Monobutyrin Can Regulate the Gut Microbiota, Which Is Beneficial for the Development of Intestinal Barrier Function and Intestinal Health in Weaned Mice.

In this study, we investigated the effect of monobutyrin (MB) on the gut microbiota and intestinal health of weaned mice. MB was administered via gavage to 21-day-old weaned mice. Samples of small intestinal and ileal contents were collected on day 1, day 7, and day 21 post-administration. Seven days of MB administration enhanced the mucin layer and morphological structure of the intestine and the integrity of the intestinal brush border. Both MB and sodium butyrate (SB) accelerated tight junction development. Compared to SB, MB modulated intestinal T cells in a distinct manner. MB increased the ratio of Treg cells in the small intestine upon the cessation of weaning. After 21 days of MB administration, enhancement of the villus structure of the ileum was observed. MB increased the proportion of Th17 cells in the ileum. MB facilitated the transition of the small intestinal microbiota toward an adult microbial community structure and enhanced the complexity of the microbial community structure. An increase in Th17 cells enhanced intestinal barrier function. The regulatory effect of MB on Th17 cells may occur through the intestinal microbiota. Therefore, MB can potentially be used to promote intestinal barrier function, especially for weaning animals, with promising application prospects.

Sodium butyrate and rosemary herb improve growth performance, biochemical profile, immunity, and carcass traits in broiler chickens.

Background: Feed additives are products used in poultry nutrition to improve the quality of feed and the safety of food byproducts from animal origin. They are promising antibiotic alternatives for the production of broilers. Aim: This study aimed to investigate the effect of sodium butyrate (SB) and RL on growth performance, biochemical profile, immunity, and carcass traits of broilers. Methods: Five hundred-one-day-old chicks of the Hubbard breed were reared on floor pens in a privet farm, Giza. The chicks were weighed on arrival (each chick weighted 43-45 gm) and randomly assigned into five equal groups, with four replicates each (25 chicks/replicate). Group 1 was fed on a broiler diet without any additions (control). The diets of groups 2 and 3 were supplemented with 500 g/ton SB and 4 kg/ton RL, respectively. In group 4, the diet was enriched with 250 g/ton SB plus 2 kg/ton RL. Chicks in group 5 were fed on a diet fortified with 500 g/ton SB plus 4 kg/ton RL. Results: Supplementation of broiler diet with 500 g/ton SB plus 4 kg /ton RL increased body weight gain (BWG) and feed efficiency ratio (FER) of birds. It decreased serum levels of aspartate aminotransferase, alanine aminotransferase, total cholesterol triglycerides, and malondialdehyde, but increased superoxide dismutase, catalase, and immunoglobulins, phagocytic activity, lysozyme activity, and nitric oxide concentrations. Antibody titers against the Newcastle disease virus were also elevated. Conclusion: Supplementation of broiler diet with 500 g/ton SB plus 4 kg/ton RL gives the best result regarding productive efficiency and immunity of broiler chickens.

[Bmal1 mediates the neuroprotective effect of sodium butyrate in a mouse model of Parkinson's disease].

OBJECTIVE: To investigate the mechanisms that mediate the neuroprotective effect of the intestinal microbial metabolite sodium butyrate (NaB) in a mouse model of Parkinson's disease (PD) via the gut-brain axis. METHODS: Thirty-nine 7-week-old male C57BL/6J mice were randomized equally into control group, PD model group, and NaB treatment group. In the latter two groups, PD models were established by intraperitoneal injection of 30 mg/kg 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) once daily for 5 consecutive days, and normal saline was injected in the control group. After modeling, the mice received daily gavage of NaB (300 mg/kg) or an equal volume of saline for 14 days. Behavioral tests were carried out to assess the changes in motor function of the mice, and Western blotting was performed to detect the expressions of tyrosine hydroxylase (TH) and α-synuclein (α-syn) in the striatum and nuclear factor-κB (NF-κB), tumor necrosis factor (TNF-α), interleukin 6 (IL-6), and the tight junction proteins ZO-1, Occludin, and Claudinin the colon. HE staining was used to observe inflammatory cell infiltration in the colon of the mice. RNA sequencing analysis was performed to identify the differentially expressed genes in mouse colon tissues, and their expressions were verified using qRT-PCR and Western blotting. RESULTS: The mouse models of PD with NaB treatment showed significantly increased movement speed and pulling strength of the limbs with obviously upregulated expressions of TH, Occludin, and Claudin and downregulated expressions of α-syn, NF-κB, TNF-α, and IL-6 (all P < 0.05). HE staining showed that NaB treatment significantly ameliorated inflammatory cell infiltration in the colon of the PD mice. RNA sequencing suggested that Bmal1 gene probably mediated the neuroprotective effect of NaB in PD mice (P < 0.05). CONCLUSION: NaB can improve motor dysfunction, reduce dopaminergic neuron loss in the striatum, and ameliorate colonic inflammation in PD mice possibly through a mechanism involving Bmal1.

