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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 -
Cells Jul 2021The microbial metabolite butyrate serves as a link between the intestinal microbiome and epithelium. The monocarboxylate transporters MCT1 and SMCT1 are the predominant... (Review)
Review
The microbial metabolite butyrate serves as a link between the intestinal microbiome and epithelium. The monocarboxylate transporters MCT1 and SMCT1 are the predominant means of butyrate transport from the intestinal lumen to epithelial cytoplasm, where the molecule undergoes rapid β-oxidation to generate cellular fuel. However, not all epithelial cells metabolize butyrate equally. Undifferentiated colonocytes, including neoplastic cells and intestinal stem cells at the epithelial crypt base preferentially utilize glucose over butyrate for cellular fuel. This divergent metabolic conditioning is central to the phenomenon known as "butyrate paradox", in which butyrate induces contradictory effects on epithelial proliferation in undifferentiated and differentiated colonocytes. There is evidence that accumulation of butyrate in epithelial cells results in histone modification and altered transcriptional activation that halts cell cycle progression. This manifests in the apparent protective effect of butyrate against colonic neoplasia. A corollary to this process is butyrate-induced inhibition of intestinal stem cells. Yet, emerging research has illustrated that the evolution of the crypt, along with butyrate-producing bacteria in the intestine, serve to protect crypt base stem cells from butyrate's anti-proliferative effects. Butyrate also regulates epithelial inflammation and tolerance to antigens, through production of anti-inflammatory cytokines and induction of tolerogenic dendritic cells. The role of butyrate in the pathogenesis and treatment of intestinal neoplasia, inflammatory bowel disease and malabsorptive states is evolving, and holds promise for the potential translation of butyrate's cellular function into clinical therapies.
Topics: Animals; Butyrates; Epithelial Cells; Gastrointestinal Microbiome; Homeostasis; Humans; Inflammation; Intestinal Mucosa
PubMed: 34359944
DOI: 10.3390/cells10071775 -
Cell Host & Microbe Oct 2022Abdominal aortic aneurysm (AAA) is an insidious and lethal vascular disease that lacks effective nonsurgical interventions. Gut microbiota dysbiosis plays key roles in...
Abdominal aortic aneurysm (AAA) is an insidious and lethal vascular disease that lacks effective nonsurgical interventions. Gut microbiota dysbiosis plays key roles in many diseases, but its relationship with AAA has not been fully elucidated. Herein, we reveal significant abnormalities in the gut microbe composition of AAA patients and confirm that gut microbiota dysbiosis is an important cause of AAA. Specifically, R. intestinalis was significantly reduced in AAA patients. Using AAA mice, we show that R. intestinalis and its metabolite butyrate significantly reduce neutrophil infiltration and NOX2-dependent neutrophil extracellular trap formation, inflammation, and abnormal phenotypic switching of vascular smooth muscle cells in the aortic wall, thereby markedly alleviating AAA development. Our research uncovers the role and mechanism of the gut microbiota in AAA development and provides insights into AAA prophylaxis from a microecological perspective.
Topics: Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Butyrates; Disease Models, Animal; Dysbiosis; Extracellular Traps; Gastrointestinal Microbiome; Mice; Mice, Inbred C57BL
PubMed: 36228585
DOI: 10.1016/j.chom.2022.09.004 -
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 -
Gut Microbes 2021Host-microbial cross-talk plays a crucial role in maintenance of gut homeostasis. However, how microbiota-derived metabolites, e.g., butyrate, regulate functions of...
