Chronic radiation proctitis refractory to steroid enema was successfully treated by metformin and sodium butyrate: a case report.

BACKGROUND: Radiation proctitis (RP) is a significant complication of pelvic radiation. Effective treatments for chronic RP are currently lacking. We report a case where chronic RP was successfully managed by metformin and butyrate (M-B) enema and suppository therapy. CASE PRESENTATION: A 70-year-old Asian male was diagnosed with prostate cancer of bilateral lobes, underwent definitive radiotherapy to the prostate of 76 Gy in 38 fractions and six months of androgen deprivation therapy. Despite a stable PSA nadir of 0.2 ng/mL for 10 months post-radiotherapy, he developed intermittent rectal bleeding, and was diagnosed as chronic RP. Symptoms persisted despite two months of oral mesalamine, mesalamine enema and hydrocortisone enema treatment. Transition to daily 2% metformin and butyrate (M-B) enema for one week led to significant improvement, followed by maintenance therapy with daily 2.0% M-B suppository for three weeks, resulting in continued reduction of rectal bleeding. Endoscopic examination and biopsy demonstrated a good therapeutic effect. CONCLUSIONS: M-B enema and suppository may be an effective treatment for chronic RP.

Butyrate as a promising therapeutic target in cancer: From pathogenesis to clinic (Review).

Cancer is one of the leading causes of mortality worldwide. The etiology of cancer has not been fully elucidated yet, and further enhancements are necessary to optimize therapeutic efficacy. Butyrate, a short­chain fatty acid, is generated through gut microbial fermentation of dietary fiber. Studies have unveiled the relevance of butyrate in malignant neoplasms, and a comprehensive understanding of its role in cancer is imperative for realizing its full potential in oncological treatment. Its full antineoplastic effects via the activation of G protein­coupled receptors and the inhibition of histone deacetylases have been also confirmed. However, the underlying mechanistic details remain unclear. The present study aimed to review the involvement of butyrate in carcinogenesis and its molecular mechanisms, with a particular emphasis on its association with the efficacy of tumor immunotherapy, as well as discussing relevant clinical studies on butyrate as a therapeutic target for neoplastic diseases to provide new insights into cancer treatment.

Effectiveness of 1-year pemafibrate treatment on steatotic liver disease: the influence of alcohol consumption.

BACKGROUND/AIMS: Pemafibrate is a selective peroxisome proliferator-activated receptor α modulator that improves serum alanine aminotransferase (ALT) in dyslipidemia patients. We previously reported that pemafibrate significantly improves liver function, serum triglyceride (TG) levels and liver stiffness in non-alcoholic fatty liver disease patients, however the influence of alcohol consumption was not considered. Therefore, we explored pemafibrate efficacy in patients with steatotic liver disease (SLD) and alcohol-associated liver disease (ALD). METHODS: We retrospectively evaluated pemafibrate efficacy on liver enzymes and lipids in metabolic dysfunction-associated SLD (MASLD) (n = 93), MASLD plus increased alcohol intake (MetALD; n = 23) and ALD (n = 22) patients who had taken pemafibrate for at least 48 weeks. Liver shear wave velocity (SWV, n = 75) was also evaluated. RESULTS: In MASLD group, ALT, aspartate aminotransferase (AST), γ-glutamyl transpeptidase (γ-GTP) and TG values were significantly decreased from baseline to week 24 and week 48 ( P  < 0.0001). ALT and TG values in MetALD group and ALT and AST values in ALD group were also significantly decreased from baseline to week 24 and week 48. Study participant SWV values decreased from baseline to week 48. We observed no significant difference in changes to ALT, AST, γ-GTP and TG (value at week 24 or week 48 minus value at baseline) among the three groups. CONCLUSION: Pemafibrate improves liver function and liver stiffness thus making it a promising therapeutic agent for SLD, even in patients with excess alcohol consumption (MetALD and ALD groups).

The Potential Role of Probiotics, Especially Butyrate Producers, in the Management of Gastrointestinal Mucositis Induced by Oncologic Chemo-Radiotherapy.

Many clinical studies have now highlighted how the composition of the intestinal microbiota can regulate the effects of many oncological therapies. In particular, the modulation of microbial composition has been shown to enhance their efficacy and reduce potential side effects. Numerous adverse events induced by chemotherapy and radiotherapy appear to be strongly associated with an alteration in the intestinal microbiota caused by these treatments. This supports the hypothesis that the modulation or correction of the microbiota may decrease the toxic impact of therapies, improving patient compliance and quality of life. Among the most debilitating disorders related to oncological treatments is certainly mucositis, and recent clinical data highlight how the deficiency of short-chain fatty acids, especially butyrate, and specifically the lack of certain bacterial groups responsible for its production (butyrate producers), is strongly associated with this disorder. It is hypothesized that restoring these elements may influence the onset and severity of adverse events. Therefore, the intake of probiotics, especially butyrate producers, and specifically Clostridium butyricum (CBM588), currently the only cultivable and usable strain with a history of data proving its safety, could be a valuable ally in oncological therapies, reducing the associated discomfort and improving compliance, efficacy, and quality of life for patients.