Microbial metabolite sodium butyrate enhances the anti-tumor efficacy of 5-fluorouracil against colorectal cancer by modulating PINK1/Parkin signaling and intestinal flora.

Colorectal cancer (CRC) is a prevalent global health issue, with 5-fluorouracil (5-FU) being a commonly used chemotherapeutic agent for its treatment. However, the efficacy of 5-FU is often hindered by drug tolerance. Sodium butyrate (NaB), a derivative of intestinal flora, has demonstrated anti-cancer properties both in vitro and in vivo through pro-apoptotic effects and has shown promise in improving outcomes when used in conjunction with traditional chemotherapy agents. This study seeks to evaluate the impact and potential mechanisms of NaB in combination with 5-FU on CRC. We employed a comprehensive set of assays, including CCK-8, EdU staining, Hoechst 33258 staining, flow cytometry, ROS assay, MMP assay, immunofluorescence, and mitophagy assay, to detect the effect of NaB on the biological function of CRC cells in vitro. Western blotting and immunohistochemistry were used to verify the above experimental results. The xenograft tumor model was established to evaluate the in vivo anti-CRC activity of NaB. Subsequently, 16S rRNA gene sequencing was used to analyze the intestinal flora. The findings of our study demonstrate that sodium butyrate (NaB) exerts inhibitory effects on tumor cell proliferation and promotes tumor cell apoptosis in vitro, while also impeding tumor progression in vivo through the enhancement of the mitophagy pathway. Furthermore, the combined treatment of NaB and 5-fluorouracil (5-FU) yielded superior therapeutic outcomes compared to monotherapy with either agent. Moreover, this combination therapy resulted in the specific enrichment of Bacteroides, LigiLactobacillus, butyric acid-producing bacteria, and acetic acid-producing bacteria in the intestinal microbiota. The improvement in the intestinal microbiota contributed to enhanced therapeutic outcomes and reduced the adverse effects of 5-FU. Taken together, these findings indicate that NaB, a histone acetylation inhibitor synthesized through intestinal flora fermentation, has the potential to significantly enhance the therapeutic efficacy of 5-FU in CRC treatment and improve the prognosis of CRC patients.

Taking SCFAs produced by Lactobacillus reuteri orally reshapes gut microbiota and elicits antitumor responses.

BACKGROUND: Colorectal cancer (CRC) incidence is increasing in recent years due to intestinal flora imbalance, making oral probiotics a hotspot for research. However, numerous studies related to intestinal flora regulation ignore its internal mechanisms without in-depth research. RESULTS: Here, we developed a probiotic microgel delivery system (L.r@(SA-CS)2) through the layer-by-layer encapsulation technology of alginate (SA) and chitosan (CS) to improve gut microbiota dysbiosis and enhance anti-tumor therapeutic effect. Short chain fatty acids (SCFAs) produced by L.r have direct anti-tumor effects. Additionally, it reduces harmful bacteria such as Proteobacteria and Fusobacteriota, and through bacteria mutualophy increases beneficial bacteria such as Bacteroidota and Firmicutes which produce butyric acid. By binding to the G protein-coupled receptor 109A (GPR109A) on the surface of colonic epithelial cells, butyric acid can induce apoptosis in abnormal cells. Due to the low expression of GPR109A in colon cancer cells, MK-6892 (MK) can be used to stimulate GPR109A. With increased production of butyrate, activated GPR109A is able to bind more butyrate, which further promotes apoptosis of cancer cells and triggers an antitumor response. CONCLUSION: It appears that the oral administration of L.r@(SA-CS)2 microgels may provide a treatment option for CRC by modifying the gut microbiota.

Autolyzed yeast and sodium butyrate supplemented alone to diets promoted improvements in performance, intestinal health and nutrient transporter in weaned piglets.

