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Cell Feb 2022The factors and mechanisms that shape the composition and function of closely related members in a complex microbial community are largely unknown. The study by Park and...
The factors and mechanisms that shape the composition and function of closely related members in a complex microbial community are largely unknown. The study by Park and colleagues reveals that the fitness of various Bacteroidales species and strains in the gut microbiome is regulated by butyrate in a glycan-dependent manner.
Topics: Bacteroidetes; Butyrates; Gastrointestinal Microbiome; Instinct; Sugars
PubMed: 35120661
DOI: 10.1016/j.cell.2021.12.037 -
Journal of Virology Jul 2020Butyrate is an abundant metabolite produced by gut microbiota. While butyrate is a known histone deacetylase inhibitor that activates expression of many genes involved...
Butyrate is an abundant metabolite produced by gut microbiota. While butyrate is a known histone deacetylase inhibitor that activates expression of many genes involved in immune system pathways, its effects on virus infections and on the antiviral type I interferon (IFN) response have not been adequately investigated. We found that butyrate increases cellular infection with viruses relevant to human and animal health, including influenza virus, reovirus, HIV-1, human metapneumovirus, and vesicular stomatitis virus. Mechanistically, butyrate suppresses levels of specific antiviral IFN-stimulated gene (ISG) products, such as RIG-I and IFITM3, in human and mouse cells without inhibiting IFN-induced phosphorylation or nuclear translocation of the STAT1 and STAT2 transcription factors. Accordingly, we discovered that although butyrate globally increases baseline expression of more than 800 cellular genes, it strongly represses IFN-induced expression of 60% of ISGs and upregulates 3% of ISGs. Our findings reveal that there are differences in the IFN responsiveness of major subsets of ISGs depending on the presence of butyrate in the cell environment, and overall, they identify a new mechanism by which butyrate influences virus infection of cells. Butyrate is a lipid produced by intestinal bacteria. Here, we newly show that butyrate reprograms the innate antiviral immune response mediated by type I interferons (IFNs). Many of the antiviral genes induced by type I IFNs are repressed in the presence of butyrate, resulting in increased virus infection and replication. Our research demonstrates that metabolites produced by the gut microbiome, such as butyrate, can have complex effects on cellular physiology, including dampening of an inflammatory innate immune pathway resulting in a proviral cellular environment. Our work further suggests that butyrate could be broadly used as a tool to increase growth of virus stocks for research and for the generation of vaccines.
Topics: Animals; Antiviral Agents; Butyrates; Cell Line; Gene Expression; Humans; Immunity, Innate; Interferon Type I; Interferons; Membrane Proteins; Mice; RNA-Binding Proteins; STAT1 Transcription Factor; STAT2 Transcription Factor; Signal Transduction; Virus Diseases; Virus Replication
PubMed: 32461320
DOI: 10.1128/JVI.00326-20 -
PloS One 2018The pancreatic secretion of insulin, a key endocrine regulator of metabolism and growth, can be greatly influenced by the gut-derived incretin hormones, namely by GIP... (Comparative Study)
Comparative Study
The pancreatic secretion of insulin, a key endocrine regulator of metabolism and growth, can be greatly influenced by the gut-derived incretin hormones, namely by GIP (Glucose-dependent Insulinotropic Peptide) and GLP-1 (Glucagon-like Peptide 1). As insulin is a major stimulator of growth, affecting its producion may be of special importance in food-producing livestock. The aim of the present study was to investigate novel ways of modulating incretin and insulin homeostasis in chickens and rabbits by nutrition, e.g. by oral butyrate application, also studying the mechanisms of incretin action in both species as a comparative approach. Acute oral butyrate challenge significantly decreased plasma GIP levels by approx. 40% in both species: significant interactions of butyrate exposure and incubation time were found in both chickens (P = 0.038 and P = 0.034 at 30 and 60 min following butyrate ingestion [1.25 g/kg BW], respectively) and rabbits (P = 0.036 and P = 0.039 at 30 and 60 min after butyrate ingestion [0.25 g/kg BW], respectively), while plasma GLP-1, insulin and glucose concentrations remained unaffected by butyrate in both species over time. These results are in contrast to butyrate's stimulating effect on both incretin and insulin secretion in mice, indicating specific, species-dependent differences even among mammalian species. Further, based on the analyzed correlations between the measured endocrine parameters (regardless of the butyrate exposure), it can be assumed that incretins may regulate pancreatic insulin release in rabbits on a partly different way compared to mice, humans and chickens.
