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EBioMedicine Apr 2018G Protein Coupled Receptor 109A (GPR109A), which belongs to the G protein coupled receptor family, can be activated by niacin, butyrate, and β-hydroxybutyric acid....
G Protein Coupled Receptor 109A (GPR109A), which belongs to the G protein coupled receptor family, can be activated by niacin, butyrate, and β-hydroxybutyric acid. Here, we assessed the anti-inflammatory activity of sodium butyrate (SB) on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis mice, an experimental model that resembles Crohn's disease, and explored the potential mechanism of SB in inflammatory bowel disease (IBD). In vivo, experimental GPR109a and wild-type (WT) mice were administered SB (5g/L) in their drinking water for 6weeks. The mice were then administered TNBS via rectal perfusion to imitate colitis. In vitro, RAW246.7 macrophages, Caco-2 cells, and primary peritoneal macrophages were used to investigate the protective roles of SB on lipopolysaccharide (LPS)-induced inflammatory response and epithelium barrier dysfunction. In vivo, SB significantly ameliorated the inflammatory response and intestinal epithelium barrier dysfunction in TNBS-induced WT mice, but failed to provide a protective effect in TNBS-induced GPR109a mice. In vitro, pre-treatment with SB dramatically inhibited the expression of TNF-α and IL-6 in LPS-induced RAW246.7 macrophages. SB inhibited the LPS-induced phosphorylation of the NF-κB p65 and AKT signaling pathways, but failed to inhibit the phosphorylation of the MAPK signaling pathway. Our data indicated that SB ameliorated the TNBS-induced inflammatory response and intestinal epithelium barrier dysfunction through activating GPR109A and inhibiting the AKT and NF-κB p65 signaling pathways. These findings therefore extend the understanding of GPR109A receptor function and provide a new theoretical basis for treatment of IBD.
Topics: Animals; Butyric Acid; Caco-2 Cells; Colon; Cytokines; Disease Models, Animal; Epithelium; Humans; Inflammation; Inflammatory Bowel Diseases; Lipopolysaccharides; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Mucin-2; Permeability; Phosphorylation; Proto-Oncogene Proteins c-akt; RAW 264.7 Cells; Signal Transduction; Survival Analysis; Tight Junctions; Transcription Factor RelA; Trinitrobenzenesulfonic Acid; Weight Loss
PubMed: 29627390
DOI: 10.1016/j.ebiom.2018.03.030 -
Frontiers in Cellular and Infection... 2022Accumulating evidence suggests that selected microbiota-derived metabolites play a significant role in both tumor prevention and supportive treatment of cancer.... (Review)
Review
Accumulating evidence suggests that selected microbiota-derived metabolites play a significant role in both tumor prevention and supportive treatment of cancer. Short-chain fatty acids (SCFAs), i.e., mainly acetate, proprionate, and butyrate, are one of them. Nowadays, it is known that butyrate is a key microbial metabolite. Therefore, in the current review, we focused on butyrate and sodium butyrate (NaB) in the context of colorectal cancer. Notably, butyrate is characterized by a wide range of beneficial properties/activities. Among others, it influences the function of the immune system, maintains intestinal barrier integrity, positively affects the efficiency of anti-cancer treatment, and may reduce the risk of mucositis induced by chemotherapy. Taking into consideration these facts, we analyzed NaB (which is a salt of butyric acid) and its impact on gut microbiota as well as anti-tumor activity by describing molecular mechanisms. Overall, NaB is available as, for instance, food with special medical purposes (depending on the country's regulation), and its administration seems to be a promising option for colorectal cancer patients.
Topics: Humans; Butyric Acid; Fatty Acids, Volatile; Gastrointestinal Microbiome; Microbiota; Colorectal Neoplasms
PubMed: 36389140
DOI: 10.3389/fcimb.2022.1023806 -
Microbiology Spectrum Oct 2022Young type 2 diabetes (T2D) affects 15% of the population, with a noted increase in cases, and T2D-related male infertility has become a serious issue in recent years....