This study investigated the effects of supplemental nucleotides, autolyzed yeast (Saccharomyces cerevisiae), and sodium butyrate in diets for nursery pigs on growth performance, diarrhea incidence, blood profile, intestinal morphology, mRNA expression of nutrient transporters, inflammatory markers, antioxidant profile, and tight junction proteins in the small intestine. One hundred eighty 21-day-old pigs (5.17 ± 0.57 kg) were assigned in a randomized block design to 1 of 4 dietary treatments: (1) CON: control, basal diet, (2) NUC: CON + nucleotides, (3) YSC: CON + lysed yeast S. cerevisiae, (4) ASB: CON + acidifier sodium butyrate. Pigs were fed for 24 days, phase 1 (21-32 days) and 2 (32-45 days). During phase 1, YSC and ASB improved average daily gain (ADG) and feed conversion (FC) compared with CON. At the overall period, ASB improved ADG and YSC improved FC compared with CON. The NUC diet did not affect growth performance. The ASB increased ileal villus height compared to CON. The YSC and ASB reduced the number of Peyer's patches in the ileum compared with CON. The YSC increased mRNA expression of nutrient transporters (SMCT2, MCT1, and PepT1), tight junction proteins (OCL and ZO-1), antioxidants (GPX), and IL1-ß in the jejunum compared with CON. The ASB increased mRNA expression of nutrient transporters (SGLT1 and MCT1), tight junction proteins (OCL and ZO-1), and antioxidants (GPX and SOD) compared with CON. In conclusion, autolyzed yeast and sodium butyrate promoted growth performance by improving the integrity of the intestinal barrier, the mRNA expression of nutrient transporters, and antioxidant enzymes in the jejunum of nursery pigs whereas supplementation of nucleotides did not show such effects.

ARHGAP10, Transcriptionally Regulated by Sodium Butyrate, Promotes Ferroptosis of Ovarian Cancer Cells.

BACKGROUND: Ovarian cancer is a highly lethal gynecologic malignancy. ARHGAP10, a member of Rho GTPase-activating proteins, is a potential tumor suppressor in ovarian cancer. However, its role and the involved mechanism need further examination. Here, we investigated whether ARHGAP10 is also associated with ferroptosis. METHODS: Lentivirus infection was used for gene overexpression or silencing. Real-time polymerase chain reaction (RT-PCR) and Western blot were used to assess mRNA and protein levels, respectively. Cell viability was assessed by Cell Counting Kit-8 (CCK-8) assay. Lipid reactive oxygen species level was measured by flow cytometry. A tumorigenicity assay was performed to evaluate tumor growth in vivo, and sections of mouse tumor tissues were examined by immunofluorescence microscopy. Chromatin Immunoprecipitation (ChIP) assay was used to assess the binding of H3K9ac to the promoter region of ARHGAP10. RESULTS: ARHGAP10 overexpression promoted ferroptosis in ovarian cancer cells, resulting in decreased cell viability, and increased lipid reactive oxygen species (ROS) level. Further, it decreased and increased GPX4 and PTGS2 expression, respectively, and also induced suppression of tumor growth in mice. Fer-1, a potent inhibitor of ferroptosis, suppressed the above effects of ARHGAP10. Contrarily, ARHGAP10 silencing alleviated ferroptosis in ovarian cancer cells, which was reversed by RSL3, a ferroptosis-inducing agent. Lastly, sodium butyrate (SB) was found to transcriptionally regulate ARHGAP10, thereby also contributing to the ferroptosis of ovarian cancer cells. CONCLUSIONS: Our results suggest that SB/ARHGAP10/GPX4 is a new signaling axis involved in inducing ferroptosis in ovarian cancer cells and suppressing tumor growth, which has potential clinical significance.

Synergistic Effect of Dietary Supplementation with Sodium Butyrate, ß-Glucan and Vitamins on Growth Performance, Cortisol Level, Intestinal Microbiome and Expression of Immune-Related Genes in Juvenile African Catfish (Clarias gariepinus).

The effect of dietary supplementation with sodium butyrate, ß-glucan and vitamins (A, D3, E, K, C) on breeding indicators and immune parameters of juvenile African catfish was examined. The fish were fed with unenriched (group C) and enriched feed with a variable proportion of sodium butyrate/ß-glucan, and constant content of vitamins (W1-W3). After the experiment, blood and the middle gut were collected. The microbiome of the gut was determined using Next Generation Sequencing (NGS). Liver tissue was collected for determination of expression of immune-related genes (HSP70, IL-1ß, TNFα). W2 and W3 were characterized by the most favorable values of breeding indicators (p < 0.05). The highest blood cortisol concentration was in group C (71.25 ± 10.45 ng/mL), and significantly the lowest in W1 (46.03 ± 7.01 ng/ mL) (p < 0.05). The dominance of Cetobacterium was observed in all study groups, with the largest share in W3 (65.25%) and W1 (61.44%). Gene expression showed an increased number of HSP70 genes in W1. IL-1ß and TNFα genes peaked at W3. The W3 variant turns out to be the most beneficial supplementation, due to the improvement of breeding and immunological parameters. The data obtained can be used to create a preparation for commercial use in the breeding of this species.

