Effect of butyrate stimulation on CD19 CAR-T cells for the treatment of Non-Hodgkin Lymphoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE269341 | GEO | 2025/10/08
REPOSITORIES: GEO
Similar Datasets
Project description:Short chain fatty acids (SCFAs) are immunomodulatory compounds produced by the microbiome through fermentation of dietary fibre. Although they are generally considered beneficial for gut health, patients suffering from inflammatory bowel disease (IBD) have shown poor tolerance to fibre-rich diets, suggesting that SCFAs may have contrary effects under inflammatory conditions. To investigate this, we examined the effect of SCFAs on human macrophages in the presence of toll-like receptor agonists. In contrast to their anti-inflammatory effects under steady state conditions, we observed that the SCFAs butyrate and propionate triggered the activation of the NLRP3 inflammasome when added in conjunction with TLR agonists. Mechanistically, butyrate and propionate activated NLRP3 by inhibiting HDACs 1-3 and 10, leading to an uneven distribution of histone hyperacetylation that resulted in alterations in the transcriptome. Specifically, there was a lack of hyperacetylation at the loci of the CFLAR and IL10 genes, two important inhibitors of NLRP3 inflammasome activation. The concurrent loss of transcription and protein expression of cFLIP and IL-10 enabled caspase-8-dependent NLRP3-inflammasome activation. SCFA-driven NLRP3 activation did not require potassium efflux and did not result in cell death but rather triggered hyperactivation and IL-1b release. Our findings demonstrate that butyrate and propionate are bacterially-derived, viability-dependent danger signals (vita-PAMPs) that regulate NLRP3 inflammasome activation through epigenetic modulation of the inflammatory response.
2024-08-19 | GSE248578 | GEO
Project description:Short chain fatty acids (SCFAs) are immunomodulatory compounds produced by the microbiome through fermentation of dietary fibre. Although they are generally considered beneficial for gut health, patients suffering from inflammatory bowel disease (IBD) have shown poor tolerance to fibre-rich diets, suggesting that SCFAs may have contrary effects under inflammatory conditions. To investigate this, we examined the effect of SCFAs on human macrophages in the presence of toll-like receptor agonists. In contrast to their anti-inflammatory effects under steady state conditions, we observed that the SCFAs butyrate and propionate triggered the activation of the NLRP3 inflammasome when added in conjunction with TLR agonists. Mechanistically, butyrate and propionate activated NLRP3 by inhibiting HDACs 1-3 and 10, leading to an uneven distribution of histone hyperacetylation that resulted in alterations in the transcriptome. Specifically, there was a lack of hyperacetylation at the loci of the CFLAR and IL10 genes, two important inhibitors of NLRP3 inflammasome activation. The concurrent loss of transcription and protein expression of cFLIP and IL-10 enabled caspase-8-dependent NLRP3-inflammasome activation. SCFA-driven NLRP3 activation did not require potassium efflux and did not result in cell death but rather triggered hyperactivation and IL-1b release. Our findings demonstrate that butyrate and propionate are bacterially-derived, viability-dependent danger signals (vita-PAMPs) that regulate NLRP3 inflammasome activation through epigenetic modulation of the inflammatory response.
2024-08-19 | GSE248577 | GEO
Project description:Background: Short-chain fatty acids (SCFAs), mainly acetate, propionate and butyrate, are produced by gut microbiota through fermentation of complex carbohydrates that cannot be digested by the human host. They affect gut health and can contribute at the distal level to the pathophysiology of several diseases, including renal pathologies. Methods: SCFA levels were measured in chronic kidney disease (CKD) patients (n = 54) at different stages of the disease and associations with renal function and inflammation parameters were examined. The impact of propionate and butyrate in pathways triggered in tubular cells under inflammatory conditions was analysed using genome-wide expression assays. Finally, a pre-clinical mouse model of folic acid-induced transition from acute kidney injury to CKD was used to analyse the preventive and therapeutic potential of these microbial metabolites in the development of CKD. Results: Faecal levels of propionate and butyrate in CKD patients gradually reduce as the disease progresses, and do so in close association with established clinical parameters for serum creatinine, blood urea nitrogen and the estimated glomerular filtration rate. Propionate and butyrate jointly downregulated the expression of 103 genes related to inflammatory processes and immune system activation triggered by TNF-α in tubular cells. In vivo, the administration of propionate and butyrate, either before or soon after injury, respectively prevented and slowed the progression of damage. This was indicated by a decrease in renal injury markers, the expression of pro-inflammatory and pro-fibrotic markers, and recovery of renal function over the long term. Conclusions: Propionate and butyrate levels are associated with a progressive loss of renal function in CKD patients. Early administration of these SCFAs prevents disease advancement in a pre-clinical model of acute renal damage, demonstrating their therapeutic potential independently of the gut microbiota.