Young type 2 diabetes (T2D) affects 15% of the population, with a noted increase in cases, and T2D-related male infertility has become a serious issue in recent years. The current study aimed to explore the improvements of alginate oligosaccharide (AOS)-modified gut microbiota on semen quality in T2D. The T2D was established in young mice of 5 weeks of age with a blood glucose level of 21.2 ± 2.2 mmol/L, while blood glucose was 8.7 ± 1.1 mM in control animals. We discovered that fecal microbiota transplantation (FMT) of AOS-improved microbiota (A10-FMT) significantly decreased blood glucose, while FMT of gut microbiota from control animals (Con-FMT) did not. Sperm concentration and motility were decreased in T2D to 10% to 20% of those in the control group, while A10-FMT brought about a recovery of around 5- to 10-fold. A10-FMT significantly increased small intestinal , while it elevated small intestinal and cecal in some extent, blood butyric acid and derivatives and eicosapentaenoic acid (EPA), and testicular docosahexaenoic acid (DHA), EPA, and testosterone and its derivatives. Furthermore, A10-FMT improved liver functions and systemic antioxidant environments. Most importantly, A10-FMT promoted spermatogenesis through the improvement in the expression of proteins important for spermatogenesis to increase sperm concentration and motility. The underlying mechanisms may be that A10-FMT increased gut-beneficial microbes and to elevate blood and/or testicular butyric acid, DHA, EPA, and testosterone to promote spermatogenesis and thus to ameliorate sperm concentration and motility. AOS-improved gut microbes could emerge as attractive candidates to treat T2D-diminished semen quality. A10-FMT benefits gut microbiota, liver function, and systemic environment via improvement in blood metabolome, consequently to favor the testicular microenvironment to improve spermatogenesis process and to boost T2D-diminished semen quality. We established that AOS-improved gut microbiota may be used to boost T2D-decreased semen quality and metabolic disease-related male subfertility.
Topics: Male; Mice; Animals; Testis; Diabetes Mellitus, Type 2; Semen Analysis; Butyric Acid; Blood Glucose; Eicosapentaenoic Acid; Docosahexaenoic Acids; Antioxidants; Semen; Gastrointestinal Microbiome; Spermatozoa; Metabolome; Testosterone; Alginates
PubMed: 36214691
DOI: 10.1128/spectrum.01423-22 -
Nutrients Mar 2022Taxifolin is a bioflavonoid which has been used to treat Inflammatory Bowel Disease. However, taxifolin on DSS-induced colitis and gut health is still unclear. Here, we...
Taxifolin is a bioflavonoid which has been used to treat Inflammatory Bowel Disease. However, taxifolin on DSS-induced colitis and gut health is still unclear. Here, we studied the effect of taxifolin on DSS-induced intestinal mucositis in mice. We measured the degree of intestinal mucosal injury and inflammatory response in DSS treated mice with or without taxifolin administration and studied the changes of fecal metabolites and intestinal microflora using 16S rRNA. The mechanism was further explored by fecal microbiota transplantation. The results showed that the weight loss and diarrhea score of the mice treated with taxifolin decreased in DSS-induced mice and longer colon length was displayed after taxifolin supplementation. Meanwhile, the expression of GPR41 and GPR43 in the colon was significantly increased by taxifolin treatment. Moreover, the expression of TNF-α, IL-1β, and IL-6 in colon tissue was inhibited by taxifolin treatment. The fecal metabolism pattern changed significantly after DSS treatment, which was reversed by taxifolin treatment. Importantly, taxifolin significantly increased the levels of butyric acid and isobutyric acid in the feces of DSS-treated mice. In terms of gut flora, taxifolin reversed the changes of , and further decreased . Fecal transplantation from taxifolin-treated mice showed a lower diarrhea score, reduced inflammatory response in the colon, and reduced intestinal mucosal damage, which may be related to the increased level of butyric acid in fecal metabolites. In conclusion, this study provides evidence that taxifolin can ameliorate DSS-induced colitis by altering gut microbiota to increase the production of SCFAs.
Topics: Animals; Butyric Acid; Colitis, Ulcerative; Dextran Sulfate; Gastrointestinal Microbiome; Mice; Quercetin; RNA, Ribosomal, 16S
PubMed: 35268045
DOI: 10.3390/nu14051069 -
Journal of Cerebral Blood Flow and... Feb 2021Sodium butyrate, a short-chain fatty acid, is predominantly produced by gut microbiota fermentation of dietary fiber and serves as an important neuromodulator in the...