Short-chain fatty acids induced lung tumor cell death and increased peripheral blood CD4+ T cells in NSCLC and control patients ex vivo.

Background: Despite therapy advances, one of the leading causes of cancer deaths still remains lung cancer. To improve current treatments or prevent non-small cell lung cancer (NSCLC), the role of the nutrition in cancer onset and progression needs to be understood in more detail. While in colorectal cancer, the influence of local microbiota derived SCFAs have been well investigated, the influence of SCFA on lung cancer cells via peripheral blood immune system should be investigated more deeply. In this respect, nutrients absorbed via the gut might affect the tumor microenvironment (TME) and thus play an important role in tumor cell growth. Objective: This study focuses on the impact of the short-chain fatty acid (SCFA) Sodium Butyrate (SB), on lung cancer cell survival. We previously described a pro-tumoral role of glucose on A549 lung adenocarcinoma cell line. In this study, we wanted to know if SB would counteract the effect of glucose and thus cultured A549 and H520 in vitro with and without SB in the presence or absence of glucose and investigated how the treatment with SB affects the survival of lung cancer cells and its influence on immune cells fighting against lung cancer. Methods: In this study, we performed cell culture experiments with A549, H520 and NSCLC-patient-derived epithelial cells under different SB levels. To investigate the influence on the immune system, we performed in vitro culture of peripheral mononuclear blood cells (PBMC) from control, smoker and lung cancer patients with increasing SB concentrations. Results: To investigate the effect of SB on lung tumor cells, we first analyzed the effect of 6 different concentrations of SB on A549 cells at 48 and 72 hours cell culture. Here we found that, SB treatment reduced lung cancer cell survival in a concentration dependent manner. We next focused our deeper analysis on the two concentrations, which caused the maximal reduction in cell survival. Here, we observed that SB led to cell cycle arrest and induced early apoptosis in A549 lung cancer cells. The expression of cell cycle regulatory proteins and A549 lung cancer stem cell markers (CD90) was induced. Additionally, this study explored the role of interferon-gamma (IFN-γ) and its receptor (IFN-γ-R1) in combination with SB treatment, revealing that, although IFN-γ-R1 expression was increased, IFN-γ did not affect the efficacy of SB in reducing tumor cell viability. Furthermore, we examined the effects of SB on immune cells, specifically CD8+ T cells and natural killer (NK) cells from healthy individuals, smokers, and NSCLC patients. SB treatment resulted in a decreased production of IFN-γ and granzyme B in CD8+ T cells and NK cells. Moreover, SB induced IFN-γ-R1 in NK cells and CD4+ T cells in the absence of glucose both in PBMCs from controls and NSCLC subjects. Conclusion: Overall, this study highlights the potential of SB in inhibiting lung cancer cell growth, triggering apoptosis, inducing cell cycle arrest, and modulating immune responses by activating peripheral blood CD4+ T cells while selectively inducing IFN-γ-R1 in NK cells in peripheral blood and inhibiting peripheral blood CD8+ T cells and NK cells. Thus, understanding the mechanisms of action of SB in the TME and its influence on the immune system provide valuable insights of potentially considering SB as a candidate for adjunctive therapies in NSCLC.

Butyrate increases methylglyoxal production through regulation of the JAK2/Stat3/Nrf2/Glo1 pathway in castration­resistant prostate cancer cells.