Topics: Animal Feed; Animals; Butyrates; Chickens; Contracts; Dietary Supplements; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Homeostasis; Incretins; Insulin; Male; Rabbits; Random Allocation; Species Specificity
PubMed: 30308056
DOI: 10.1371/journal.pone.0205512 -
Journal of Dairy Science Oct 2023This study was conducted to investigate the role of Na on ruminal short-chain fatty acid (SCFA) absorption and barrier function when isolated ruminal epithelium was...
This study was conducted to investigate the role of Na on ruminal short-chain fatty acid (SCFA) absorption and barrier function when isolated ruminal epithelium was exposed to high and low pH ex vivo. Nine Holstein steer calves (322 ± 50.9 kg of body weight) consuming 7.05 ± 1.5 kg dry matter of a total mixed ration were euthanized and ruminal tissue was collected from the caudal-dorsal blind sac. Tissues were mounted between 2 halves of Ussing chambers (3.14 cm) and exposed to buffers that contained low (10 mM) or high (140 mM) Na with low (6.2) or high (7.4) mucosal pH. The same buffer solutions were used on the serosal side except that pH was maintained at 7.4. Buffers used to evaluate SCFA uptake contained bicarbonate to determine total uptake or excluded bicarbonate and included nitrate to determine noninhibitable uptake. Bicarbonate-dependent uptake was calculated as the difference between the total and noninhibitable uptake. Acetate (25 mM) and butyrate (25 mM) were spiked with 2-H-acetate and 1-C-butyrate, respectively, and were then added to the mucosal side, incubated for 1 min, and tissues were analyzed to evaluate rates of SCFA uptake. Tissue conductance (G) and the mucosal-to-serosal flux of 1-H-mannitol were used to assess barrier function. There were no Na × pH interactions for butyrate or acetate uptake. Decreasing mucosal pH from 7.4 to 6.2 increased total acetate and butyrate uptake, and bicarbonate-dependent acetate uptake. Flux of 1-H-mannitol was not affected by treatment. However, high Na concentration reduced G and prevented an increase in G from flux period 1 to flux period 2. The results of this study indicate that although providing more Na to the ruminal epithelium does not affect SCFA uptake or mannitol flux, it may help stabilize tissue integrity.
Topics: Animals; Cattle; Butyrates; Sodium; Bicarbonates; Epithelium; Fatty Acids, Volatile; Acetates; Hydrogen-Ion Concentration; Mannitol; Rumen
PubMed: 37210365
DOI: 10.3168/jds.2022-23052 -
American Journal of Physiology.... Oct 2020The loss of the intestinal Na/H exchanger isoform 8 (NHE8) results in an ulcerative colitis-like condition with reduction of mucin production and dysbiosis, indicating...
The loss of the intestinal Na/H exchanger isoform 8 (NHE8) results in an ulcerative colitis-like condition with reduction of mucin production and dysbiosis, indicating that NHE8 plays an important role in intestinal mucosal protection. The aim of this study was to investigate the potential rebalance of the altered microbiota community of NHE8-deficient mice via fecal microbiota transplantation (FMT) and feeding probiotic VSL#3. We also aimed to stimulate mucin production by sodium butyrate administration via enema. Data from 16S rRNA sequencing showed that loss of NHE8 contributes to colonic microbial dysbiosis with reduction of butyrate-producing bacteria. FMT increased bacterial adhesion in the colon in NHE8 knockout (NHE8KO) mice. Periodic-acid Schiff reagent (PAS) stain and quantitative PCR showed no changes in mucin production during FMT. In mice treated with the probiotic VSL#3, a reduction of and segmented filamentous bacteria (SFB) in NHE8KO mouse colon was detected and an increase in goblet cell theca was observed. In NHE8KO mice receiving sodium butyrate (NaB), 1 mM NaB stimulated Muc2 expression without changing goblet cell theca, but 10 mM NaB induced a significant reduction of goblet cell theca without altering Muc2 expression. Furthermore, 5 mM and 10 mM NaB-treated HT29-MTX cells displayed increased apoptosis, while 0.5 mM NaB stimulated Muc2 gene expression. These data showed that loss of NHE8 leads to dysbiosis with reduction of butyrate-producing bacteria and FMT and VSL#3 failed to rebalance the microbiota in NHE8KO mice. Therefore, FMT, VSL#3, and NaB are not able to restore mucin production in the absence of NHE8 in the intestine. Loss of Na/H exchanger isoform 8 (NHE8), a Slc9 family of exchanger that contributes to sodium uptake, cell volume regulation, and intracellular pH homeostasis, resulted in dysbiosis with reduction of butyrate-producing bacteria and decrease of Muc2 production in the intestine in mice. Introducing fecal microbiota transplantation (FMT) and VSL#3 in NHE8 knockout (NHE8KO) mice failed to rebalance the microbiota in these mice. Furthermore, administration of FMT, VSL#3, and sodium butyrate was unable to restore mucin production in the absence of NHE8 in the intestine.