Sodium butyrate, a short-chain fatty acid, is predominantly produced by gut microbiota fermentation of dietary fiber and serves as an important neuromodulator in the central nervous system. Recent experimental evidence has suggested that sodium butyrate may be an endogenous ligand for two orphan G protein-coupled receptors, GPR41 and GP43, which regulate apoptosis and inflammation in ischemia-related pathologies, including stroke. In the present study, we evaluated the potential efficacy and mechanism of action of short-chain fatty acids in a rat model of middle cerebral artery occlusion (MCAO). Fatty acids were intranasally administered 1 h post MCAO. Short-chain fatty acids, especially sodium butyrate, reduced infarct volume and improved neurological function at 24 and 72 h after MCAO. At 24 h, the effects of MCAO, increased apoptosis, were ameliorated after treatment with sodium butyrate, which increased the expressions of GPR41, PI3K and phosphorylated Akt. To confirm these mechanistic links and characterize the GPR active subunit, PC12 cells were subjected to oxygen-glucose deprivation and reoxygenation, and pharmacological and siRNA interventions were used to reverse efficacy. Taken together, intranasal administration of sodium butyrate activated PI3K/Akt via GPR41/Gβγ and attenuated neuronal apoptosis after MCAO.
Topics: Animals; Apoptosis; Butyric Acid; Infarction, Middle Cerebral Artery; Male; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley
PubMed: 32151222
DOI: 10.1177/0271678X20910533 -
Biomedicine & Pharmacotherapy =... Apr 2023Alcohol abuse triggers neuroinflammation, leading to neuronal damage and further memory and cognitive impairment. Few satisfactory advances have been made in the...
BACKGROUND
Alcohol abuse triggers neuroinflammation, leading to neuronal damage and further memory and cognitive impairment. Few satisfactory advances have been made in the management of alcoholic central nervous impairment. Therefore, novel and more practical treatment options are urgently needed. Butyrate, a crucial metabolite of short-chain fatty acids (SCFAs), has been increasingly demonstrated to protect against numerous metabolic diseases. However, the impact of butyrate on chronic alcohol consumption-induced central nervous system (CNS) lesions remains unknown.
METHODS
In this study, we assessed the possible effects and underlying mechanisms of butyrate on the attenuation of alcohol-induced CNS injury in mice. Firstly, sixty female C57BL/6 J mice were randomly divided into 4 groups: pair-fed (PF) group (PF/CON), alcohol-fed (AF) group (AF/CON), PF with sodium butyrate (NaB) group (PF/NaB) and AF with NaB group (AF/NaB). Each group was fed a modified Lieber-DeCarli liquid diet with or without alcohol. After six weeks of feeding, the mice were euthanized and the associated indicators were investigated.
RESULTS
As indicated by the behavioral tests and brain morphology, dietary NaB administration significantly ameliorated aberrant behaviors, including locomotor hypoactivity, anxiety disorder, depressive behavior, impaired learning, spatial recognition memory, and effectively reduced chronic alcoholic central nervous system damage. To further understand the underlying mechanisms, microglia-mediated inflammation and the associated M1/M2 polarization were measured separately. Firstly, pro-inflammatory TNF-α, IL-1β, and IL-6 in brain and peripheral blood circulation were decreased, but IL-10 were increased in the AF/NaB group compared with the AF/CON group. Consistently, the abnormal proportions of activated and resting microglial cells in the hippocampus and cortex regions after excessive alcohol consumption were significantly reduced with NaB treatment. Moreover, the rectification of microglia polarization (M1/M2) imbalance was found after NaB administration via binding GPR109A, up-regulating the expression of PPAR-γ and down-regulating TLR4/NF-κB activation. In addition to the direct suppression of neuroinflammation, intriguingly, dietary NaB intervention remarkably increased the levels of intestinal tight junction protein occludin and gut morphological barrier, attenuated the levels of serum lipopolysaccharide (LPS) and dysbiosis of gut microbiota, suggesting that NaB supplementation effectively improved the integrity and permeability of gut microecology. Finally, the neurotransmitters including differential Tryptophan (Trp) and Kynurenine (Kyn) were found with dietary NaB administration, which showed significantly altered and closely correlated with the gut microbiota composition, demonstrating the complex interactions in the microbiome-gut-brain axis involved in the efficacy of dietary NaB therapy for alcoholic CNS lesions.
CONCLUSION
Dietary microbial metabolite butyrate supplementation ameliorates chronic alcoholic central nervous damage and improves related memory and cognitive functions through suppressing microglia-mediated neuroinflammation by GPR109A/PPAR-γ/TLR4-NF-κB signaling pathway and modulating microbiota-gut-brain axis.
