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Advances in Nutrition (Bethesda, Md.) Jan 2018Butyrate, a four-carbon short-chain fatty acid, is produced through microbial fermentation of dietary fibers in the lower intestinal tract. Endogenous butyrate... (Review)
Review
Butyrate, a four-carbon short-chain fatty acid, is produced through microbial fermentation of dietary fibers in the lower intestinal tract. Endogenous butyrate production, delivery, and absorption by colonocytes have been well documented. Butyrate exerts its functions by acting as a histone deacetylase (HDAC) inhibitor or signaling through several G protein-coupled receptors (GPCRs). Recently, butyrate has received particular attention for its beneficial effects on intestinal homeostasis and energy metabolism. With anti-inflammatory properties, butyrate enhances intestinal barrier function and mucosal immunity. However, the role of butyrate in obesity remains controversial. Growing evidence has highlighted the impact of butyrate on the gut-brain axis. In this review, we summarize the present knowledge on the properties of butyrate, especially its potential effects and mechanisms involved in intestinal health and obesity.
Topics: Anti-Inflammatory Agents; Butyrates; Colon; Dietary Fiber; Energy Metabolism; Fermentation; Gastrointestinal Microbiome; Glycolipids; Histone Deacetylase Inhibitors; Humans; Intestinal Absorption; Intestinal Mucosa; Obesity; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 29438462
DOI: 10.1093/advances/nmx009 -
Molecules (Basel, Switzerland) Jan 2021Worldwide obesity is a public health concern that has reached pandemic levels. Obesity is the major predisposing factor to comorbidities, including type 2 diabetes,... (Review)
Review
Worldwide obesity is a public health concern that has reached pandemic levels. Obesity is the major predisposing factor to comorbidities, including type 2 diabetes, cardiovascular diseases, dyslipidemia, and non-alcoholic fatty liver disease. The common forms of obesity are multifactorial and derive from a complex interplay of environmental changes and the individual genetic predisposition. Increasing evidence suggest a pivotal role played by alterations of gut microbiota (GM) that could represent the causative link between environmental factors and onset of obesity. The beneficial effects of GM are mainly mediated by the secretion of various metabolites. Short-chain fatty acids (SCFAs) acetate, propionate and butyrate are small organic metabolites produced by fermentation of dietary fibers and resistant starch with vast beneficial effects in energy metabolism, intestinal homeostasis and immune responses regulation. An aberrant production of SCFAs has emerged in obesity and metabolic diseases. Among SCFAs, butyrate emerged because it might have a potential in alleviating obesity and related comorbidities. Here we reviewed the preclinical and clinical data that contribute to explain the role of butyrate in this context, highlighting its crucial contribute in the diet-GM-host health axis.
Topics: Acetates; Animals; Butyrates; Dietary Fiber; Energy Metabolism; Fatty Acids, Volatile; Gastrointestinal Microbiome; Humans; Obesity; Propionates; Protective Agents
PubMed: 33525625
DOI: 10.3390/molecules26030682 -
Nutrients May 2023: Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder characterized by aberrant immune responses and... (Review)
Review
: Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder characterized by aberrant immune responses and compromised barrier function in the gastrointestinal tract. IBD is associated with altered gut microbiota and their metabolites in the colon. Butyrate, a gut microbial metabolite, plays a crucial role in regulating immune function, epithelial barrier function, and intestinal homeostasis. In this review, we aim to present an overview of butyrate synthesis and metabolism and the mechanism of action of butyrate in maintaining intestinal homeostasis and to discuss the therapeutic implications of butyrate in IBD. We searched the literature up to March 2023 through PubMed, Web of Science, and other sources using search terms such as butyrate, inflammation, IBD, Crohn's disease, and ulcerative colitis. Clinical studies in patients and preclinical studies in rodent models of IBD were included in the summary of the therapeutic implications of butyrate. Research in the last two decades has shown the beneficial effects of butyrate on gut immune function and epithelial barrier function. Most of the preclinical and clinical studies have shown the positive effect of butyrate oral supplements in reducing inflammation and maintaining remission in colitis animal models and IBD patients. However, butyrate enema showed mixed effects. Butyrogenic diets, including germinated barley foodstuff and oat bran, are found to increase fecal butyrate concentrations and reduce the disease activity index in both animal models and IBD patients. The current literature suggests that butyrate is a potential add-on therapy to reduce inflammation and maintain IBD remission. Further clinical studies are needed to determine if butyrate administration alone is an effective therapeutic treatment for IBD.