Effects of Pemafibrate on Reducing Oxidative Stress and Augmenting Angiogenesis in Ischemic Limb Tissue.

OBJECTIVE: Oxidative damage is observed in the ischemic limbs of patients with arteriosclerosis obliterans. We investigated whether pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, reduced oxidative stress in ischemic limbs and consequently rescued limb damage in model mice. MATERIALS AND METHODS: We surgically induced hind-limb ischemia in mice and orally administered pemafibrate solution (P-05 group, 0.5 mg/kg/day; P-10 group, 1.0 mg/kg/day) or control solution (control group). Seven days after the surgery, differences in reactive oxygen species (ROS) contents, antioxidative enzyme and transcription factor expression, blood flow, and capillary density in ischemic limbs were assessed. RESULTS: Tissue ROS levels were lower in the P-05 and P-10 groups compared with those in the control group. Although the tissue expression levels of nuclear factor-erythroid 2-related factor 2 increased in the P-10 group compared with that in the control group, no corresponding changes were observed in the tissue expression of four antioxidative enzymes. The limb salvage rates and capillary densities in ischemic limbs were higher in the P-05 and P-10 groups than that in the control group. CONCLUSION: Pemafibrate treatment reduced oxidative stress and augmented angiogenesis in ischemic limbs, contributing to prevention of limb damage in mice.

Butyrate alleviates renal inflammation and fibrosis in a rat model of polycystic ovarian syndrome by suppression of SDF-1.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is a multifactorial condition with metabolic-related complications, such as diabetic nephropathy and chronic renal disorder, which are the leading cause of renal transplant globally. Protective effects of histone deacetylase (HDAC) inhibitors (HDACi) have been documented in metabolic-linked pathologies. Nonetheless, the current study investigated the restorative role of HDACi, butyrate in experimental PCOS-induced renal disorder. MATERIALS AND METHODS: Female Wistar rats (8-week-old) were divided into groups; control, butyrate-treated, letrozole and letrozole + butyrate-treated groups. To induce PCOS, 1 mg/kg of letrozole was given (oral gavage) for 21 days. After confirmation of PCOS, 200 mg/kg of butyrate (oral gavage) was administered for 6 weeks. RESULTS: Rats with PCOS revealed disruption in glucose homeostasis (hyperinsulinemia and impaired glucose tolerance and insulin resistance) and presented with the phenotypes of PCOS (hyperandrogenism, multiple ovarian cysts and elevated LH/FSH ratio). Increased plasma and renal triglycerides and inflammatory (TNF-α/SDF-1/NF-κB) markers were observed with elevated levels of TGFß-1, renal lipid peroxidation and redox imbalance (GGT, GSH, HIF-1α). Interestingly, animals with PCOS reported increased body weight as well as renal mass. Whereas, heightened levels of plasma urea, creatinine and creatine kinase indicating renal dysfunction, characterized by renal apoptosis (Caspase-6) and increased HDAC2 levels. Notwithstanding, administration of butyrate averted the alterations. CONCLUSION: The present investigation demonstrates that PCOS declines renal function, which is accompanied by renal inflammation, apoptosis and fibrosis. The study further suggests that butyrate, an HDAC2i restores renal function by suppressing renal SDF-1 with subsequent attenuation of renal inflammation, apoptosis and fibrosis.

High-fat diet promotes colitis-associated tumorigenesis by altering gut microbial butyrate metabolism.

Background: Dietary fat intake is associated with an increased risk of colitis associated cancer (CAC). A high-fat diet (HFD) leads to systemic low-grade inflammation. The colon is believed to be the first organ suffering from inflammation caused by the infiltration of pro-inflammatory macrophages, and promotes CAC progression. We explored the role of HFD in driving CAC by altering gut microbial butyrate metabolism. Methods: Changes in the gut microbiota caused by HFD were investigated via HFD treatment or fecal microbiota transplantation (FMT). The underlying mechanisms were further explored by analyzing the role of gut microbiota, microbial butyrate metabolism, and NLRP3 inflammasome in colon tissues in a CAC mouse model. Results: HFD accelerated CAC progression in mice, and it could be reversed by broad-spectrum antibiotics (ABX). 16S-rRNA sequencing revealed that HFD inhibited the abundance of butyrate-producing bacteria in the gut. The level of short-chain fatty acids (SCFAs), especially butyrate, in the gut of mice treated with HFD was significantly reduced. In addition, treatment with exogenous butyrate reversed the M1 polarization of proinflammatory macrophages, aggravation of intestinal inflammation, and accelerated tumor growth induced by HFD; the NLRP3/Caspase-1 pathway activated by HFD in the colon was also significantly inhibited. In vitro, macrophages were treated with lipopolysaccharide combined with butyrate to detect the M1 polarization level and NLRP3/Caspase-1 pathway expression, and the results were consistent with those of the in vivo experiments. Conclusion: HFD drives colitis-associated tumorigenesis by inducing gut microbial dysbiosis and inhibiting butyrate metabolism to skew macrophage polarization. Exogenous butyrate is a feasible new treatment strategy for CAC, and has good prospect for clinical application.