Topics: Mice; Female; Animals; Microglia; Brain-Gut Axis; Neuroinflammatory Diseases; NF-kappa B; Toll-Like Receptor 4; Peroxisome Proliferator-Activated Receptors; Mice, Inbred C57BL; Ethanol; Butyric Acid
PubMed: 36709599
DOI: 10.1016/j.biopha.2023.114308 -
Cell Death & Disease Apr 2023Evidence shows that short-chain fatty acids (SCFAs) play an important role in health maintenance and disease development. In particular, butyrate is known to induce...
Evidence shows that short-chain fatty acids (SCFAs) play an important role in health maintenance and disease development. In particular, butyrate is known to induce apoptosis and autophagy. However, it remains largely unclear whether butyrate can regulate cell ferroptosis, and the mechanism by which has not been studied. In this study, we found that RAS-selective lethal compound 3 (RSL3)- and erastin-induced cell ferroptosis were enhanced by sodium butyrate (NaB). With regard to the underlying mechanism, our results showed that NaB promoted ferroptosis by inducing lipid ROS production via downregulating the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). Moreover, the FFAR2-AKT-NRF2 axis and FFAR2-mTORC1 axis accounts for the NaB-mediated downregulation of SLC7A11 and GPX4, respectively, in a cAMP-PKA-dependent manner. Functionally, we found that NaB can inhibit tumor growth and the inhibitory effect could be eliminated by administrating MHY1485 (mTORC1 activator) and Ferr-1 (ferroptosis inhibitor). Altogether, in vivo results suggest that NaB treatment is correlated to the mTOR-dependent ferroptosis and consequent tumor growth through xenografts and colitis-associated colorectal tumorigenesis, implicating the potential clinical applications of NaB for future colorectal cancer treatments. Based on all these findings, we have proposed a regulatory mechanism via which butyrate inhibits the mTOR pathway to control ferroptosis and consequent tumorigenesis.
Topics: Humans; Butyric Acid; Carcinogenesis; Cell Transformation, Neoplastic; Ferroptosis; Mechanistic Target of Rapamycin Complex 1; TOR Serine-Threonine Kinases
PubMed: 37185889
DOI: 10.1038/s41419-023-05778-0 -
Gut Microbes Dec 2023Recent studies have demonstrated that the antitumor immunity of immune cells can be modulated by gut microbiota and their metabolites. However, the underlying mechanisms...
Recent studies have demonstrated that the antitumor immunity of immune cells can be modulated by gut microbiota and their metabolites. However, the underlying mechanisms remain unclear. Here, we showed that the serum butyric acid level is positively correlated with the expression of programmed cell death-1 (PD-1) on circulating CD8 and Vγ9 Vδ2 (Vδ2) T cells in patients with non-small cell lung cancer (NSCLC). Responder NSCLC patients exhibited higher levels of serum acetic acid, propionic acid, and butyric acid than non-responders. Depletion of the gut microbiota reduces butyrate levels in both feces and serum in tumor-bearing mice. Mechanistically, butyrate increased histone 3 lysine 27 acetylation (H3K27ac) at the promoter region of and in human CD8 T cells, thereby promoting the expression of PD-1/CD28 and enhancing the efficacy of anti-PD-1 therapy. Butyrate supplementation promotes the expression of antitumor cytokines in cytotoxic CD8 T cells by modulating the T-cell receptor (TCR) signaling pathway. Collectively, our findings reveal that the metabolite butyrate of the gut microbiota facilitates the efficacy of anti-PD-1 immunotherapy by modulating TCR signaling of cytotoxic CD8 T cells, and is a highly promising therapeutic biomarker for enhancing antitumor immunity.
Topics: Humans; Animals; Mice; CD8-Positive T-Lymphocytes; Butyric Acid; CD28 Antigens; Carcinoma, Non-Small-Cell Lung; Gastrointestinal Microbiome; Lung Neoplasms; Antineoplastic Agents; Signal Transduction; Receptors, Antigen, T-Cell
PubMed: 37635362
DOI: 10.1080/19490976.2023.2249143 -
Neurogastroenterology and Motility Oct 2020Butyrate has shown anti-inflammatory and regenerative properties, providing symptomatic relief when orally supplemented in patients suffering from various colonic... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Butyrate has shown anti-inflammatory and regenerative properties, providing symptomatic relief when orally supplemented in patients suffering from various colonic diseases. We investigated the effect of a colonic-delivery formulation of butyrate on the fecal microbiota of patients with inflammatory bowel diseases (IBDs).