Topics: Animals; Crohn Disease; Colitis, Ulcerative; Butyrates; Gastrointestinal Microbiome; Inflammatory Bowel Diseases; Inflammation
PubMed: 37242159
DOI: 10.3390/nu15102275 -
Circulation Research Oct 2022Despite available clinical management strategies, chronic kidney disease (CKD) is associated with severe morbidity and mortality worldwide, which beckons new solutions....
BACKGROUND
Despite available clinical management strategies, chronic kidney disease (CKD) is associated with severe morbidity and mortality worldwide, which beckons new solutions. Host-microbial interactions with a depletion of in CKD are reported. However, the mechanisms about if and how can be used as a probiotic to treat CKD remains unknown.
METHODS
We evaluated the microbial compositions in 2 independent CKD populations for any potential probiotic. Next, we investigated if supplementation of such probiotic in a mouse CKD model can restore gut-renal homeostasis as monitored by its effects on suppression on renal inflammation, improvement in gut permeability and renal function. Last, we investigated the molecular mechanisms underlying the probiotic-induced beneficial outcomes.
RESULTS
We observed significant depletion of in the patients with CKD in both Western (n=283) and Eastern populations (n=75). Supplementation of to CKD mice reduced renal dysfunction, renal inflammation, and lowered the serum levels of various uremic toxins. These are coupled with improved gut microbial ecology and intestinal integrity. Moreover, we demonstrated that the beneficial effects in kidney induced by -derived butyrate were through the GPR (G protein-coupled receptor)-43.
CONCLUSIONS
Using a mouse CKD model, we uncovered a novel beneficial role of in the restoration of renal function in CKD, which is, at least in part, attributed to the butyrate-mediated GPR-43 signaling in the kidney. Our study provides the necessary foundation to harness the therapeutic potential of for ameliorating CKD.
Topics: Animals; Butyrates; Disease Models, Animal; Faecalibacterium prausnitzii; Inflammation; Kidney; Receptors, G-Protein-Coupled; Renal Insufficiency, Chronic
PubMed: 36164984
DOI: 10.1161/CIRCRESAHA.122.320184 -
Science Advances Nov 2023Inflammation-associated insulin resistance is a key trigger of gestational diabetes mellitus (GDM), but the underlying mechanisms and effective interventions remain...
Inflammation-associated insulin resistance is a key trigger of gestational diabetes mellitus (GDM), but the underlying mechanisms and effective interventions remain unclear. Here, we report the association of placental inflammation (tumor necrosis factor-α) and abnormal maternal glucose metabolism in patients with GDM, and a high fermentable dietary fiber (HFDF; ) could reduce GDM development through gut flora-short-chain fatty acid-placental inflammation axis in GDM mouse model. Mechanistically, HFDF increases abundances of and butyrate, reduces placental-derived inflammation by enhancing gut barrier and inhibiting the transfer of bacterial-derived lipopolysaccharide, and ultimately resists high-fat diet-induced insulin resistance. and butyrate have similar anti-GDM and anti-placental inflammation effects, and they can ameliorate placental function and pregnancy outcome effects probably by dampening placental immune dysfunction. These findings demonstrate the involvement of important placental inflammation-related mechanisms in the progression of GDM and the great potential of HFDFs to reduce susceptibility to GDM through gut-flora-placenta axis.
Topics: Animals; Mice; Pregnancy; Humans; Female; Diabetes, Gestational; Placenta; Insulin Resistance; Butyrates; Inflammation
PubMed: 37922350
DOI: 10.1126/sciadv.adi7337 -
British Journal of Pharmacology Dec 2019Acute pancreatitis (AP) is a common acute abdominal condition, frequently associated with intestinal barrier dysfunction, which aggravates AP retroactively. Butyrate...
BACKGROUND AND PURPOSE
Acute pancreatitis (AP) is a common acute abdominal condition, frequently associated with intestinal barrier dysfunction, which aggravates AP retroactively. Butyrate exhibits anti-inflammatory effects in a variety of inflammatory diseases. However, its potential beneficial effect on AP and the underlying mechanisms have not been investigated.
EXPERIMENTAL APPROACH
Experimental AP was induced by caerulein hyperstimulation in wild-type and GPR109A mice. Sodium butyrate was administered intragastrically for 7 days prior to caerulein hyperstimulation. Anti-inflammatory mechanisms of butyrate were further investigated in peritoneal macrophages.
