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Archives of Oral Biology Mar 2021The purpose of this study was to clarify the relationship between bacteria-induced butyric acid and periodontal disease progression.
OBJECTIVE
The purpose of this study was to clarify the relationship between bacteria-induced butyric acid and periodontal disease progression.
DESIGN
Normal human gingival fibroblasts were exposed to butyric acid (0, 1, 5, 10, and 15 mM) adjusted to a pH of 7.2-7.4 using sodium hydroxide for 0-96 h and cell viability was evaluated. In addition, the effects of butyric acid on the production of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in gingival fibroblasts were analyzed by real-time RT-PCR, ELISA, western blotting, and stromelysin zymography.
RESULTS
Butyric acid reduced the viability of gingival fibroblasts in a concentration- and time-dependent manner. Furthermore, butyric acid promoted production of MMP-1, MMP-3, and MMP-10 in gingival fibroblasts and suppressed TIMP-2 protein production.
CONCLUSIONS
Butyric acid promoted overproduction of MMPs, resulting in a disruption of the balance between MMPs and TIMPs expression in gingival fibroblasts. Our study suggests that the butyric acid produced by causative bacteria stimulates excessive MMP expression in periodontal tissue, leading to destruction of the tissue.
Topics: Butyric Acid; Cells, Cultured; Fibroblasts; Gingiva; Humans; Matrix Metalloproteinases; Tissue Inhibitor of Metalloproteinases
PubMed: 33485112
DOI: 10.1016/j.archoralbio.2020.105035 -
Microbiology Spectrum Jun 2023Patients with ulcerative colitis (UC) have low response rates to anti-integrin medications, necessitating the identification of noninvasive biomarkers for predicting...
Patients with ulcerative colitis (UC) have low response rates to anti-integrin medications, necessitating the identification of noninvasive biomarkers for predicting remission to anti-integrin therapy. In this study, patients with moderate to severe UC commencing anti-integrin therapy ( = 29), inactive to mild UC patients ( = 13), and healthy controls ( = 11) were selected. Besides clinical evaluation, fecal samples were collected at baseline and week 14 from moderate to severe UC patients. The clinical remission was defined based on the Mayo score. Fecal samples were assessed with 16S rRNA gene sequencing, liquid chromatography-tandem mass spectrometry, and gas chromatography-mass spectrometry (GC-MS). We identified that was significantly more abundant in the remission group ( < 0.001) than that of nonremission group at phylum level for patients commencing vedolizumab. GC-MS analysis revealed that the concentrations of butyric acid ( = 0.024) and isobutyric acid ( = 0.042) were significantly higher in the remission group compared to the nonremission group at baseline. Finally, the combination of , butyric acid, and isobutyric acid improved the diagnosis of early remission to anti-integrin therapy (area under the concentration-time curve = 0.961). We identified significantly higher phylum level diversity of in remission than the nonremission groups at baseline. Notably, the combination of gut microbiome and metabonomic profiles improved the diagnosis of early remission to anti-integrin therapy. It is reported that patients with ulcerative colitis (UC) have low response rates to anti-integrin medications in the latest VARSITY study. Therefore, our primary goals were to discover differences in the gut microbiome and metabonomics patterns between early remission and nonremission patients and to explore the diagnostic value in predicting clinical remission to anti-integrin therapy accurately. In this study, we found that was significantly more abundant in the remission group ( < 0.001) than that of nonremission group at phylum level for patients commencing vedolizumab. Gas chromatography-mass spectrometry analysis revealed that the concentrations of butyric acid ( = 0.024) and isobutyric acid ( = 0.042) were significantly higher in the remission group compared with the nonremission group at baseline. Notably, the combination of , butyric acid, and isobutyric acid improved the diagnosis of early remission to anti-integrin therapy (area under the concentration-time curve = 0.961).
Topics: Humans; Colitis, Ulcerative; Integrins; Butyric Acid; Gastrointestinal Microbiome; RNA, Ribosomal, 16S; Metabolomics; Treatment Outcome
PubMed: 37199618
DOI: 10.1128/spectrum.01457-23 -
Molecules (Basel, Switzerland) Aug 2023Prostate-specific membrane antigen (PSMA)-based low-molecular-weight agents using beta(β)-particle-emitting radiopharmaceuticals is a new treatment paradigm for...
