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Communications Biology Oct 2023Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Ethanol consumption has been reported to reduce morbidity in RA patients, but the mechanism behind it...
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Ethanol consumption has been reported to reduce morbidity in RA patients, but the mechanism behind it remains unclear. Our results showed that Muribaculaceae was predominant in the gut microbiota of mice after ethanol treatment, and the levels of microbiota metabolite acetate were increased. Acetate reduced arthritis severity in collagen-induced arthritis (CIA) mice, which was associated with a decrease in the articular neutrophils and the myeloperoxidase-deoxyribonucleic acid complex in serum. Meanwhile, in vitro experiments confirmed that acetate affected neutrophil activity by acting on G-protein-coupled receptor 43, which reduced endoplasmic reticulum stress in neutrophils and inhibited neutrophil extracellular traps formation. Furthermore, exogenous acetate reversed CIA mice with exacerbated gut microbial disruption, further confirming that the effect of gut microbial metabolite acetate on neutrophils in vivo is crucial for the immune regulation. Our findings illuminate the metabolic and cellular mechanisms of the gut-joint axis in the regulation of autoimmune arthritis, and may offer alternative avenues to replicate or induce the joint-protective benefits of ethanol without associated detrimental effects.
Topics: Humans; Mice; Animals; Extracellular Traps; Arthritis, Rheumatoid; Neutrophils; Arthritis, Experimental; Acetates
PubMed: 37884797
DOI: 10.1038/s42003-023-05473-y -
Emerging Topics in Life Sciences Feb 2024Short-chain fatty acids are known modulators of host-microbe interactions and can affect human health, inflammation, and outcomes of microbial infections. Acetate is the... (Review)
Review
Short-chain fatty acids are known modulators of host-microbe interactions and can affect human health, inflammation, and outcomes of microbial infections. Acetate is the most abundant but least well-studied of these modulators, with most studies focusing on propionate and butyrate, which are considered to be more potent. In this mini-review, we summarize current knowledge of acetate as an important anti-inflammatory modulator of interactions between hosts and microorganisms. This includes a summary of the pathways by which acetate is metabolized by bacteria and human cells, the functions of acetate in bacterial cells, and the impact that microbially derived acetate has on human immune function.
Topics: Humans; Fatty Acids, Volatile; Propionates; Acetates; Butyrates; Bacteria
PubMed: 36945843
DOI: 10.1042/ETLS20220092 -
Nature Communications Nov 2023Nephron endowment at birth impacts long-term renal and cardiovascular health, and it is contingent on the nephron progenitor cell (NPC) pool. Glycolysis modulation is...
Nephron endowment at birth impacts long-term renal and cardiovascular health, and it is contingent on the nephron progenitor cell (NPC) pool. Glycolysis modulation is essential for determining NPC fate, but the underlying mechanism is unclear. Combining RNA sequencing and quantitative proteomics we identify 267 genes commonly targeted by Wnt activation or glycolysis inhibition in NPCs. Several of the impacted pathways converge at Acetyl-CoA, a co-product of glucose metabolism. Notably, glycolysis inhibition downregulates key genes of the Mevalonate/cholesterol pathway and stimulates NPC differentiation. Sodium acetate supplementation rescues glycolysis inhibition effects and favors NPC maintenance without hindering nephrogenesis. Six2Cre-mediated removal of ATP-citrate lyase (Acly), an enzyme that converts citrate to acetyl-CoA, leads to NPC pool depletion, glomeruli count reduction, and increases Wnt4 expression at birth. Sodium acetate supplementation counters the effects of Acly deletion on cap-mesenchyme. Our findings show a pivotal role of acetyl-CoA metabolism in kidney development and uncover new avenues for manipulating nephrogenesis and preventing adult kidney disease.