Host-microbial cross-talk plays a crucial role in maintenance of gut homeostasis. However, how microbiota-derived metabolites, e.g., butyrate, regulate functions of neutrophils in the pathogenesis of inflammatory bowel disease (IBD) remains elusive. We sought to investigate the effects of butyrate on IBD neutrophils and elucidate the therapeutic potential in regulating mucosal inflammation. Peripheral neutrophils were isolated from IBD patients and healthy donors, and profiles of proinflammatory cytokines and chemokines were determined by qRT-PCR and ELISA, respectively. The migration and release of neutrophil extracellular traps (NETs) were studied by a Transwell model and immunofluorescence, respectively. The role of butyrate in regulating IBD neutrophils was evaluated in a DSS-induced colitis model in mice. We found that butyrate significantly inhibited IBD neutrophils to produce proinflammatory cytokines, chemokines, and calprotectins. Blockade of GPCR signaling with pertussis toxin (PTX) did not interfere the effects whereas pan-histone deacetylase (HDAC) inhibitor, trichostatin A (TSA) effectively mimicked the role of butyrate. Furthermore, studies confirmed that butyrate suppressed neutrophil migration and formation of NETs from both CD and UC patients. RNA sequencing analysis revealed that the immunomodulatory effects of butyrate on IBD neutrophils were involved in leukocyte activation, regulation of innate immune response and response to oxidative stress. Consistently, oral administration of butyrate markedly ameliorated mucosal inflammation in DSS-induced murine colitis through inhibition of neutrophil-associated immune responses such as proinflammatory mediators and NET formation. Our data thus reveal that butyrate constrains neutrophil functions and may serve as a novel therapeutic potential in the treatment of IBD.
Topics: Animals; Butyrates; Cells, Cultured; Colitis; Cytokines; Disease Models, Animal; Extracellular Traps; Gastrointestinal Microbiome; Histone Deacetylase Inhibitors; Histone Deacetylases; Homeostasis; Host Microbial Interactions; Humans; Hydroxamic Acids; Immunity, Innate; Inflammatory Bowel Diseases; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Neutrophils; Oxidative Stress; Pertussis Toxin; Receptors, G-Protein-Coupled
PubMed: 34494943
DOI: 10.1080/19490976.2021.1968257 -
Cell Communication and Signaling : CCS Aug 2023Short-chain fatty acids (SCFAs) are the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract. The absorption of SCFAs is... (Review)
Review
Short-chain fatty acids (SCFAs) are the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract. The absorption of SCFAs is mediated by substrate transporters, such as monocarboxylate transporter 1 and sodium-coupled monocarboxylate transporter 1, which promote cellular metabolism. An increasing number of studies have implicated metabolites produced by microorganisms as crucial executors of diet-based microbial influence on the host. SCFAs are important fuels for intestinal epithelial cells (IECs) and represent a major carbon flux from the diet, that is decomposed by the gut microbiota. SCFAs play a vital role in multiple molecular biological processes, such as promoting the secretion of glucagon-like peptide-1 by IECs to inhibit the elevation of blood glucose, increasing the expression of G protein-coupled receptors such as GPR41 and GPR43, and inhibiting histone deacetylases, which participate in the regulation of the proliferation, differentiation, and function of IECs. SCFAs affect intestinal motility, barrier function, and host metabolism. Furthermore, SCFAs play important regulatory roles in local, intermediate, and peripheral metabolisms. Acetate, propionate, and butyrate are the major SCFAs, they are involved in the regulation of immunity, apoptosis, inflammation, and lipid metabolism. Herein, we review the diverse functional roles of this major class of bacterial metabolites and reflect on their ability to affect intestine, metabolic, and other diseases. Video Abstract.
Topics: Fatty Acids, Volatile; Butyrates; Propionates; Gastrointestinal Tract; Apoptosis
PubMed: 37596634
DOI: 10.1186/s12964-023-01219-9 -
British Journal of Pharmacology Jan 2022Muscle protein catabolism in patients with diabetic nephropathy (DN) results in striking loss of muscle proteins, which increases morbidity and mortality risks. Evidence...
BACKGROUND AND PURPOSE
Muscle protein catabolism in patients with diabetic nephropathy (DN) results in striking loss of muscle proteins, which increases morbidity and mortality risks. Evidence shows that short-chain fatty acids (SCFAs) play an important role in health maintenance and disease development. Recently, the connection between butyrate (a SCFA) and DN has been revealed, although the relationship between butyrate and muscle atrophy remains unclear.