Prostate-specific membrane antigen (PSMA)-based low-molecular-weight agents using beta(β)-particle-emitting radiopharmaceuticals is a new treatment paradigm for patients with metastatic castration-resistant prostate cancer. Although results have been encouraging, there is a need to improve the tumor residence time of current PSMA-based radiotherapeutics. Albumin-binding moieties have been used strategically to enhance the tumor uptake and retention of existing PSMA-based investigational agents. Previously, we developed a series of PSMA-based, β-particle-emitting, low-molecular-weight compounds. From this series, Lu-L1 was selected as the lead agent because of its reduced off-target radiotoxicity in preclinical studies. The ligand L1 contains a PSMA-targeting Lys-Glu urea moiety with an N-bromobenzyl substituent in the ε-amino group of Lys. Here, we structurally modified Lu-L1 to improve tumor targeting using two known albumin-binding moieties, 4-(-iodophenyl) butyric acid moiety (IPBA) and ibuprofen (IBU), and evaluated the effects of linker length and composition. Six structurally related PSMA-targeting ligands (Alb-L1-Alb-L6) were synthesized based on the structure of Lu-L1. The ligands were assessed for in vitro binding affinity and were radiolabeled with Lu following standard protocols. All Lu-labeled analogs were studied in cell uptake and selected cell efficacy studies. In vivo pharmacokinetics were investigated by conducting tissue biodistribution studies for Lu-Alb-L2-Lu-Alb-L6 (2 h, 24 h, 72 h, and 192 h) in male NSG mice bearing human PSMA+ PC3 PIP and PSMA- PC3 flu xenografts. Preliminary therapeutic ratios of the agents were estimated from the area under the curve (AUC) of the tumors, blood, and kidney uptake values. Compounds were obtained in >98% radiochemical yields and >99% purity. PSMA inhibition constants (s) of the ligands were in the ≤10 nM range. The long-linker-based agents, Lu-Alb-L4 and Lu-Alb-L5, displayed significantly higher tumor uptake and retention ( < 0.001) than the short-linker-bearing Lu-Alb-L2 and Lu-Alb-L3 and a long polyethylene glycol (PEG) linker-bearing agent, Lu-Alb-L6. The area under the curve (AUC) of the PSMA+ PC3 PIP tumor uptake of Lu-Alb-L4 and Lu-Alb-L5 were >4-fold higher than Lu-Alb-L2, Lu-Alb-L3, and Lu-Alb-L6, respectively. Also, the PSMA+ PIP tumor uptake (AUC) of Lu-Alb-L2 and Lu-Alb-L3 was ~1.5-fold higher than Lu-Alb-L6. However, the lowest blood AUC and kidney AUC were associated with Lu-Alb-L6 from the series. Consequently, Lu-Alb-L6 displayed the highest ratios of AUC(tumor)-to-AUC(blood) and AUC(tumor)-to-AUC(kidney) values from the series. Among the other agents, Lu-Alb-L4 demonstrated a nearly similar ratio of AUC(tumor)-to-AUC(blood) as Lu-Alb-L6. The tumor-to-blood ratio was the dose-limiting therapeutic ratio for all of the compounds. Conclusions: Lu-Alb-L4 and Lu-Alb-L6 showed high tumor uptake in PSMA+ tumors and tumor-to-blood ratios. The data suggest that linker length and composition can be modulated to generate an optimized therapeutic agent.
Topics: Humans; Male; Animals; Mice; Ligands; Tissue Distribution; Albumins; Beta Particles; Butyric Acid
PubMed: 37630410
DOI: 10.3390/molecules28166158 -
Journal of Cellular and Molecular... Aug 2020Gut microbiota and short-chain fatty acids (SCFAs) are associated with the development of various human diseases. In this study, we examined the role of astragaloside IV...
Gut microbiota and short-chain fatty acids (SCFAs) are associated with the development of various human diseases. In this study, we examined the role of astragaloside IV in modulating mouse gut microbiota structure and the generation of SCFAs, as well as in slow transit constipation (STC). An STC model was established by treating mice with loperamide, in which the therapeutic effects of astragaloside IV were evaluated. The microbiota community structure and SCFA content were analysed by 16S rRNA gene sequencing and gas chromatography-mass spectrometry, respectively. The influence of butyrate on STC was assessed using a mouse model and Cajal cells (ICC). Astragaloside IV promoted defecation, improved intestinal mobility, suppressed ICC loss and alleviated colonic lesions in STC mice. Alterations in gut microbiota community structure in STC mice, such as decreased Lactobacillus reuteri diversity, were improved following astragaloside IV treatment. Moreover, astragaloside IV up-regulated butyric acid and valeric acid, but decreased isovaleric acid, in STC mouse stools. Butyrate promoted defecation, improved intestinal mobility, and enhanced ICC proliferation by regulating the AKT-NF-κB signalling pathway. Astragaloside IV promoted intestinal transit in STC mice and inhibited ICC loss by regulating the gut microbiota community structure and generating butyric acid.