Topics: Acetyl Coenzyme A; Sodium Acetate; Nephrons; Kidney; Stem Cells
PubMed: 38007516
DOI: 10.1038/s41467-023-43513-7 -
Microbiome Oct 2023Ruminant livestock production is a considerable source of enteric methane (CH) emissions. In a previous study, we found that dietary inclusions of Bacillus subtilis (BS)...
BACKGROUND
Ruminant livestock production is a considerable source of enteric methane (CH) emissions. In a previous study, we found that dietary inclusions of Bacillus subtilis (BS) and Macleaya cordata extract (MCE) increased dry matter intake and milk production, while reduced enteric CH emission in dairy cows. The objective of this study was to further elucidate the impact of feeding BS and MCE on rumen methanogenesis in dairy cows using rumen metagenomics techniques.
RESULTS
Sixty dairy cows were blocked in 20 groups of 3 cows accordingly to their live weight, milk yield, and days in milk, and within each group, the 3 cows were randomly allocated to 1 of 3 treatments: control diet (CON), control diet plus BS (BS), and control diet plus MCE (MCE). After 75 days of feeding experimental diets, 12 cows were selected from each treatment for collection of rumen samples for the metagenomic sequencing. Results showed that BS decreased ruminal acetate and butyrate, while increased propionate concentrations, resulting in decreased acetate:propionate ratio. The metagenomics analysis revealed that MCE reduced relative abundances of Methanobrevibacter wolinii, Methanobrevibacter sp. AbM4, Candidatus Methanomassiliicoccus intestinalis, Methanobrevibacter cuticularis, Methanomicrobium mobile, Methanobacterium formicicum, and Methanobacterium congolense. Both BS and MCE reduced relative abundances of Methanosphaera sp. WGK6 and Methanosphaera stadtmanae. The co-occurrence network analysis of rumen bacteria and archaea revealed that dietary treatments influenced microbial interaction patterns, with BS and MCE cows having more and stronger associations than CON cows. The random forest and heatmaps analysis demonstrated that the Halopenitus persicus was positively correlated with fat- and protein-corrected milk yield; Clostridium sp. CAG 269, Clostridium sp. 27 14, Haloarcula rubripromontorii, and Methanobrevibacter curvatus were negatively correlated with rumen acetate and butyrate concentrations, and acetate:propionate ratio, whereas Selenomonas rumiantium was positively correlated with those variables.
CONCLUSIONS
The present results provided new information for mitigation of enteric methane emissions of dairy cows by feeding BS and MCE to influence rumen microbial activities. This fundamental knowledge is essential for developing enteric CH4 reduction strategies to mitigate climate change and reduce dietary energy waste. Video Abstract.
Topics: Female; Cattle; Animals; Lactation; Bacillus subtilis; Rumen; Propionates; Methane; Diet; Microbiota; Acetates; Butyrates; Plant Extracts; Fermentation
PubMed: 37858227
DOI: 10.1186/s40168-023-01654-3 -
World Journal of Gastroenterology Sep 2023The liver is one of the organs most commonly involved in metastatic disease, especially due to its unique vascularization. It's well known that liver metastases... (Review)
Review
The liver is one of the organs most commonly involved in metastatic disease, especially due to its unique vascularization. It's well known that liver metastases represent the most common hepatic malignant tumors. From a practical point of view, it's of utmost importance to evaluate the presence of liver metastases when staging oncologic patients, to select the best treatment possible, and finally to predict the overall prognosis. In the past few years, imaging techniques have gained a central role in identifying liver metastases, thanks to ultrasonography, contrast-enhanced computed tomography (CT), and magnetic resonance imaging (MRI). All these techniques, especially CT and MRI, can be considered the non-invasive reference standard techniques for the assessment of liver involvement by metastases. On the other hand, the liver can be affected by different focal lesions, sometimes benign, and sometimes malignant. On these bases, radiologists should face the differential diagnosis between benign and secondary lesions to correctly allocate patients to the best management. Considering the above-mentioned principles, it's extremely important to underline and refresh the broad spectrum of liver metastases features that can occur in everyday clinical practice. This review aims to summarize the most common imaging features of liver metastases, with a special focus on typical and atypical appearance, by using MRI.