Cancer cells are characterized by increased glycolysis, known as the Warburg effect, which leads to increased production of cytotoxic methylglyoxal (MGO) and apoptotic cell death. Cancer cells often activate the protective nuclear factor erythroid 2­related factor2 (Nrf2)/glyoxalase1 (Glo1) system to detoxify MGO. The effects of sodium butyrate (NaB), a product of gut microbiota, on Nrf2/Glos/MGO pathway and the underlying mechanisms in prostate cancer (PCa) cells were investigated in the present study. Treatment with NaB induced the cell death and reduced the proliferation of PCa cells (DU145 and LNCap). Moreover, the protein kinase RNA-like endoplasmic reticulum kinase/Nrf2/Glo1 pathway was greatly inhibited by NaB, thereby accumulating MGO-derived adduct hydroimidazolone (MG-H1). In response to a high amount of MGO, the expression of Nrf2 and Glo1 was attenuated, coinciding with an increased cellular death. NaB also markedly inhibited the Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (Stat3) pathway. Conversely, co­treatment with Colivelin, a Stat3 activator, significantly reversed the effects of NaB on Glo1 expression, MG-H1 production, and the cell migration and viability. As expected, overexpression of Stat3 or Glo1 reduced NaB­induced cell death. The activation of calcium/calmodulin dependent protein kinase II gamma and reactive oxygen species production also contributed to the anticancer effect of NaB. The present study, for the first time, demonstrated that NaB greatly increases MGO production through suppression of the JAK2/Stat3/Nrf2/Glo1 pathway in DU145 cells, a cell line mimicking castration­resistant PCa (CRPC), suggesting that NaB may be a potential agent for PCa therapy.

Differential responses of rumen and fecal fermentation and microbiota of Liaoning cashmere goats after 2-hydroxy-4-(methylthio) butanoic acid isopropyl ester supplementation.

The 2-hydroxy-4-(methylthio) butanoic acid isopropyl ester (HMBi), a rumen protective methionine, has been extensively studied in dairy cows and beef cattle and has been shown to regulate gastrointestinal microbiota and improve production performance. However, knowledge of the application of HMBi on cashmere goats and the simultaneous study of rumen and hindgut microbiota is still limited. In this study, HMBi supplementation increased the concentration of total serum protein, the production of microbial protein in the rumen and feces, as well as butyrate production in the feces. The results of PCoA and PERMANOVA showed no significant difference between the rumen microbiota, but there was a dramatic difference between the fecal microbiota of the two groups of Cashmere goats after the HMBi supplementation. Specifically, in the rumen, HMBi significantly increased the relative abundance of some fiber-degrading bacteria (such as Fibrobacter) compared with the CON group. In the feces, as well as a similar effect as in the rumen (increasing the relative abundance of some fiber-degrading bacteria, such as Lachnospiraceae FCS020 group and ASV32), HMBi diets also increased the proliferation of butyrate-producing bacteria (including Oscillospiraceae UCG-005 and Christensenellaceae R-7 group). Overall, these results demonstrated that HMBi could regulate the rumen and fecal microbial composition of Liaoning cashmere goats and benefit the host.

Fusobacterium nucleatum-induced imbalance in microbiome-derived butyric acid levels promotes the occurrence and development of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) ranks among the most prevalent malignant tumors globally. Recent reports suggest that Fusobacterium nucleatum (F. nucleatum) contributes to the initiation, progression, and prognosis of CRC. Butyrate, a short-chain fatty acid derived from the bacterial fermentation of soluble dietary fiber, is known to inhibit various cancers. This study is designed to explore whether F. nucleatum influences the onset and progression of CRC by impacting the intestinal metabolite butyric acid. AIM: To investigate the mechanism by which F. nucleatum affects CRC occurrence and development. METHODS: Alterations in the gut microbiota of BALB/c mice were observed following the oral administration of F. nucleatum. Additionally, DLD-1 and HCT116 cell lines were exposed to sodium butyrate (NaB) and F. nucleatum in vitro to examine the effects on proliferative proteins and mitochondrial function. RESULTS: Our research indicates that the prevalence of F. nucleatum in fecal samples from CRC patients is significantly greater than in healthy counterparts, while the prevalence of butyrate-producing bacteria is notably lower. In mice colonized with F. nucleatum, the population of butyrate-producing bacteria decreased, resulting in altered levels of butyric acid, a key intestinal metabolite of butyrate. Exposure to NaB can impair mitochondrial morphology and diminish mitochondrial membrane potential in DLD-1 and HCT116 CRC cells. Consequently, this leads to modulated production of adenosine triphosphate and reactive oxygen species, thereby inhibiting cancer cell proliferation. Additionally, NaB triggers the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, blocks the cell cycle in HCT116 and DLD-1 cells, and curtails the proliferation of CRC cells. The combined presence of F. nucleatum and NaB attenuated the effects of the latter. By employing small interfering RNA to suppress AMPK, it was demonstrated that AMPK is essential for NaB's inhibition of CRC cell proliferation. CONCLUSION: F. nucleatum can promote cancer progression through its inhibitory effect on butyric acid, via the AMPK signaling pathway.