Topics: Animals; Antidiarrheals; Butyric Acid; Constipation; Feces; Female; Gastrointestinal Microbiome; Loperamide; Male; Mice; Saponins; Triterpenes
PubMed: 32628809
DOI: 10.1111/jcmm.15586 -
NPJ Biofilms and Microbiomes Dec 2023Spinal cord injury (SCI) can reshape gut microbial composition, significantly affecting clinical outcomes in SCI patients. However, mechanisms regarding gut-brain...
Spinal cord injury (SCI) can reshape gut microbial composition, significantly affecting clinical outcomes in SCI patients. However, mechanisms regarding gut-brain interactions and their clinical implications have not been elucidated. We hypothesized that short-chain fatty acids (SCFAs), intestinal microbial bioactive metabolites, may significantly affect the gut-brain axis and enhance functional recovery in a mouse model of SCI. We enrolled 59 SCI patients and 27 healthy control subjects and collected samples. Thereafter, gut microbiota and SCFAs were analyzed using 16 S rDNA sequencing and gas chromatography-mass spectrometry, respectively. We observed an increase in Actinobacteriota abundance and a decrease in Firmicutes abundance. Particularly, the SCFA-producing genera, such as Faecalibacterium, Megamonas, and Agathobacter were significantly downregulated among SCI patients compared to healthy controls. Moreover, SCI induced downregulation of acetic acid (AA), propionic acid (PA), and butyric acid (BA) in the SCI group. Fecal SCFA contents were altered in SCI patients with different injury course and injury segments. Main SCFAs (AA, BA, and PA) were administered in combination to treat SCI mice. SCFA supplementation significantly improved locomotor recovery in SCI mice, enhanced neuronal survival, promoted axonal formation, reduced astrogliosis, and suppressed microglial activation. Furthermore, SCFA supplementation downregulated NF-κB signaling while upregulating neurotrophin-3 expression following SCI. Microbial sequencing and metabolomics analysis showed that SCI patients exhibited a lower level of certain SCFAs and related bacterial strains than healthy controls. SCFA supplementation can reduce inflammation and enhance nourishing elements, facilitating the restoration of neurological tissues and the improvement of functional recuperation. Trial registration: This study was registered in the China Clinical Trial Registry ( www.chictr.org.cn ) on February 13, 2017 (ChiCTR-RPC-17010621).
Topics: Humans; Mice; Animals; Dysbiosis; Fatty Acids, Volatile; Acetic Acid; Spinal Cord Injuries; Bacteria; Butyric Acid
PubMed: 38092763
DOI: 10.1038/s41522-023-00466-5 -
Cells Jun 2023The enteric nervous system is affected by inflammatory bowel diseases (IBD). Gut microbiota ferments dietary fibers and produces short-chain fatty acids, such as...
The enteric nervous system is affected by inflammatory bowel diseases (IBD). Gut microbiota ferments dietary fibers and produces short-chain fatty acids, such as Butyrate, which bind to G protein-coupled receptors, such as GPR41, and contribute to maintaining intestinal health. This work aimed to study the GPR41 in myenteric neurons and analyze the effect of Butyrate in mice submitted to experimental ulcerative colitis. The 2, 4, 6 trinitrobenzene sulfonic acid (TNBS) was injected intrarectally in C57BL/6 mice (Colitis). Sham group received ethanol (vehicle). One group was treated with 100 mg/kg of Sodium Butyrate (Butyrate), and the other groups received saline. Animals were euthanized 7 days after colitis induction. Analyzes demonstrated colocalization of GPR41 with neurons immunoreactive (-ir) to nNOS and ChAT-ir and absence of colocalization of the GPR41 with GFAP-ir glia. Quantitative results demonstrated losses of nNOS-ir, ChAT-ir, and GPR41-ir neurons in the Colitis group and Butyrate treatment attenuated neuronal loss. The number of GFAP-ir glia increased in the Colitis group, whereas Butyrate reduced the number of these cells. In addition, morphological alterations observed in the Colitis group were attenuated in the Butyrate group. The presence of GPR41 in myenteric neurons was identified, and the treatment with Butyrate attenuated the damage caused by experimental ulcerative colitis.