Topics: Humans; Contrast Media; Gadolinium DTPA; Liver Neoplasms; Magnetic Resonance Imaging; Liver
PubMed: 37901445
DOI: 10.3748/wjg.v29.i36.5180 -
NPJ Biofilms and Microbiomes Dec 2023Spinal cord injury (SCI) can reshape gut microbial composition, significantly affecting clinical outcomes in SCI patients. However, mechanisms regarding gut-brain...
Spinal cord injury (SCI) can reshape gut microbial composition, significantly affecting clinical outcomes in SCI patients. However, mechanisms regarding gut-brain interactions and their clinical implications have not been elucidated. We hypothesized that short-chain fatty acids (SCFAs), intestinal microbial bioactive metabolites, may significantly affect the gut-brain axis and enhance functional recovery in a mouse model of SCI. We enrolled 59 SCI patients and 27 healthy control subjects and collected samples. Thereafter, gut microbiota and SCFAs were analyzed using 16 S rDNA sequencing and gas chromatography-mass spectrometry, respectively. We observed an increase in Actinobacteriota abundance and a decrease in Firmicutes abundance. Particularly, the SCFA-producing genera, such as Faecalibacterium, Megamonas, and Agathobacter were significantly downregulated among SCI patients compared to healthy controls. Moreover, SCI induced downregulation of acetic acid (AA), propionic acid (PA), and butyric acid (BA) in the SCI group. Fecal SCFA contents were altered in SCI patients with different injury course and injury segments. Main SCFAs (AA, BA, and PA) were administered in combination to treat SCI mice. SCFA supplementation significantly improved locomotor recovery in SCI mice, enhanced neuronal survival, promoted axonal formation, reduced astrogliosis, and suppressed microglial activation. Furthermore, SCFA supplementation downregulated NF-κB signaling while upregulating neurotrophin-3 expression following SCI. Microbial sequencing and metabolomics analysis showed that SCI patients exhibited a lower level of certain SCFAs and related bacterial strains than healthy controls. SCFA supplementation can reduce inflammation and enhance nourishing elements, facilitating the restoration of neurological tissues and the improvement of functional recuperation. Trial registration: This study was registered in the China Clinical Trial Registry ( www.chictr.org.cn ) on February 13, 2017 (ChiCTR-RPC-17010621).
Topics: Humans; Mice; Animals; Dysbiosis; Fatty Acids, Volatile; Acetic Acid; Spinal Cord Injuries; Bacteria; Butyric Acid
PubMed: 38092763
DOI: 10.1038/s41522-023-00466-5 -
Microbiome Sep 2023High-copper diets have been widely used to promote growth performance of pigs, but excess copper supplementation can also produce negative effects on ecosystem stability...
BACKGROUND
High-copper diets have been widely used to promote growth performance of pigs, but excess copper supplementation can also produce negative effects on ecosystem stability and organism health. High-copper supplementation can damage the intestinal barrier and disturb the gut microbiome community. However, the specific relationship between high-copper-induced intestinal damage and gut microbiota or its metabolites is unclear.
OBJECTIVE
Using fecal microbiota transplantation and metagenomic sequencing, responses of colonic microbiota to a high-copper diet was profiled. In addition, via comparison of specific bacteria and its metabolites rescue, we investigated a network of bacteria-metabolite interactions involving conversion of specific metabolites as a key mechanism linked to copper-induced damage of the colon.