Protective effects of sodium butyrate on fluorosis in rats by regulating bone homeostasis and serum metabolism.

Fluorosis due to high fluoride levels in drinking water profoundly affects the development of human skeletal and dental structures. Sodium butyrate (NaB) has been found to regulate overall bone mass and prevent pathological bone loss. However, the mechanism of NaB action on fluorosis remains unclear. In this study, a rat model of fluorosis induced by 100 mg/L sodium fluoride was used to investigate the impact of NaB on bone homeostasis and serum metabolomics. It was found that NaB significantly reduced the levels of bone resorption markers CTX-Ⅰ and TRACP-5B in fluorosis rats. Moreover, NaB increased calcium and magnesium levels in bone, while decreasing phosphorus levels. In addition, NaB improved various bone microstructure parameters, including bone mineral density (BMD), trabecular thickness (Tb. Th), trabecular bone separation (Tb. SP), and structural model index (SMI) in the femur. Notably, NaB intervention also enhanced the antioxidant capacity of plasma in fluorosis rats. Furthermore, a comprehensive analysis of serum metabolomics by LC-MS revealed a significant reversal trend of seven biomarkers after the intervention of NaB. Finally, pathway enrichment analysis based on differential metabolites indicated that NaB exerted protective effects on fluorosis by modulating arginine and proline metabolic pathways. These findings suggest that NaB has a beneficial effect on fluorosis and can regulate bone homeostasis by ameliorating metabolic disorders.

The effect of butyric acid and nucleotides supplementation on broiler (Gallus gallus domesticus) growth performance, immune status, intestinal histology, and serum parameters.

Background: Butyric acid and its derivatives support the immune system, lessen inflammation, and lessen oxidative stress in broilers in addition to preserving gut homeostasis and epithelial integrity. Broiler performance has also been demonstrated to rise with the addition of nucleotides to the diet. Aim: The purpose of the study was to ascertain the effects of butyric acid and nucleotides added to feed on the overall performance, immunity, oxidant/antioxidant enzyme levels, intestinal histology, and hepatic functions of broilers. Methods: Four experimental groups of thirty chickens, each were used in the present study. The groups were assigned as a control group that received normal diet without additives, butyrate (B) group received the diet supplemented with butyric acid (250 g/ton feed), nucleotides (N) group received the diet supplemented with nucleotides (200 g/ton feed), and the fourth group received the diet supplemented with a combination of butyrate and nucleotide (BN) (250 g/ton B feed, and 200 g/ton N feed, respectively). Necrotic enteritis was produced in ten birds from each group to assess the immune-modulatory effect of these supplements, antioxidant status, intestinal histology, and liver functions were measured in all experimental groups. Results: The addition of butyric acid and nucleotides to feed enhanced body weight, growth performance, hepatic functions, and antioxidant capabilities. Histological sections of the gut from challenged or unchallenged (with necrotic enteritis) groups in the BN group showed considerable improvement, as shown by strong proliferation in intestinal crypts and villus enterocytes. Conclusion: Nucleotides and butyric acid can be added to broiler feeding regimens to enhance growth and health.

Sodium propionate oral supplementation ameliorates depressive-like behavior through gut microbiome and histone 3 epigenetic regulation.

Major depressive disorder (MDD) is a global health concern, affecting over 250 million individuals worldwide. In recent years, the gut-brain axis has emerged as a promising field for understanding the pathophysiology of MDD. Microbial metabolites, such as short-chain fatty acids (SCFAs)-acetate, butyrate, and propionate-, have gained attention for their potential to influence epigenetic modifications within the host brain. However, the precise mechanisms through which these metabolites participate in MDD pathophysiology remain elusive. This study was designed to investigate the effects of oral SCFA supplementation in adult male Wistar rats subjected to chronic unpredictable mild stress (CUMS). A subset of control and CUMS-exposed rats received different supplementations: sodium acetate (NaOAc) at a concentration of 60 mM, sodium butyrate (NaB) at 40 mM, sodium propionate (NaP) at 50 mM, or a mixture of these SCFAs. The gut microbiome was assessed through 16S rRNA sequencing, and epigenetic profiling was performed using Western blot analysis. Results demonstrated that NaP supplementation significantly alleviated anhedonia in stressed animals, as evidenced by improved performance in the sucrose consumption test. This ameliorative effect was potentially associated with the modulation of gut bacterial communities, accompanied by the attenuation of the region-specific epigenetic dysregulation in the brain of the animals exposed to chronic stress. These findings suggest a potential association between gut dysbiosis and stress response, and NaP could be a promising target for future MDD interventions. However, further studies are needed to fully elucidate the underlying mechanisms of these effects.

