therapeutic Potential of the Oral Supplementation of Gut Metabolite Acetate in Mitigating Traumatic Stress-Induced Impairments in Male Rats

The Transcription Factors AcuK and AcuM Influence Siderophore Biosynthesis of Aspergillus fumigatus.

The mold Aspergillus fumigatus employs two high-affinity uptake systems, reductive iron assimilation (RIA) and siderophore-mediated iron acquisition (SIA), for the acquisition of the essential trace element iron. SIA has previously been shown to be crucial for virulence in mammalian hosts. Here, we show that a lack of AcuK or AcuM, transcription factors required for the activation of gluconeogenesis, decreases the production of both extra- and intracellular siderophores in A. fumigatus. The lack of AcuM or AcuK did not affect the expression of genes involved in RIA and SIA, suggesting that these regulators do not directly regulate iron homeostasis genes, but indirectly affect siderophore production through their influence on metabolism. Consistent with this, acetate supplementation reversed the intracellular siderophore production defect of ΔacuM and ΔacuK. Moreover, ΔacuM and ΔacuK displayed a similar growth defect under iron limitation and iron sufficiency, which suggests they have a general role in carbon metabolism apart from gluconeogenesis. In agreement with a potential role of the glyoxylate cycle in adaptation to iron starvation, transcript levels of the malate synthase-encoding acuE were found to be upregulated by iron limitation that is partially dependent on AcuK and AcuM. Together, these data demonstrate the influence of iron availability on carbon metabolism.

Effects of Sodium Acetate Supplementation on Growth, Hematologic and Plasma Biochemical Parameter, Lipid Deposition, and Intestinal Health of Juvenile Golden Pompano Trachinotus ovatus Fed High-Lipid Diets.

Experimental diets were formulated including the suitable lipid level (10%, PC), the high-lipid level (16%, HL), and HL containing sodium acetate diets (HS). Three diets were fed golden pompano (Trachinotus ovatus) (initial body weight: 12.88 ± 0.03 g) for 8 weeks. The results showed HL diets significantly increased hepatosomatic index (HSI) and abdominal fat percentage (ASF), aggravated liver lipid deposition, and caused blood metabolic disorder and liver damage (P < 0.05). Moreover, the fish fed HL diets significantly decreased intestinal villus number (VN) and muscular layer thickness (MLT) (P < 0.05), accompanied with an increased trend in the relative abundance of intestinal pathogenic bacteria such as Mycoplasma and Photobacterium. However, the fish fed HS diets significantly decreased the HSI and AFP, relieved hepatic lipid deposition, improved blood and liver metabolism, and intestinal morphology in comparison to the fish fed HL diets (P < 0.05). More importantly, sodium acetate addition improved intestinal microbiota by inhibiting the proportion of pathogens (Mycoplasma and Vibrio) and increasing the abundance of probiotics (Bacteroidales_S24-7_group_norank, Cetobacterium, Bacteroides, and Lachnospiraceae_NK4A136_group). Furthermore, there was a strong correlation between these bacteria (Mycoplasma, Vibrio, Lachnospiraceae_NK4A136_group, Bacteroidales_S24-7_group_norank, Bacteroides, and Cetobacterium) and main physiological indices. In conclusion, sodium acetate improved blood performance, alleviated hepatic lipid deposition induced by HL diets, and boosted the growth and intestinal health for golden pompano.

Host microbiome associated low intestinal acetate correlates with progressive NLRP3-dependent hepatic-immunotoxicity in early life microcystin-LR exposure

BackgroundMicrocystins (MCs), potent hepatotoxins pose a significant health risk to humans, particularly children, who are more vulnerable due to higher water intake and increased exposure during recreational activities.MethodsHere, we investigated the role of host microbiome-linked acetate in modulating inflammation caused by early-life exposure to the cyanotoxin Microcystin-LR (MC-LR) in a juvenile mice model.ResultsOur study revealed that early-life MC-LR exposure disrupted the gut microbiome, leading to a depletion of key acetate-producing bacteria and decreased luminal acetate concentration. Consequently, the dysbiosis hindered the establishment of a gut homeostatic microenvironment and disrupted gut barrier function. The NOD-like receptor family pyrin domain – containing 3 (NLRP3) inflammasome, a key player in MC-induced hepatoxicity emerged as a central player in this process, with acetate supplementation effectively preventing NLRP3 inflammasome activation, attenuating hepatic inflammation, and decreasing pro-inflammatory cytokine production. To elucidate the mechanism underlying the association between early-life MC-LR exposure and the progression of metabolic dysfunction associated steatotic liver disease (MASLD), we investigated the role of acetate binding to its receptor -G-protein coupled receptor 43 (GPR43) on NLRP3 inflammasome activation. Our results demonstrated that acetate-GPR43 signaling was crucial for decreasing NLRP3 protein levels and inhibiting NLRP3 inflammasome assembly. Further, acetate-induced decrease in NLRP3 protein levels was likely mediated through proteasomal degradation rather than autophagy. Overall, our findings underscore the significance of a healthy gut microbiome and its metabolites, particularly acetate, in the progression of hepatotoxicity induced by early life toxin exposure, crucial for MASLD progression.ConclusionsThis study highlights potential therapeutic targets in gut dysbiosis and NLRP3 inflammasome activation for mitigating toxin-associated inflammatory liver diseases.

Epigenetic landscape analysis reveals the significance of early reduced chromatin accessibility in osteoclastogenesis.

Recently improved techniques could provide snapshots of chromatin structure generated based on chromatin accessibility. Since chromatin accessibility determines transcriptional potential, it has been attempted in a variety of cell systems. However, there has been no genome-wide analysis of chromatin accessibility for the entire murine osteoclast (OC) differentiation process. We performed an Assay for Transposase-Accessible Chromatin (ATAC)-sequencing (seq) during RANKL-induced OC differentiation and found that global chromatin accessibility decreased, especially early in OC differentiation. The global histone H3K27Ac level, an active histone modification mark, was diminished during OC differentiation by western blot and histone extract experiments. Its genomic enrichment was also reduced based on publicly available H3K27Ac chromatin immunoprecipitation (ChIP)-seq data. ATAC-seq and H3K27Ac ChIP-seq data demonstrated that RANKL induced a less accessible chromatin state during OC differentiation. Restoration of reduced H3K27Ac, presumably representing accessible states upon acetate treatment, suppresses OC differentiation by provoking immune-related gene expression. Subsequential integrative analysis of ATAC-seq, RNA-seq after acetate treatment, and H3K27Ac ChIP-seq reveals that Irf8 and its downstream targets are the most vulnerable to chromatin accessibility changes and acetate supplementation. Taken together, our study generated chromatin accessibility maps during the whole OC differentiation and suggested perturbation of chromatin accessibility might be a potential therapeutic strategy for excessive OC diseases.