RESULTS
High copper induced colonic damage, Lactobacillus extinction, and reduction of SCFA (acetate and butyrate) concentrations in pigs. LefSe analysis and q-PCR results confirmed the extinction of L. johnsonii. In addition, transplanting copper-rich fecal microbiota to ABX mice reproduced the gut characteristics of the pig donors. Then, L. johnsonii rescue could restore decreased SCFAs (mainly acetate and butyrate) and colonic barrier damage including thinner mucus layer, reduced colon length, and tight junction protein dysfunction. Given that acetate and butyrate concentrations exhibited a positive correlation with L. johnsonii abundance, we investigated how L. johnsonii exerted its effects by supplementing acetate and butyrate. L. johnsonii and butyrate administration but not acetate could correct the damaged colonic barrier. Acetate administration had no effects on butyrate concentration, indicating blocked conversion from acetate to butyrate. Furthermore, L. johnsonii rescue enriched a series of genera with butyrate-producing ability, mainly Lachnospiraceae NK4A136 group.
CONCLUSIONS
For the first time, we reveal the microbiota-mediated mechanism of high-copper-induced colonic damage in piglets. A high-copper diet can induce extinction of L. johnsonii which leads to colonic barrier damage and loss of SCFA production. Re-establishment of L. johnsonii normalizes the SCFA-producing pathway and restores colonic barrier function. Mechanistically, Lachnospiraceae NK4A136 group mediated conversion of acetate produced by L. johnsonii to butyrate is indispensable in the protection of colonic barrier function. Collectively, these findings provide a feasible mitigation strategy for gut damage caused by high-copper diets. Video Abstract.
Topics: Mice; Animals; Swine; Butyrates; Lactobacillus johnsonii; Copper; Acetates; Microbiota
PubMed: 37777765
DOI: 10.1186/s40168-023-01655-2 -
BMJ Open Sep 2023COVID-19 has caused morbidity, hospitalisation and mortality worldwide. Despite effective vaccines, there is still a need for effective treatments, especially for people... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
COVID-19 has caused morbidity, hospitalisation and mortality worldwide. Despite effective vaccines, there is still a need for effective treatments, especially for people in the community. Dietary supplements have long been used to treat respiratory infections, and preliminary evidence indicates some may be effective in people with COVID-19. We sought to evaluate whether a combination of vitamin C, vitamin D, vitamin K and zinc could improve overall health and decrease symptom burden in outpatients diagnosed with COVID-19.
METHODS
Participants were randomised to receive either vitamin C (6 g), vitamin D (1000 units), vitamin K (240 μg) and zinc acetate (75 mg) or placebo daily for 21 days and were followed for 12 weeks. An additional loading dose of 50 000 units vitamin D (or placebo) was given on day one. The primary outcome was participant-reported overall health using the EuroQol Visual Assessment Scale summed over 21 days. Secondary outcomes included health status, symptom severity, symptom duration, delayed return to usual health, frequency of hospitalisation and mortality.
RESULTS
90 patients (46 control, 44 treatment) were randomised. The study was stopped prematurely due to insufficient capacity for recruitment. The mean difference (control-treatment) in cumulative overall health was -37.4 (95% CI -157.2 to 82.3), p=0.53 on a scale of 0-2100. No clinically or statistically significant differences were seen in any secondary outcomes.
INTERPRETATION
In this double-blind, placebo-controlled, randomised trial of outpatients diagnosed with COVID-19, the dietary supplements vitamin C, vitamin D, vitamin K and zinc acetate showed no clinically or statistically significant effects on the documented measures of health compared with a placebo when given for 21 days. Termination due to feasibility limited our ability to demonstrate the efficacy of these supplements for COVID-19. Further research is needed to determine clinical utility.
TRIAL REGISTRATION NUMBER
NCT04780061.
Topics: Humans; SARS-CoV-2; COVID-19; Zinc Acetate; Dietary Supplements; Vitamins; Ascorbic Acid; Cholecalciferol; Vitamin K 2
PubMed: 37739466
DOI: 10.1136/bmjopen-2023-073761 -
The EMBO Journal Aug 2023Acetate, a major by-product of glycolytic metabolism in Escherichia coli and many other microorganisms, has long been considered a toxic waste compound that inhibits...
