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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 -
Current Microbiology Apr 2020Gamma-Aminobutyric acid (GABA) is a non-protein amino acid widely distributed in nature. It is produced through irreversible α-decarboxylation of glutamate by enzyme... (Review)
Review
Gamma-Aminobutyric acid (GABA) is a non-protein amino acid widely distributed in nature. It is produced through irreversible α-decarboxylation of glutamate by enzyme glutamate decarboxylase (GAD). GABA and GAD have been found in plants, animals, and microorganisms. GABA is distributed throughout the human body and it is involved in the regulation of cardiovascular conditions such as blood pressure and heart rate, and plays a role in the reduction of anxiety and pain. Although researchers had produced GABA by chemical method earlier it became less acceptable as it pollutes the environment. Researchers now use a more promising microbial method for the production of GABA. In the drug and food industry, demand for GABA is immense. So, large scale conversion of GABA by microbes has got much attention. So this review focuses on the isolation source, production, and functions of GABA in the microbial system. We also summarize the mechanism of action of GABA and its shunt pathway.
Topics: Animals; Bacteria; Butyric Acid; Glutamate Decarboxylase; Glutamic Acid; Humans; Metabolic Networks and Pathways; gamma-Aminobutyric Acid
PubMed: 31844936
DOI: 10.1007/s00284-019-01839-w -
Pharmacological Research Oct 2019The gut microbiota and its short chain fatty acid (SCFA) metabolites have been established to play an important protective role against neurodegenerative diseases. Our...
The gut microbiota and its short chain fatty acid (SCFA) metabolites have been established to play an important protective role against neurodegenerative diseases. Our previous study demonstrated that cerebral ischemic stroke triggers dysfunctional gut microbiota and increased intestinal permeability. In this study, we aimed to clarify the mechanism by which gut microbiota and SCFAs can treat cerebral ischemic stroke in rat middle cerebral artery occlusion models and use the information to develop new therapies. Our results show that oral administration of non-absorbable antibiotics reduced neurological impairment and the cerebral infarct volume, relieved cerebral edemas, and decreased blood lipid levels by altering the gut microbiota. We also found that ischemic stroke decreased intestinal levels of SCFAs. And that transplanting fecal microbiota rich in these metabolites was an effective means of treating the condition. Compared with other SCFAs, butyric acid showed the highest negative correlation with ischemic stroke. Supplementation with butyric acid treated models of ischemic stroke effectively by remodeling the gut microbiota, enriching the beneficial Lactobacillus, and repairing the leaky gut. In conclusion, interfering with the gut microbiota by transplanting fecal bacteria rich in SCFAs and supplementing with butyric acid were found to be effective treatments for cerebral ischemic stroke.
Topics: Animals; Brain Ischemia; Butyric Acid; Fatty Acids, Volatile; Fecal Microbiota Transplantation; Feces; Gastrointestinal Microbiome; Lactobacillus; Male; Microbiota; Rats; Rats, Sprague-Dawley; Stroke
PubMed: 31425750
DOI: 10.1016/j.phrs.2019.104403 -
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 -
The Journal of Endocrinology Jun 2020This study aimed to assess the effects of three major SCFAs (acetate, propionate, and butyrate) on NASH phenotype in mice. C57BL/6 mice were fed a methionine- and...
This study aimed to assess the effects of three major SCFAs (acetate, propionate, and butyrate) on NASH phenotype in mice. C57BL/6 mice were fed a methionine- and choline-deficient (MCD) diet and treated with sodium acetate, sodium propionate, or sodium butyrate during the 6-week feeding period. SCFA treatment significantly reduced serum levels of alanine aminotransferase and aspartate transaminase, the numbers of lipid droplets, and the levels of triglycerides and cholesterols in livers of the mice compared with control treatment. SCFAs also reduced MCD-induced hepatic aggregation of macrophages and proinflammatory responses. Among the three SCFAs, sodium acetate (NaA) revealed the best efficacy at alleviating MCD-induced hepatic steatosis and inflammation. Additionally, NaA increased AMP-activated protein kinase activation in the liver and induced the expression of fatty acid oxidation gene in both the liver and cultured hepatocytes. In vitro, NaA decreased MCD-mimicking media-induced proinflammatory responses in macrophages to a greater extent than in hepatocytes. These results indicated that NaA alleviates steatosis in a manner involving AMPK activation. Also, NaA alleviation of hepatic inflammation appears to be due to, in large part, suppression of macrophage proinflammatory activation. SCFAs may represent as a novel and viable approach for alleviating NASH.
Topics: Acetates; Alanine Transaminase; Animals; Aspartate Aminotransferases; Butyrates; Butyric Acid; Fatty Acids, Volatile; Fatty Liver; Hepatocytes; Inflammation; Macrophages; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Propionates; Sodium Acetate
PubMed: 32302970
DOI: 10.1530/JOE-20-0018 -
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 -
Apoptosis : An International Journal on... Aug 2023Ferroptosis is a form of programmed cell death with important biological functions in the progression of various diseases, and targeting ferroptosis is a new tumor...
Ferroptosis is a form of programmed cell death with important biological functions in the progression of various diseases, and targeting ferroptosis is a new tumor treatment strategy. Studies have shown that sodium butyrate plays a tumor-suppressing role in the progression of various tumors, however, the mechanism of NaBu in endometrial cancer is unclear. Cell viability, clone formation, proliferation, migration, invasion abilities and cell cycle distribution were assessed by CCK8 assay, Clone formation ability assay, EdU incorporation, Transwell chambers and flow cytometry. The level of ferroptosis was assayed by the levels of ROS and lipid peroxidation, the ratio of GSH/GSSG and the morphology of mitochondria. Molecular mechanisms were explored by metabolome, transcriptome, RNA-pulldown and mass spectrometry. The in-vivo mechanism was validated using subcutaneous xenograft model. In this study, NaBu was identified to inhibit the progression of endometrial cancer in vitro and in vivo. Mechanistically, RBM3 has a binding relationship with SLC7A11 mRNA. NaBu indirectly downregulates the expression of SLC7A11 by promoting the expression of RBM3, thereby promoting ferroptosis in endometrial cancer cells. In conclusion, Sodium butyrate can promote the expression of RBM3 and indirectly downregulate the expression of SLC7A11 to stimulate ferroptosis, which may be a promising cancer treatment strategy.
Topics: Humans; Female; Butyric Acid; Ferroptosis; Apoptosis; Endometrial Neoplasms; Mitochondria; RNA-Binding Proteins; Amino Acid Transport System y+
PubMed: 37170022
DOI: 10.1007/s10495-023-01850-4