KEY RESULTS
Butyrate prophylaxis attenuated AP as shown by reduced serum amylase and lipase levels, pancreatic oedema, myeloperoxidase activity, and improved pancreatic morphology. Amelioration of pancreatic damage by butyrate was associated with reduced levels of TNF-α, IL-6, and CCL2 and suppressed activation of the NLRP3 inflammasome in both pancreas and colon. Further, butyrate ameliorated pancreatic inflammation by suppressing interactions between histone deacetylase 1 (HDAC1) and AP1 and STAT1 with increased histone acetylation at H3K9, H3K14, H3K18, and H3K27 loci, resulting in suppression of NLRP3 inflammasome activation and modulation of immune cell infiltration in pancreas. Additionally, butyrate mediated STAT1/AP1-NLRP3 inflammasome suppression via HDAC1 inhibition was demonstrated in peritoneal macrophage. In colon, butyrate inhibited NLRP3 inflammasome activation via GPR109A. Accordingly, the modulatory effects of butyrate on AP, AP-associated gut dysfunction, and NLRP3 inflammasome activation were diminished in GPR109A mice.
CONCLUSION AND IMPLICATIONS
Our study dissected tissue-specific anti-inflammatory mechanisms of butyrate during AP, suggesting that increased colonic levels of butyrate may be a strategy to protect against AP.
Topics: Acute Disease; Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Butyrates; Ceruletide; Female; Intestinal Diseases; Intestine, Small; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Pancreas; Pancreatitis
PubMed: 31347703
DOI: 10.1111/bph.14806 -
Frontiers in Endocrinology 2023Over the past few decades, increasing prevalence of obesity caused an enormous medical, social, and economic burden. As the sixth most important risk factor contributing... (Review)
Review
Over the past few decades, increasing prevalence of obesity caused an enormous medical, social, and economic burden. As the sixth most important risk factor contributing to the overall burden of disease worldwide, obesity not only directly harms the human body, but also leads to many chronic diseases such as diabetes, cardiovascular diseases (CVD), nonalcoholic fatty liver disease (NAFLD), and mental illness. Weight loss is still one of the most effective strategies against obesity and related disorders. Recently, the link between intestinal microflora and metabolic health has been constantly established. Butyrate, a four-carbon short-chain fatty acid, is a major metabolite of the gut microbiota that has many beneficial effects on metabolic health. The anti-obesity activity of butyrate has been demonstrated, but its mechanisms of action have not been fully described. This review summarizes current knowledge of butyrate, including its production, absorption, distribution, metabolism, and the effect and mechanisms involved in weight loss and obesity-related diseases. The aim was to contribute to and advance our understanding of butyrate and its role in obesity. Further exploration of butyrate and its pathway may help to identify new anti-obesity.
Topics: Humans; Butyrates; Obesity; Fatty Acids, Volatile; Risk Factors; Weight Loss
PubMed: 36909336
DOI: 10.3389/fendo.2023.1098881 -
Diabetes Jul 2009We examined the role of butyric acid, a short-chain fatty acid formed by fermentation in the large intestine, in the regulation of insulin sensitivity in mice fed a...
OBJECTIVE
We examined the role of butyric acid, a short-chain fatty acid formed by fermentation in the large intestine, in the regulation of insulin sensitivity in mice fed a high-fat diet.
RESEARCH DESIGN AND METHODS
In dietary-obese C57BL/6J mice, sodium butyrate was administrated through diet supplementation at 5% wt/wt in the high-fat diet. Insulin sensitivity was examined with insulin tolerance testing and homeostasis model assessment for insulin resistance. Energy metabolism was monitored in a metabolic chamber. Mitochondrial function was investigated in brown adipocytes and skeletal muscle in the mice.
RESULTS
On the high-fat diet, supplementation of butyrate prevented development of insulin resistance and obesity in C57BL/6 mice. Fasting blood glucose, fasting insulin, and insulin tolerance were all preserved in the treated mice. Body fat content was maintained at 10% without a reduction in food intake. Adaptive thermogenesis and fatty acid oxidation were enhanced. An increase in mitochondrial function and biogenesis was observed in skeletal muscle and brown fat. The type I fiber was enriched in skeletal muscle. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression was elevated at mRNA and protein levels. AMP kinase and p38 activities were elevated. In the obese mice, supplementation of butyrate led to an increase in insulin sensitivity and a reduction in adiposity.