Topics: Animals; Butyrates; Butyric Acid; Colon; Dysbiosis; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Goblet Cells; HT29 Cells; Humans; Intestinal Mucosa; Lactobacillus; Mice; Mice, Knockout; Mucins; Probiotics; Sodium-Hydrogen Exchangers
PubMed: 32755385
DOI: 10.1152/ajpgi.00246.2020 -
Nutrients Jul 2022The pathogenesis of ulcerative colitis (UC) is unclear, but it is generally believed to be closely related to an imbalance in gut microbiota. () might play a key role...
The pathogenesis of ulcerative colitis (UC) is unclear, but it is generally believed to be closely related to an imbalance in gut microbiota. () might play a key role in suppressing intestinal inflammation, but the mechanism of its anti-inflammatory effect is unknown. In this study, we investigated the role of and Toll-like receptor 5 (TLR5) in relieving mouse colitis. We found that significantly upregulated the transcription of TLR5 in intestinal epithelial cells (IECs) and improved colonic inflammation in a colitis mouse model. The flagellin of activated the release of anti-inflammatory factors (IL-10, TGF-β) and reduced inflammation in IECs. Furthermore, butyrate, the main metabolic product secreted by , regulated the expression of TLR5 in IECs. Our data show that butyrate increased the binding of the transcription factor Sp3 (specificity protein 3) to the TLR5 promoter regions, upregulating TLR5 transcription. This work provides new insight into the anti-inflammatory effects of in colitis and a potential target for UC prevention and treatment.
Topics: Animals; Anti-Inflammatory Agents; Butyrates; Clostridiales; Colitis; Colitis, Ulcerative; Inflammation; Intestinal Mucosa; Mice; Signal Transduction; Toll-Like Receptor 5
PubMed: 35893896
DOI: 10.3390/nu14153041 -
Biomedicine & Pharmacotherapy =... Sep 2023Short-chain fatty acids (SCFAs) derived from the fermentation of carbohydrates by gut microbiota play a crucial role in regulating host physiology. Among them, acetate,... (Review)
Review
Short-chain fatty acids (SCFAs) derived from the fermentation of carbohydrates by gut microbiota play a crucial role in regulating host physiology. Among them, acetate, propionate, and butyrate are key players in various biological processes. Recent research has revealed their significant functions in immune and inflammatory responses. For instance, butyrate reduces the development of interferon-gamma (IFN-γ) generating cells while promoting the development of regulatory T (Treg) cells. Propionate inhibits the initiation of a Th2 immune response by dendritic cells (DCs). Notably, SCFAs have an inhibitory impact on the polarization of M2 macrophages, emphasizing their immunomodulatory properties and potential for therapeutics. In animal models of asthma, both butyrate and propionate suppress the M2 polarization pathway, thus reducing allergic airway inflammation. Moreover, dysbiosis of gut microbiota leading to altered SCFA production has been implicated in prostate cancer progression. SCFAs trigger autophagy in cancer cells and promote M2 polarization in macrophages, accelerating tumor advancement. Manipulating microbiota- producing SCFAs holds promise for cancer treatment. Additionally, SCFAs enhance the expression of hypoxia-inducible factor 1 (HIF-1) by blocking histone deacetylase, resulting in increased production of antibacterial effectors and improved macrophage-mediated elimination of microorganisms. This highlights the antimicrobial potential of SCFAs and their role in host defense mechanisms. This comprehensive review provides an in-depth analysis of the latest research on the functional aspects and underlying mechanisms of SCFAs in relation to macrophage activities in a wide range of diseases, including infectious diseases and cancers. By elucidating the intricate interplay between SCFAs and macrophage functions, this review aims to contribute to the understanding of their therapeutic potential and pave the way for future interventions targeting SCFAs in disease management.