Topics: Mice; Animals; Colitis, Ulcerative; Mice, Inbred C57BL; Colitis; Neurons; Butyric Acid
PubMed: 37443707
DOI: 10.3390/cells12131672 -
Poultry Science Sep 2015An experiment with 288 male (Ross 308) 1-d-old broilers was conducted to test the hypothesis that a coarse diet supplemented with butyric acid (BA) and fermentable...
An experiment with 288 male (Ross 308) 1-d-old broilers was conducted to test the hypothesis that a coarse diet supplemented with butyric acid (BA) and fermentable carbohydrates (FC) improves performance of broilers with a poorly digestible protein source. The interaction effects of diet structure (fine or coarse), FC supplementation (with or without), and BA supplementation (with or without) in a poorly digestible diet based on rapeseed meal (RSM) were tested in a factorial arrangement of 8 (2×2×2) dietary treatments. The coarseness of the diet affected feed intake (FI) (P<0.001), BW gain (P=0.001), and the feed conversion ratio (FCR) (P=0.001) positively. Broilers fed the coarse diets had, on average, 14% heavier gizzards and 11, 7, 5, and 6% lower relative empty weights of the crop, duodenum, jejunum, and ileum, respectively, compared with those fed the fine diets. Dietary coarseness resulted in, on average, 6% greater ileal protein digestibility, 20% lower gizzard pH, 19% greater villus height, 18% lower crypt depth, and 23% reduced cecal branched chain fatty acids (BCFA) compared with chickens fed the fine diets. Broilers fed BA-supplemented diets had an improved FCR (P=0.004) and decreased crypt depth (P<0.001) compared with those fed diets without BA. Fermentable carbohydrate supplementation did not influence growth performance, gut development, or contents of total BCFA and total biogenic amines in the cecal digesta (P>0.05). Supplementation with FC, however, decreased the cecal concentration of spermine by approximately 31% compared with broilers fed diets without FC (P=0.002). In conclusion, feeding a coarse diet supplemented with BA improved performance of broilers fed a diet containing a poorly digestible protein source. The negative effects of a poorly digestible protein source can thus be partly counterbalanced by coarse grinding and BA supplementation in the diet.
Topics: Animal Nutritional Physiological Phenomena; Animals; Butyric Acid; Carbohydrate Metabolism; Cecum; Chickens; Diet; Fermentation; Intestines; Male; Random Allocation
PubMed: 26175052
DOI: 10.3382/ps/pev003 -
Molecules and Cells Apr 2018L-pipecolic acid is a non-protein amino acid commonly found in plants, animals, and microorganisms. It is a well-known precursor to numerous microbial secondary...
L-pipecolic acid is a non-protein amino acid commonly found in plants, animals, and microorganisms. It is a well-known precursor to numerous microbial secondary metabolites and pharmaceuticals, including anticancer agents, immunosuppressants, and several antibiotics. Lysine cyclodeaminase (LCD) catalyzes β-deamination of L-lysine into L-pipecolic acid using β-nicotinamide adenine dinucleotide as a cofactor. Expression of a human homolog of LCD, μ-crystallin, is elevated in prostate cancer patients. To understand the structural features and catalytic mechanisms of LCD, we determined the crystal structures of LCD (SpLCD) in (i) a binary complex with NAD, (ii) a ternary complex with NAD and L-pipecolic acid, (iii) a ternary complex with NAD and L-proline, and (iv) a ternary complex with NAD and L-2,4-diamino butyric acid. The overall structure of SpLCD was similar to that of ornithine cyclodeaminase from . In addition, SpLCD recognized L-lysine, L-ornithine, and L-2,4-diamino butyric acid despite differences in the active site, including differences in hydrogen bonding by Asp236, which corresponds with Asp228 from ornithine cyclodeaminase. The substrate binding pocket of SpLCD allowed substrates smaller than lysine to bind, thus enabling binding to ornithine and L-2,4-diamino butyric acid. Our structural and biochemical data facilitate a detailed understanding of substrate and product recognition, thus providing evidence for a reaction mechanism for SpLCD. The proposed mechanism is unusual in that NAD is initially converted into NADH and then reverted back into NAD at a late stage of the reaction.
Topics: Ammonia-Lyases; Butyric Acid; Humans; Lysine; Models, Molecular; Ornithine; Protein Binding
PubMed: 29629557
DOI: 10.14348/molcells.2018.2313 -
Poultry Science Feb 2020The present study evaluated the effects of butyric acid supplementation and Saccharomyces boulardii (alone or in combination) on growth performance, nutrient...