EXPERIMENTAL APPROACH
We studied changes in serum butyrate levels in DN patients using metabolomic analyses. In db/db mice, protective effects of butyrate on DN-induced muscle atrophy. were explored. Inhibition of muscle atrophy by butyrate and the underlying mechanism(s) were studied in C2C12 cells exposed to high glucose/lipopolysaccharide (HG/LPS).
KEY RESULTS
Butyrate levels in DN patients were significantly decreased. In db/db mice, supplementing normal diet with butyrate improved intestinal barrier function. Concurrently, butyrate alleviated muscle atrophy, promoted PI3K/Akt/mTOR signalling, and suppressed oxidative stress and autophagy in skeletal muscle of db/db mice, and in HG/LPS-exposed C2C12 cells. Further, FFA2 receptors, key components of SCFA signalling, were decreased in skeletal muscle of db/db mice and in HG/LPS-exposed C2C12 cells. Overexpression of FFA2 receptors activated PI3K/Akt/mTOR signalling and inhibited oxidative stress and autophagy in HG/LPS-exposed C2C12 cells. Silencing of FFA2 blocked PI3K/Akt/mTOR signalling that was improved by butyrate, as well as the suppression of oxidative stress and reduction of autophagy.
CONCLUSION AND IMPLICATION
Butyrate exerts protective effects on muscle atrophy induced by DN by enhancing intestinal barrier function and activating the FFA2 receptor-mediated PI3K/Akt/mTOR pathway.
Topics: Animals; Butyrates; Diabetes Mellitus; Diabetic Nephropathies; Humans; Mice; Muscle, Skeletal; Muscular Atrophy; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases
PubMed: 34638162
DOI: 10.1111/bph.15693 -
Journal of Experimental & Clinical... Jan 2022Immune checkpoint inhibitor-related cardiotoxicity is one of the most lethal adverse effects, and thus, the identification of underlying mechanisms for developing...
BACKGROUND
Immune checkpoint inhibitor-related cardiotoxicity is one of the most lethal adverse effects, and thus, the identification of underlying mechanisms for developing strategies to overcome it has clinical importance. This study aimed to investigate whether microbiota-host interactions contribute to PD-1/PD-L1 inhibitor-related cardiotoxicity.
METHODS
A mouse model of immune checkpoint inhibitor-related cardiotoxicity was constructed by PD-1/PD-L1 inhibitor BMS-1 (5 and 10 mg/kg), and cardiomyocyte apoptosis and cardiotoxicity were determined by hematoxylin and eosin, Masson's trichome and TUNEL assays. 16S rRNA sequencing was used to define the gut microbiota composition. Gut microbiota metabolites short-chain fatty acids (SCFAs) were determined by HPLC. The serum levels of myocardial enzymes (creatine kinase, aspartate transaminase, creatine kinase-MB and lactate dehydrogenase) and the production of M1 factors (TNF-α and IL-1β) were measured by ELISA. The colonic macrophage phenotype was measured by mmunofluorescence and qPCR. The expression of Claudin-1, Occludin, ZO-1 and p-p65 was measured by western blot. The gene expression of peroxisome proliferator-activated receptor α (PPARα) and cytochrome P450 (CYP) 4X1 was determined using qPCR. Statistical analyses were performed using Student's t-test for two-group comparisons, and one-way ANOVA followed by Student-Newman-Keul test for multiple-group comparisons.
RESULTS
We observed intestinal barrier injury and gut microbiota dysbiosis characterized by Prevotellaceae and Rikenellaceae genus depletion and Escherichia-Shigella and Ruminococcaceae genus enrichment, accompanied by low butyrate production and M1-like polarization of colonic macrophages in BMS-1 (5 and 10 mg/kg)-induced cardiotoxicity. Fecal microbiota transplantation mirrored the effect of BMS-1 on cardiomyocyte apoptosis and cardiotoxicity, while macrophage depletion and neutralization of TNF-α and IL-1β greatly attenuated BMS-1-induced cardiotoxicity. Importantly, Prevotella loescheii recolonization and butyrate supplementation alleviated PD-1/PD-L1 inhibitor-related cardiotoxicity. Mechanistically, gut microbiota dysbiosis promoted M1-like polarization of colonic macrophages and the production of proinflammatory factors TNF-α and IL-1β through downregulation of PPARα-CYP4X1 axis.