Acetate, a major by-product of glycolytic metabolism in Escherichia coli and many other microorganisms, has long been considered a toxic waste compound that inhibits microbial growth. This counterproductive auto-inhibition represents a major problem in biotechnology and has puzzled the scientific community for decades. Recent studies have however revealed that acetate is also a co-substrate of glycolytic nutrients and a global regulator of E. coli metabolism and physiology. Here, we used a systems biology strategy to investigate the mutual regulation of glycolytic and acetate metabolism in E. coli. Computational and experimental analyses demonstrate that decreasing the glycolytic flux enhances co-utilization of acetate with glucose. Acetate metabolism thus compensates for the reduction in glycolytic flux and eventually buffers carbon uptake so that acetate, rather than being toxic, actually enhances E. coli growth under these conditions. We validated this mechanism using three orthogonal strategies: chemical inhibition of glucose uptake, glycolytic mutant strains, and alternative substrates with a natively low glycolytic flux. In summary, acetate makes E. coli more robust to glycolytic perturbations and is a valuable nutrient, with a beneficial effect on microbial growth.
Topics: Escherichia coli; Glycolysis; Acetates; Carbon; Biotechnology; Glucose
PubMed: 37303231
DOI: 10.15252/embj.2022113079 -
Arthritis Research & Therapy Aug 2023Rheumatoid arthritis (RA) is one of the most prevalent and debilitating joint diseases worldwide. RA is characterized by synovial inflammation (synovitis), which is...
BACKGROUND
Rheumatoid arthritis (RA) is one of the most prevalent and debilitating joint diseases worldwide. RA is characterized by synovial inflammation (synovitis), which is linked to the development of joint destruction. Magnetic resonance imaging and ultrasonography are widely being used to detect the presence and extent of synovitis. However, these techniques do not reveal the activation status of inflammatory cells such as macrophages that play a crucial role in synovitis and express CD64 (Fc gamma receptor (FcγR)I) which is considered as macrophage activation marker.
OBJECTIVES
We aimed to investigate CD64 expression and its correlation with pro-inflammatory cytokines and pro-damaging factors in human-derived RA synovium. Furthermore, we aimed to set up a molecular imaging modality using a radiolabeled CD64-specific antibody as a novel imaging tracer that could be used to determine the extent and phenotype of synovitis using optical and nuclear imaging.
METHODS
First, we investigated CD64 expression in synovium of early- and late-stage RA patients and studied its correlation with the expression of pro-inflammatory and tissue-damaging factors. Next, we conjugated an anti-CD64 antibody with IRDye 800CW and diethylenetriamine penta-acetic acid (DTPA; used for In labeling) and tested its binding on cultured THP1 cells, ex vivo RA synovium explants and its imaging potential in SCID mice implanted with human RA synovium explants obtained from RA patients who underwent total joint replacement.
RESULTS
We showed that CD64 is expressed in synovium of early and late-stage RA patients and that FCGR1A/CD64 expression is strongly correlated with factors known to be involved in RA progression. Combined, this makes CD64 a useful marker for imaging the extent and phenotype of synovitis. We reported higher binding of the [In]In-DTPA-IRDye 800CW anti-CD64 antibody to in vitro cultured THP1 monocytes and ex vivo RA synovium compared to isotype control. In human RA synovial explants implanted in SCID mice, the ratio of uptake of the antibody in synovium over blood was significantly higher when injected with anti-CD64 compared to isotype and injecting an excess of unlabeled antibody significantly reduced the antibody-binding associated signal, both indicating specific receptor binding.
CONCLUSION
Taken together, we successfully developed an optical and nuclear imaging modality to detect CD64 in human RA synovium in vivo.
Topics: Mice; Animals; Humans; Mice, SCID; Molecular Imaging; Synovitis; Arthritis, Rheumatoid; Biomarkers; Antibodies; Immunoglobulin Isotypes; Pentetic Acid
PubMed: 37653557
DOI: 10.1186/s13075-023-03147-y