Grape seed proanthocyanidin extract promotes skeletal muscle fiber type transformation through modulation of cecal microbiota and enhanced butyric acid production.

The conversion of fast-twitch fibers into slow-twitch fibers within skeletal muscle plays a crucial role in improving physical stamina and safeguarding against metabolic disorders in individuals. Grape seed proanthocyanidin extract (GSPE) possesses numerous pharmacological and health advantages, effectively inhibiting the onset of chronic illnesses. However, there is a lack of research on the specific mechanisms by which GSPE influences muscle physiology and gut microbiota. This study aims to investigate the role of gut microbiota and their metabolites in GSPE regulation of skeletal muscle fiber type conversion. In this experiment, 54 male BALB/c mice were randomly divided into three groups: basal diet, basal diet supplemented with GSPE, and basal diet supplemented with GSPE and antibiotics. During the feeding period, glucose tolerance and forced swimming tests were performed. After euthanasia, samples of muscle and feces were collected for analysis. The results showed that GSPE increased the muscle mass and anti-fatigue capacity of the mice, as well as the expression of slow-twitch fibers. However, the beneficial effects of GSPE on skeletal muscle fibers disappeared after adding antibiotics to eliminate intestinal microorganisms, suggesting that GSPE may play a role by regulating intestinal microbial structure. In addition, GSPE increased the relative abundance of Blautia, Muribaculaceae, and Enterorhabdus, as well as butyrate production. Importantly, these gut microbes exhibited a significant positive correlation with the expression of slow-twitch muscle fibers. In conclusion, supplementation with GSPE can increase the levels of slow-twitch fibers by modulating the gut microbiota, consequently prolonging the duration of exercise before exhaustion. PRACTICAL APPLICATION: This research suggests that grape seed proanthocyanidin extract (GSPE) has potential applications in improving physical stamina and preventing metabolic disorders. By influencing the gut microbiota and increasing butyric acid production, GSPE contributes to the conversion of fast-twitch muscle fibers into slow-twitch fibers, thereby enhancing anti-fatigue capacity and exercise endurance. While further studies are needed, incorporating GSPE into dietary supplements or functional foods could support individuals seeking to optimize their exercise performance and overall metabolic health.

Butyric acid and prospects for creation of new medicines based on its derivatives: a literature review.

The widespread use of antimicrobials causes antibiotic resistance in bacteria. The use of butyric acid and its derivatives is an alternative tactic. This review summarizes the literature on the role of butyric acid in the body and provides further prospects for the clinical use of its derivatives and delivery methods to the animal body. Thus far, there is evidence confirming the vital role of butyric acid in the body and the effectiveness of its derivatives when used as animal medicines and growth stimulants. Butyric acid salts stimulate immunomodulatory activity by reducing microbial colonization of the intestine and suppressing inflammation. Extraintestinal effects occur against the background of hemoglobinopathy, hypercholesterolemia, insulin resistance, and cerebral ischemia. Butyric acid derivatives inhibit histone deacetylase. Aberrant histone deacetylase activity is associated with the development of certain types of cancer in humans. Feed additives containing butyric acid salts or tributyrin are used widely in animal husbandry. They improve the functional status of the intestine and accelerate animal growth and development. On the other hand, high concentrations of butyric acid stimulate the apoptosis of epithelial cells and disrupt the intestinal barrier function. This review highlights the biological activity and the mechanism of action of butyric acid, its salts, and esters, revealing their role in the treatment of various animal and human diseases. This paper also discussed the possibility of using butyric acid and its derivatives as surface modifiers of enterosorbents to obtain new drugs with bifunctional action.

Gut microbiota-derived butyrate restores impaired regulatory T cells in patients with AChR myasthenia gravis via mTOR-mediated autophagy.