Growth performance, nutrient digestibility, bone mineralization, and hormone profile in broilers fed with phosphorus-deficient diets supplemented with butyric acid and Saccharomyces boulardii.
The present study evaluated the effects of butyric acid supplementation and Saccharomyces boulardii (alone or in combination) on growth performance, nutrient digestibility, bone mineralization, and blood hormones of male broiler chickens fed a diet including reduced levels of nonphytate phosphorus (NPP). The chickens were allocated to 6 dietary treatments: 1) positive control diet with adequate amounts of NPP (PC; 0.48, 0.43, and 0.39% in the starter, grower, and finisher period, respectively); 2) negative control diet with low amounts of NPP (NC; 0.38, 0.33, and 0.29% in the starter, grower, and finisher period, respectively); 3) NC plus 500 FTU/kg microbial phytase (PHY); 4) NC plus 0.2% butyric acid (BA); 5) NC plus 1 × 10 cfu/kg S. boulardii (SB); 6) NC plus butyric acid and S. boulardii (BA+SB). Each treatment had 5 pen replicates of 25 birds. After 6 wk, the body weight and ADG in birds fed with any of the diets were higher (P < 0.001) than those in birds fed with the NC diet, where the birds fed with the PHY and BA+SB diets had the highest values. However, only the PHY diet improved (P = 0.041) overall F:G. All diets, except the SB diet, resulted in the increased apparent ileal digestibility coefficient (AIDC) of CP, AME, and tibia ash content and decreased serum alkaline phosphatase level compared with the NC diet (P < 0.05). Broiler chickens fed with the PHY, SB, and BA+SB diets also had increased AIDC of phosphorus (P = 0.017) than those fed with the NC and PC diets. Feeding PC, PHY, and BA+SB diets increased (P = 0.007) the tibia phosphorus content but decreased (P = 0.033) serum parathyroid hormone concentration. Overall, the present data indicate that the simultaneous inclusion of butyric acid plus S. boulardii in the low-NPP diets was beneficial for improving growth rate and bone mineralization, but not for feed efficiency.
Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Butyric Acid; Calcification, Physiologic; Calcium; Chickens; Diet; Dietary Supplements; Digestion; Dose-Response Relationship, Drug; Hormones; Nutrients; Phosphorus; Probiotics; Random Allocation; Saccharomyces boulardii
PubMed: 32029169
DOI: 10.1016/j.psj.2019.10.046 -
Journal of Oral Science Mar 2012Short-chain fatty acids (SCFAs) are metabolites from anaerobic periodontopathic bacteria that induce apoptosis in immune cells such as lymphocytes, monocytes and...
Short-chain fatty acids (SCFAs) are metabolites from anaerobic periodontopathic bacteria that induce apoptosis in immune cells such as lymphocytes, monocytes and macrophages. However, it remains unclear if SCFAs from pathogens induce apoptosis in monocytes/macrophages similarly with lymphocytes. This study investigated whether SCFAs-induced apoptosis is equal among the immunoregulatory cells. Cell apoptosis of the employed human cells was evaluated after treatment with culture supernatants from various periodontopathic bacteria or sodium butyrate. Apoptosis and viability were determined by detection of DNA fragmentation and using an MTS assay kit, respectively. Porphyromonas gingivalis and Fusobacterium nucleatum culture filtrates strongly induced apoptosis whereas Prevotella nigrescens and Prevotella intermedia culture filtrates failed to induce apoptosis in the THP-1 and U937 human monocyte and macrophage cell lines. Healthy gingival fibroblasts and oral epithelial cells were resistant to all the culture filtrates. Gas-liquid chromatography detected butyric acid in P. gingivalis (21.0-34.0 mM) and F. nucleatum (36.0 mM) in culture filtrates, whereas, only trace levels were seen in P. nigrescens and P. intermedia. These results suggest that butyric acid produced by periodontopathic bacteria severely damages immunoregulatory cells in a consistent manner and, likewise, could be involved in mediating periodontal chronic inflammation.
Topics: Aggregatibacter actinomycetemcomitans; Apoptosis; Butyric Acid; Cell Line, Tumor; Culture Media, Conditioned; Fusobacterium nucleatum; Humans; Lymphocytes; Monocytes; Porphyromonas gingivalis
PubMed: 22466881
DOI: 10.2334/josnusd.54.7