CONCLUSIONS
Dietary supplementation of butyrate can prevent and treat diet-induced insulin resistance in mouse. The mechanism of butyrate action is related to promotion of energy expenditure and induction of mitochondria function.
Topics: Adipose Tissue, Brown; Animals; Body Temperature; Butyrates; Dietary Fats; Energy Metabolism; Histone Deacetylases; Insulin; Insulin Resistance; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mitochondria, Muscle; Muscle Fibers, Skeletal; Muscle, Skeletal; Obesity; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Reverse Transcriptase Polymerase Chain Reaction; Trans-Activators; Transcription Factors
PubMed: 19366864
DOI: 10.2337/db08-1637 -
Gut Microbes Dec 2023Gut bacteria provide benefits to the host and have been implicated in inflammatory bowel disease (IBD), where adherent-invasive (AIEC) pathobionts (., strain LF82) are...
Gut bacteria provide benefits to the host and have been implicated in inflammatory bowel disease (IBD), where adherent-invasive (AIEC) pathobionts (., strain LF82) are associated with Crohn's disease. -LF82 causes fragmentation of the epithelial mitochondrial network, leading to increased epithelial permeability. We hypothesized that butyrate would limit the epithelial mitochondrial disruption caused by -LF82. Human colonic organoids and the T84 epithelial cell line infected with -LF82 (MOI = 100, 4 h) showed a significant increase in mitochondrial network fission that was reduced by butyrate (10 mM) co-treatment. Butyrate reduced the loss of mitochondrial membrane potential caused by -LF82 and increased expression of PGC-1 mRNA, the master regulator of mitochondrial biogenesis. Metabolomics revealed that butyrate significantly altered -LF82 central carbon metabolism leading to diminished glucose uptake and increased succinate secretion. Correlating with preservation of mitochondrial network form/function, butyrate reduced -LF82 transcytosis across T84-cell monolayers. The use of the G-protein inhibitor, pertussis toxin, implicated GPCR signaling as critical to the effect of butyrate, and the free fatty acid receptor three (FFAR3, GPR41) agonist, AR420626, reproduced butyrate's effect in terms of ameliorating the loss of barrier function and reducing the mitochondrial fragmentation observed in -LF82 infected T84-cells and organoids. These data indicate that butyrate helps maintain epithelial mitochondrial form/function when challenged by -LF82 and that this occurs, at least in part, via FFAR3. Thus, loss of butyrate-producing bacteria in IBD in the context of pathobionts would contribute to loss of epithelial mitochondrial and barrier functions that could evoke disease and/or exaggerate a low-grade inflammation.
Topics: Humans; Escherichia coli; Escherichia coli Infections; Intestinal Mucosa; Fatty Acids, Nonesterified; Butyrates; Gastrointestinal Microbiome; Crohn Disease; Bacterial Adhesion
PubMed: 38078655
DOI: 10.1080/19490976.2023.2281011 -
Nature Communications Mar 2023Liver-resident natural killer cells, a unique lymphocyte subset in liver, develop locally and play multifaceted immunological roles. However, the mechanisms for the...
Liver-resident natural killer cells, a unique lymphocyte subset in liver, develop locally and play multifaceted immunological roles. However, the mechanisms for the maintenance of liver-resident natural killer cell homeostasis remain unclear. Here we show that early-life antibiotic treatment blunt functional maturation of liver-resident natural killer cells even at adulthood, which is dependent on the durative microbiota dysbiosis. Mechanistically, early-life antibiotic treatment significantly decreases butyrate level in liver, and subsequently led to defective liver-resident natural killer cell maturation in a cell-extrinsic manner. Specifically, loss of butyrate impairs IL-18 production in Kupffer cells and hepatocytes through acting on the receptor GPR109A. Disrupted IL-18/IL-18R signaling in turn suppresses the mitochondrial activity and the functional maturation of liver-resident natural killer cells. Strikingly, dietary supplementation of experimentally or clinically used Clostridium butyricum restores the impaired liver-resident natural killer cell maturation and function induced by early-life antibiotic treatment. Our findings collectively unmask a regulatory network of gut-liver axis, highlighting the importance of the early-life microbiota in the development of tissue-resident immune cells.
Topics: Butyrates; Gastrointestinal Microbiome; Interleukin-18; Liver; Killer Cells, Natural
PubMed: 36973277
DOI: 10.1038/s41467-023-37419-7