METHODS
In this double-blind, placebo-controlled, pilot study, 49 IBD patients (n = 19 Crohn's disease, CD and n = 30 ulcerative colitis, UC) were randomized to oral administration of microencapsulated-sodium-butyrate (BLM) or placebo for 2 months, in addition to conventional therapy. Eighteen healthy volunteers (HVs) were recruited to provide a healthy microbiota model of the local people. Fecal microbiota from stool samples was assessed by 16S sequencing. Clinical disease activity and quality of life (QoL) were evaluated before and after treatment.
KEY RESULTS
At baseline, HVs showed a different microbiota composition compared with IBD patients. Sodium-butyrate altered the gut microbiota of IBD patients by increasing bacteria able to produce SCFA in UC patients (Lachnospiraceae spp.) and the butyrogenic colonic bacteria in CD patients (Butyricicoccus). In UC patients, QoL was positively affected by treatment.
CONCLUSIONS AND INFERENCES
Sodium-butyrate supplementation increases the growth of bacteria able to produce SCFA with potentially anti-inflammatory action. The clinical impact of this finding requires further investigation.
Topics: Administration, Oral; Adult; Aged; Butyric Acid; Capsules; Double-Blind Method; Female; Gastrointestinal Microbiome; Histamine Antagonists; Humans; Inflammatory Bowel Diseases; Male; Middle Aged; Pilot Projects; Young Adult
PubMed: 32476236
DOI: 10.1111/nmo.13914 -
World Journal of Gastroenterology Jan 2017To investigate whether gut microbiota metabolite sodium butyrate (NaB) is an effective substance for attenuating non-alcoholic fatty liver disease (NAFLD) and the...
AIM
To investigate whether gut microbiota metabolite sodium butyrate (NaB) is an effective substance for attenuating non-alcoholic fatty liver disease (NAFLD) and the internal mechanisms.
METHODS
Male C57BL/6J mice were divided into three groups, normal control were fed standard chow and model group were fed a high-fat diet (HFD) for 16 wk, the intervention group were fed HFD for 16 wk and treated with NaB for 8 wk. Gut microbiota from each group were detected at baseline and at 16 wk, liver histology were evaluated and gastrointestinal barrier indicator such as zonula occluden-1 (ZO-1) were detected by immunohistochemistry and realtime-PCR, further serum or liver endotoxin were determined by ELISA and inflammation- or metabolism-associated genes were quantified by real-time PCR.
RESULTS
NaB corrected the HFD-induced gut microbiota imbalance in mice, while it considerably elevated the abundances of the beneficial bacteria , and . These bacteria can produce butyric acid in what seems like a virtuous circle. And butyrate restored HFD induced intestinal mucosa damage, increased the expression of ZO-1 in small intestine, further decreased the levels of gut endotoxin in serum and liver compared with HF group. Endotoxin-associated genes such as TLR4 and Myd88, pro-inflammation genes such as MCP-1, TNF-α, IL-1, IL-2, IL-6 and IFN-γ in liver or epididymal fat were obviously downregulated after NaB intervention. Liver inflammation and fat accumulation were ameliorated, the levels of TG and cholesterol in liver were decreased after NaB intervention, NAS score was significantly decreased, metabolic indices such as FBG and HOMA-IR and liver function indicators ALT and AST were improved compared with HF group.
CONCLUSION
NaB may restore the dysbiosis of gut microbiota to attenuate steatohepatitis, which is suggested to be a potential gut microbiota modulator and therapeutic substance for NAFLD.
Topics: Animals; Butyric Acid; Cytokines; Diet, High-Fat; Drug Evaluation, Preclinical; Dysbiosis; Gastrointestinal Microbiome; Humans; Immunohistochemistry; Inflammation; Intestinal Mucosa; Lactobacillus; Liver; Liver Function Tests; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Real-Time Polymerase Chain Reaction; Specific Pathogen-Free Organisms; Tumor Necrosis Factor-alpha; Zonula Occludens-1 Protein
PubMed: 28104981
DOI: 10.3748/wjg.v23.i1.60