CONCLUSIONS
Intestinal barrier dysfunction amplifies PD-1/PD-L1 inhibitor-related cardiotoxicity by upregulating proinflammatory factors TNF-α and IL-1β in colonic macrophages via downregulation of butyrate-PPARα-CYP4X1 axis. Thus, targeting gut microbiota to polarize colonic macrophages away from the M1-like phenotype could provide a potential therapeutic strategy for PD-1/PD-L1 inhibitor-related cardiotoxicity.
Topics: Animals; Butyrates; Cardiotoxicity; Colon; Cytochrome P-450 Enzyme System; Disease Models, Animal; Fecal Microbiota Transplantation; Humans; Immune Checkpoint Inhibitors; Macrophages; Male; Mice; Transfection
PubMed: 34980222
DOI: 10.1186/s13046-021-02201-4 -
JAMA Network Open Dec 2022The pediatric obesity disease burden imposes the necessity of new effective strategies. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
The pediatric obesity disease burden imposes the necessity of new effective strategies.
OBJECTIVE
To determine whether oral butyrate supplementation as an adjunct to standard care is effective in the treatment of pediatric obesity.
DESIGN, SETTING, AND PARTICIPANTS
A randomized, quadruple-blind, placebo-controlled trial was performed from November 1, 2020, to December 31, 2021, at the Tertiary Center for Pediatric Nutrition, Department of Translational Medical Science, University of Naples Federico II, Naples, Italy. Participants included children aged 5 to 17 years with body mass index (BMI) greater than the 95th percentile.
INTERVENTIONS
Standard care for pediatric obesity supplemented with oral sodium butyrate, 20 mg/kg body weight per day, or placebo for 6 months was administered.
MAIN OUTCOMES AND MEASURES
The main outcome was the decrease of at least 0.25 BMI SD scores at 6 months. The secondary outcomes were changes in waist circumference; fasting glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, ghrelin, microRNA-221, and interleukin-6 levels; homeostatic model assessment of insulin resistance (HOMA-IR); dietary and lifestyle habits; and gut microbiome structure. Intention-to-treat analysis was conducted.
RESULTS
Fifty-four children with obesity (31 girls [57%], mean [SD] age, 11 [2.91] years) were randomized into the butyrate and placebo groups; 4 were lost to follow-up after receiving the intervention in the butyrate group and 2 in the placebo group. At intention-to-treat analysis (n = 54), children treated with butyrate had a higher rate of BMI decrease greater than or equal to 0.25 SD scores at 6 months (96% vs 56%, absolute benefit increase, 40%; 95% CI, 21% to 61%; P < .01). At per-protocol analysis (n = 48), the butyrate group showed the following changes as compared with the placebo group: waist circumference, -5.07 cm (95% CI, -7.68 to -2.46 cm; P < .001); insulin level, -5.41 μU/mL (95% CI, -10.49 to -0.34 μU/mL; P = .03); HOMA-IR, -1.14 (95% CI, -2.13 to -0.15; P = .02); ghrelin level, -47.89 μg/mL (95% CI, -91.80 to -3.98 μg/mL; P < .001); microRNA221 relative expression, -2.17 (95% CI, -3.35 to -0.99; P < .001); and IL-6 level, -4.81 pg/mL (95% CI, -7.74 to -1.88 pg/mL; P < .001). Similar patterns of adherence to standard care were observed in the 2 groups. Baseline gut microbiome signatures predictable of the therapeutic response were identified. Adverse effects included transient mild nausea and headache reported by 2 patients during the first month of butyrate intervention.
CONCLUSIONS AND RELEVANCE
Oral butyrate supplementation may be effective in the treatment of pediatric obesity.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04620057.
Topics: Child; Female; Humans; Butyrates; Cholesterol; Double-Blind Method; Ghrelin; Insulin; MicroRNAs; Pediatric Obesity; Male; Adolescent
PubMed: 36469320
DOI: 10.1001/jamanetworkopen.2022.44912 -
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