2024-05-02 | GSE221506 | GEO
Project description:We investigated the influence of SCFAs on human, monocyte derived DCs that represent a reliable in vitro model to study circulating DCs, one of the key regulators of our immune system. We studied the individual effect exerted by SCFA, the main metabolic end-products of fermentation by anaerobic bacteria in the gut, on the gene expression of immature and mature DC, exploring the potential of circulating bacterial metabolites to directly influence immune system cells. We found that SCFAs have little effect on the transcriptome of immature DC, whereas the transcriptome of mature DC was highly perturbed especially by butyrate and propionate. Our findings show an overall down-regulation of LPS-induced inflammatory responses and provide new insights into host-microbiome interactions. In this dataset, we include the expression data obtained from immature and matured (via lipopolysaccharide, LPS) human monocyte-derived dendritic cells untreated and treated with 1mM of acetate, butyrate, or propionate.
2015-12-28 | GSE66989 | GEO
Project description:Background and Aims: Many inflammatory diseases are associated with microbial dysbiosis, which may considerably alter the production of short-chain fatty acids (SCFAs). SCFAs are produced in the large bowel through bacterial fermentation of dietary fiber and play an important role in maintaining gut homeostasis. SCFAs, particularly acetate and butyrate, show beneficial immunomodulatory effects contributing to the prevention of inflammatory and allergic reactions. Thus, reduced production of SCFAs may impact on the mucosal immune responses critical to fighting pathogens. This study aims to determine the influence of SCFAs on a murine model of colonic bacterial infection. Methods: In the present study, we used acetate- (HAMSA) or butyrate- (HAMSB) yielding diets to deliver high concentrations of individual SCFAs to the large bowel of mice infected with C. rodentium. We assessed the effects of these SCFAs on clinical burden and gut pathogenicity in correlation with changes in bacteria growth, fecal microbiota composition, function and changes in the immunological profile. Results: Here we show in vitro that acetate and butyrate directly inhibited growth of the attaching and effacing (A/E) pathogen C. rodentium in a bacteriostatic manner. This correlated with reduced expression of Tir, a gene responsible for bacterial adherence and pathogenicity. Interestingly, HAMSA-fed mice presented reduced clinical scores during C. rodentium infection associated with high concentrations of fecal acetate. This was linked with compositional and functional changes in the microbiota when examining 16s sequencing and proteomics analysis. The HAMSA mediated is protection involved increased expression IL-22 and Muc-2 in the colon and increased numbers of CD8αα+ TCRγδ T cells in the colonic epithelium. These effects were dependent on GPR43, a metabolite-sensing GPCR that binds acetate. Conclusions: We established a promising new approach to moderate bacterial gut infections by manipulating the gut microbiota and mucosal immune tolerance through diets that yield the SCFA acetate.
2022-02-15 | PXD008149 | Pride
Project description:Fiber diet plays a beneficial role in neurocognitive disorders, like dementia and Alzheimer’s Disease. However, insufficient fiber consumption in public increases the concern about public health, particularly about neurocognitive diseases. To survey the association between fiber dietary and neurocognitive performances, mice were subjected to normal-fiber diet or low-fiber diet during gestation, and the neurocognitive functions of the offspring were assessed. We found that maternal low-fiber diet impaired the cognitive functions, and the impairments can be reversed by butyrate, rather than propionate intake. Mechanism studies showed that HDAC4 might become the most potential mediator in butyrate-dependent neurocognitive improvement. Besides, using human maternal serum and paired umbilical cord blood samples, we demonstrated that the SCFA levels in offspring are positively correlated with levels in maternal serum. Those results provide a solid basis for not only maternal fiber diet regulates neurocognitive functions in offspring through altering SCFA levels, but clinical practice in SCFAs-dependent maternal intervention for offspring health.