Topics: Male; Animals; Propionates; Fatty Acids, Volatile; Butyrates; Inflammation; Gastrointestinal Microbiome; Macrophages
PubMed: 37542852
DOI: 10.1016/j.biopha.2023.115276 -
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 -
Biomedicine & Pharmacotherapy =... Jul 2022Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer. The characteristic excessive stromatogenesis accompanying the growth of this tumor is believed to...
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer. The characteristic excessive stromatogenesis accompanying the growth of this tumor is believed to contribute to chemoresistance which, together with drug toxicity, results in poor clinical outcome. An increasing number of studies are showing that gut microbiota and their metabolites are implicated in cancer pathogenesis, progression and response to therapies. In this study we tested butyrate, a product of dietary fibers' bacterial fermentation, whose anticancer and anti-inflammatory functions are known. We provided in vitro evidence that, beside slowing proliferation, butyrate enhanced gemcitabine effectiveness against two human pancreatic cancer cell lines, mainly inducing apoptosis. In addition, we observed that, when administered to a PDAC mouse model, alone or combined with gemcitabine treatment, butyrate markedly reduced the cancer-associated stromatogenesis, preserved intestinal mucosa integrity and affected fecal microbiota composition by increasing short chain fatty acids producing bacteria and decreasing some pro-inflammatory microorganisms. Furthermore, a biochemical serum analysis showed butyrate to ameliorate some markers of kidney and liver damage, whereas a metabolomics approach revealed a deep modification of lipid metabolism, which may affect tumor progression or response to therapy. Such results support that butyrate supplementation, in addition to conventional therapies, can interfere with pancreatic cancer biology and response to treatment and can alleviate some damages associated to cancer itself or to chemotherapy.
Topics: Animals; Bacteria; Butyrates; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Deoxycytidine; Mice; Pancreatic Neoplasms; Gemcitabine
PubMed: 35617803
DOI: 10.1016/j.biopha.2022.113163 -
Journal of Investigative Medicine : the... Jan 2022Short-chain fatty acids (SCFAs), the end products of fermentation carried out by the intestinal microbiota, were demonstrated to produce anti-oxidant and...
Short-chain fatty acids (SCFAs), the end products of fermentation carried out by the intestinal microbiota, were demonstrated to produce anti-oxidant and anti-inflammatory effects. Butyrate, part of the SCFAs, also shows the same effect. Renal ischemia/reperfusion (I/R) injury commonly occurs in renal transplantation and is often accompanied by oxidative stresses and inflammatory responses. In this study, we explore butyrate effect on renal I/R injury and SCFAs changes in renal transplant. Male Sprague-Dawley rats were pretreated with butyrate as research, and underwent the surgery of renal ischemia for 45 min followed by reperfusion. 90 rats were randomly divided into 3 groups (n=30 each group): (1) sham-operated group; (2) butyrate-treated group; (3) control group. The samples of blood and renal were collected immediately for further studies. Thirty-two patients were enrolled to investigate the levels of SCFAs after the renal transplantation. Rats model showed that butyrate treatments significantly enhanced the function and structure of kidney, as evidenced by the lower serum creatinine levels and less pathological damages of renal tissue. With the recovery of renal function after renal transplantation, SCFAs increased, which were negatively correlated with creatinine. Butyrate expressed like SCFAs. In this study, we demonstrated that butyrate increased with the recovery of renal function after renal transplantation. Most importantly, butyrate treatments alleviated the renal damages caused by I/R via the upregulation of intracellular oxidant stress and inflammations.
Topics: Acute Kidney Injury; Animals; Butyrates; Creatinine; Fatty Acids; Fatty Acids, Volatile; Humans; Kidney; Kidney Transplantation; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury
PubMed: 34426459
DOI: 10.1136/jim-2020-001715