More than 80% of patients with myasthenia gravis (MG) are positive for anti-acetylcholine receptor (AChR) antibodies. Regulatory T cells (Tregs) suppress overproduction of these antibodies, and patients with AChR antibody-positive MG (AChR MG) exhibit impaired Treg function and reduced Treg numbers. The gut microbiota and their metabolites play a crucial role in maintaining Treg differentiation and function. However, whether impaired Tregs correlate with gut microbiota activity in patients with AChR MG remains unknown. Here, we demonstrate that butyric acid-producing gut bacteria and serum butyric acid level are reduced in patients with AChR MG. Butyrate supplementation effectively enhanced Treg differentiation and their suppressive function of AChR MG. Mechanistically, butyrate activates autophagy of Treg cells by inhibiting the mammalian target of rapamycin. Activation of autophagy increased oxidative phosphorylation and surface expression of cytotoxic T-lymphocyte-associated protein 4 on Treg cells, thereby promoting Treg differentiation and their suppressive function in AChR MG. This observed effect of butyrate was blocked using chloroquine, an autophagy inhibitor, suggesting the vital role of butyrate-activated autophagy in Tregs of patients with AChR MG. We propose that gut bacteria derived butyrate has potential therapeutic efficacy against AChR MG by restoring impaired Tregs.

Butyrate alleviates alcoholic liver disease-associated inflammation through macrophage regulation and polarization via the HDAC1/miR-155 axis.

BACKGROUND: We recently found that butyrate could ameliorate inflammation of alcoholic liver disease (ALD) in mice. However, the exact mechanism remains incompletely comprehended. Here, we examined the role of butyrate on ALD-associated inflammation through macrophage (Mψ) regulation and polarization using in vivo and in vitro experiments. METHODS: For in vivo experiments, C57BL/6J mice were fed modified Lieber-DeCarli liquid diets supplemented with or without ethanol and sodium butyrate (NaB). After 6 weeks of treatment, mice were euthanized and associated indicators were analyzed. For in vitro experiments, lipopolysaccharide (LPS)-induced inflammatory murine RAW264.7 cells were treated with NaB or miR-155 inhibitor/mimic to verify the anti-inflammatory effect and underlying mechanism. RESULTS: The administration of NaB alleviated pathological damage and associated inflammation, including LPS, tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1ß levels in ALD mice. NaB intervention restored the imbalance of macrophage polarization by inhibiting inducible nitric oxide synthase (iNOS) and elevating arginase-1 (Arg-1). Moreover, NaB reduced histone deacetylase-1 (HDAC1), nuclear factor kappa-B (NF-κB), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), and miR-155 expression in ALD mice, but also increased peroxisome proliferator-activated receptor-γ (PPAR-γ). Thus, MiR-155 was identified as a strong regulator of ALD. To further penetrate the role of miR-155, LPS-stimulated RAW264.7 cells co-cultured with NaB were treated with the specific inhibitor or mimic. Intriguingly, miR-155 was capable of negatively regulated inflammation with NaB intervention by targeting SOCS1, SHIP1, and IRAK-M genes. CONCLUSION: Butyrate suppresses the inflammation in mice with ALD by regulating macrophage polarization via the HDAC1/miR-155 axis, which may potentially contribute to the novel therapeutic treatment for the disease.

Exploring the combined anti-cancer effects of sodium butyrate and celastrol in glioblastoma cell lines: a novel therapeutic approach.

Glioblastoma, a highly aggressive and lethal brain cancer, lacks effective treatment options and has a poor prognosis. In our study, we explored the potential anti-cancer effects of sodium butyrate (SB) and celastrol (CEL) in two glioblastoma cell lines. SB, a histone deacetylase inhibitor, and CEL, derived from the tripterygium wilfordii plant, act as mTOR and proteasome inhibitors. Both can cross the blood-brain barrier, and they exhibit chemo- and radiosensitive properties in various cancer models. GB cell lines LN-405 and T98G were treated with SB and CEL. Cell viability was assessed by MTT assay and IC50 values were obtained. Gene expression of DNA repair, apoptosis, and autophagy-related genes was analyzed by RT-PCR. Cell cycle distribution was determined using flow cytometry. Viability assays using MTT assay revealed IC50 values of 26 mM and 22.7 mM for SB and 6.77 µM, and 9.11 µM for CEL in LN-405 and T98G cells, respectively. Furthermore, we examined the expression levels of DNA repair genes (MGMT, MLH-1, MSH-2, MSH-6), apoptosis genes (caspase-3, caspase-8, caspase-9), and an autophagy gene (ATG-6) using real-time polymerase chain reaction. Additionally, flow cytometry analysis revealed alterations in cell cycle distribution following treatment with SB, CEL and their combination. These findings indicate that SB and CEL may act through multiple mechanisms, including DNA repair inhibition, apoptosis induction, and autophagy modulation, to exert their anti-cancer effects in glioblastoma cells. This is the first study providing novel insights into the potential therapeutic effects of SB and CEL in glioblastoma.