2020-08-25 | GSE147022 | GEO
Project description:Short-chain fatty acids (SCFAs) are the end-products of bacterial fermentation of dietary fibre, and can play a crucial role in regulating immunity and metabolism in the gut and peripheral tissues. Here we show that butyrrate, an SCFA, displayed antiviral effects in chicken respiratory epithelial cells, likely via the regulation of interferon-stimulated genes, particularly OASL. The observed antiviral signaling mechanism would involve HDAC inhibition and Sp1-dependent regulation of the OASL promoter, shedding light on new mechanisms through which the GM regulates poultry mucosal immunity along the gut-lung axis in the chicken.
2024-08-28 | E-MTAB-14346 | biostudies-arrayexpress
Project description:Intestinal epithelial cells and the intestinal microbiota are in a mutualistic relationship that is dependent on communication. This communication is multifaceted, but one aspect is communication through compounds produced by the microbiota such as the short-chain fatty acids (SCFAs) butyrate, propionate and acetate. Studying the effects of SCFAs and especially butyrate in intestinal epithelial cell lines like Caco-2 cells has been proven problematic. In contrast to the in vivo intestinal epithelium, Caco-2 cells do not use butyrate as an energy source, leading to a build-up of butyrate. Therefore, we used human induced pluripotent stem cell derived intestinal epithelial cells, grown as a cell layer, to study the effects of butyrate, propionate and acetate on whole genome gene expression in the cells. For this, cells were exposed to concentrations of 1 and 10 mM of the individual short-chain fatty acids for 24 hours. Unique gene expression profiles were observed for each of the SCFAs in a concentration-dependent manner. Evaluation on both an individual gene level and pathway level showed that butyrate induced the biggest effects followed by propionate and then acetate. Several known effects of SCFAs on intestinal cells were confirmed, such as effects on metabolism and immune responses. The changes in metabolic pathways in the intestinal epithelial cell layers in this study demonstrate that there is a switch in energy source from glucose to SCFAs, thus induced pluripotent stem cell derived intestinal epithelial cell are responding in a similar manner to SCFAs as in vivo intestinal tissues.
2022-08-08 | GSE200309 | GEO
Project description:Effect of butyrate stimulation on CD19 CAR-T cells for the treatment of Non-Hodgkin Lymphoma
| PRJNA1121250 | ENA
Project description:The gut microbiome engenders colonization resistance against the diarrheal pathogen Clostridioides difficile but the molecular basis of this colonization resistance is incompletely understood. A prominent class of gut microbiome-produced metabolites important for colonization resistance against C. difficile is short chain fatty acids (SCFAs). In particular, one SCFA (butyrate) decreases the fitness of C. difficile in vitro and is correlated with C. difficile-inhospitable gut environments, both in mice and in humans. Here, we demonstrate that butyrate-dependent growth inhibition in C. difficile occurs under conditions where C. difficile also produces butyrate as a metabolic end product. Furthermore, we show that exogenous butyrate is internalized into C. difficile cells and is incorporated into intracellular CoA pools where it is metabolized in a reverse (energetically unfavorable) direction to crotonyl-CoA and (S)-3-hydroxybutyryl-CoA and/or 4-hydroxybutyryl-CoA. This internalization of butyrate and reverse metabolic flow of butyrogenic pathway(s) in C. difficile coincides with alterations in toxin release and sporulation. Together, this work highlights butyrate as a marker of a C. difficile inhospitable environment to which C. difficile responds by releasing its diarrheagenic toxins and producing environmentally-resistant spores necessary for transmission between hosts. These findings provide foundational data for understanding the molecular and genetic basis of how C. difficile growth is inhibited by butyrate and how butyrate alters C. difficile virulence in the face of a highly competitive and dynamic gut environment.
2023-12-21 | GSE249810 | GEO