Short Chain Fatty Acid ⇒ Succinate {60000045} Record Keys Parent:Short Chain Fatty Acid Definition:Succinate Queue:[ ] Details Initialisation date:2020-09-17 Specification: Succinic acidSource: [ ] LinksInfolink Meta Information Structural Type:Fatty acid Functional Type:[ ] Function:Immun regulator, Pro-inflammatory Notes: [ ]Shared Reference Notes [1.1] [#Hypertension] - Elevated putative succinate-producing bacteria and #Acetate-producing bacteria > respectively, lower and higher mean arterial pressure in mouse - #Prevotella and #Klebsiella > overrepresented in individuals with pHTN or HTN. [1.2] [#Obesity] - Maternal consumption of #Sweeteners > altered cecal microbial composition and metabolism of #Propionate/#Lactate in their offspring. - Offspring daily body weight gain, liver weight and body fat > correlate positively to the relative abundance of key microbes and enzymes involved in succinate/#Propionate production while negatively correlated to that of #Lactose degradation and #Lactate production. - The altered #Propionate/#Lactate production in the cecum of weanlings from aspartame and stevia consuming dams implicates an altered ratio of dietary carbohydrate digestion, mainly #Lactose, in the small intestine vs. microbial fermentation in the large intestine. [1.3] [#Diabetes Type 2] [#Short Chain Fatty Acid] - SCFAs-induced improvements in adipose tissue metabolism can prevent insulin resistance, while succinate improves the host insulin sensitivity while preventing obesity. [#Obesity] - increased levels of succinate (an important metabolite of glucose metabolism) in plasma and feces of obese patients and a positive correlation between succinate levels and body weight. [1.4] [#High-protein diet] - the microbiota of high protein fed mice produces significantly higher quantities of extracellular vesicles, compared to those of mice fed high-carbohydrate or high-fat diets. These extracellular vesicles activate Toll-like receptor 4 to increase the epithelial expression of IgA-inducing cytokine, APRIL, B cell chemokine, CCL28, and the IgA transporter, PIGR. - succinate, produced in high concentrations by microbiota of high protein fed animals, increases generation of reactive oxygen species by bacteria, which in turn promotes extracellular vesicles production. [1.5] [#Human breast milk, #Infants] Infant > Breastfeeding > decreased #Acetate and increased succinate [1.6] [#Alzheimer’s disease] - The microbial pathways most associated with preclinical AD status in regression models share succinate as a product. - Succinate, known largely as an intermediate of the tricarboxylic acid cycle, is also a bacterial metabolite produced in the gut that has been associated with #Obesity and inflammatory bowel disease and is increasingly appreciated as immunomodulatory. [#Alzheimer’s disease] [#Short Chain Fatty Acid] - succinate is a major precursor for the short-chain fatty acid (SCFA) #Propionate, which has previously been found to be elevated in symptomatic individuals with AD, as well as in AD mouse models, compared with healthy controls. [1.7] - abundance of succinate-metabolizing #Odoribacteraceae was lower in #Obesity, with a significant variation in the gut microbiome under #Mediterranean diet. [1.8] - #Propionate biosynthesis at phylum level occurs via two modes: the #Lactate pathway regulated by #Firmicutes and the succinate pathway by #Bacteroidetes [1.9] [#Clostridioides difficile] - Succinate can promote the growth of some beneficial bacteria like #Clostridia spp. - It also allows harmful bacteria like C. difficile to thrive, [#Inflamatory bowel disease] - Abnormally high levels of succinate have been linked to inflammatory diseases like IBD and #Obesity. - This is likely due to succinate’s ability to stimulate pro-inflammatory immune cells. - #Vitamin B12 is a cofactor for the enzyme methylmalonyl-CoA mutase (MCM), which converts succinyl-CoA to methylmalonate in the succinate-#Propionate pathway. - Limiting #Vitamin B12 levels can lead to an accumulation of succinate. - succinate produced by the gut microbiota has the potential to regulate host homeostasis and treat diseases such as inflammation. - By signalling through its receptor SUCNR1, succinate enhances the activation of macrophages, dendritic cells, tuft cells, and T cells. - This can help fight infection but also exacerbate chronic inflammation. - the major producers of succinate in the mammalian gut belong to the phylum #Bacteroidota [#Inflamatory bowel disease] - administration of succinate to mice (mutants with chronic inflammatory arthritis and IBD) and to anti-CD3E-treated mice reduces intestinal inflammation and modulates the immune response in a tuft cell-dependent manner - succinate may initially trigger protective mechanisms in response to inflammation and subsequently add to inflammatory processes dysregulating the overall response and contributing to disease - members of the genus #Succinivibrio have been shown to produce succinates that promote tuft cell expansion and resolve intestinal inflammation in mice. [1.11] [#Prevotella copri] - succinate production by P. copri was shown to enhance #Glucose metabolism and insulin level [1.12] [#Cancer] - Succinate possesses the capacity to regulate tumorigenesis within specific intrinsic microenvironments. - succinate is now acknowledged as a classical tumorigenic signal, alongside its well-established association with inflammation. - accumulation of succinate in M1 macrophages is closely associated with the activation of toll-like receptor 4 (TLR4) signaling. Upon activation by LPS, TLR4 signaling is triggered, resulting in the disruption of the Krebs cycle - The accumulation of succinate has the potential to enhance inflammatory signaling and greatly influence the immuno-inflammatory response. - Succinate has been found to facilitate the production of cytokines through synergistic interactions with certain ligands, including tumor necrosis factor-α (TNF-α) - Succinate induces the activation of SUCNR1, which subsequently initiates signaling cascades via multiple pathways. Comparable to Gβ and Gγ signaling cascades, succinate stimulation results in the mobilization of calcium ions (Ca2+), accumulation of inositol trisphosphate (IP3), and phosphorylation involving extracellular regulated kinase (ERK) - During the state of ischemia, the absence of #Oxygen induces a reduction in mitochondrial respiration and a rise in the accumulation of succinate. [1.13] [#Autism] - #Citrate levels were higher in future ASD, consistent with increased succinate and #Citrate in urine, while #Uridine levels in stool positively correlated with #Faecalibacterium. [1.14] - #Parabacteroides distasonis alleviates #Obesity and metabolic dysfunctions via production of succinate and #Secondary bile acids. - Administration of #Parabacteroides distasonis leads to increased bile salt hydrolase (BSH) activity, inhibition of intestinal FXR signaling and decreased TCDCA levels in liverReferences Notes (1) [1.16]