The metabolite butyrate produced by gut microbiota inhibits cachexia-associated skeletal muscle atrophy by regulating intestinal barrier function and macrophage polarization.

OBJECTIVE: Cachexia, marked by muscle atrophy, poses substantial challenges for prevention and treatment. This study delves into the unclear role of butyrate, a gut microbiota metabolite, in cachexia by examining gut microbiota and short-chain fatty acid (SCFA) profiles in human and mouse fecal samples. METHODS: We analyzed cachexia-associated gut microbiota and SCFA profiles using 16S rRNA sequencing and metabolomic techniques. Mouse cachexia models were developed with C26 cells, and LPS was used to induce muscle cell atrophy in C2C12 cells. We evaluated butyrate's in vivo effects on intestinal health, muscle preservation, inflammation, and macrophage activity. In vitro studies focused on butyrate's influence on macrophage polarization and the subsequent effects on muscle cells. RESULTS: Both cachexia patients and mice exhibited gut microbiota imbalances, irregular butyrate concentrations, and a decline in butyrate-producing bacteria. In vivo tests showed that butyrate counteract cachexia-induced muscle atrophy by adjusting the Akt/mTOR/Foxo3a and Fbox32/Trim63 pathways. These butyrate also bolstered intestinal barrier integrity, minimized endotoxin migration, and mitigated oxidative stress. Furthermore, butyrate curtailed inflammation and macrophage penetration in muscles. In vitro experimental results demonstrate that butyrate inhibit macrophage polarization towards the M1 phenotype and promote polarization towards the M2 phenotype. Both M1 and M2 macrophages influence the aforementioned pathways and oxidative stress, participating in the regulation of muscle cell atrophy. CONCLUSION: Our study delineates the intricate interplay between gut microbiota dysbiosis, butyrate fluctuations, and cachexia progression. Butyrate not only reinforces the intestinal barrier but also orchestrates macrophage polarization, mitigating muscle atrophy and averting cachexia-induced muscle deterioration. Concurrently, the M1 and M2 macrophages play pivotal roles in modulating skeletal muscle cell atrophy. This highlights the potential of utilizing the gut-derived metabolite butyrate as a promising therapeutic approach for addressing cachexia-related issues.

The impact of microbiota-derived short-chain fatty acids on macrophage activities in disease: Mechanisms and therapeutic potentials.

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.

Butyrate Protects against Clostridium difficile Infection by Regulating Bile Acid Metabolism.

Clostridium difficile infection (CDI) is caused by a prevalent nosocomial enteric pathogen, leading to high morbidity and mortality. CDI recurrence after antibiotic treatment is high; therefore, it is necessary to develop novel therapeutics against this enteric pathogen. Butyrate is used to treat many diseases because it provides energy, has anti-inflammatory properties, and maintains intestinal barrier function. An anti-CDI effect for butyrate has been reported; however, the specific mechanism remains elusive. This study aimed to explore the potential role and mechanism of butyrate in the treatment of CDI. Using a CDI mouse model, we found that butyrate significantly inhibited CDI development by regulating bile acid metabolism. Dysregulation of fecal bile acid was significantly higher, and levels of short-chain fatty acids were significantly lower in patients with CDI than those in controls. In CDI mice, butyrate exhibited a protective role by enhancing barrier protection, exerting anti-inflammatory effects, and regulating bile acid metabolism. Butyrate treatment also regulated the production of bile salt hydrolase (BSH) flora and activated farnesoid X receptor (FXR), and its therapeutic effects were reduced in CDI mice treated with BSH or FXR inhibitors. Thus, butyrate treatment may serve as a novel therapeutic approach for patients with CDI. IMPORTANCE Here, we show that levels of fecal short-chain fatty acids (SCFAs), particularly butyrate, are reduced, and normal colon structure is damaged in patients with CDI compared with those in healthy individuals. Bile acid (BA) metabolic disorder in patients with CDI is characterized by increased primary BA levels and decreased secondary BAs. In mice, butyrate alters BA metabolism in CDI and may play a vital role in CDI treatment by promoting secondary BA metabolism. Lastly, butyrate-mediated therapeutic effects in CDI require FXR. Our findings demonstrate that butyrate treatment significantly decreases the severity of CDI-induced colitis in mice and affects BA metabolism and FXR activation, which provides a potential alternative treatment for CDI.

Butyrate Modification Promotes Intestinal Absorption and Hepatic Cancer Cells Targeting of Ferroptosis Inducer Loaded Nanoparticle for Enhanced Hepatocellular Carcinoma Therapy.

Sorafenib is an oral-administered first-line drug for hepatocellular carcinoma (HCC) treatment. However, the therapeutic efficacy of sorafenib is relatively low. Here, an oral delivery platform that increases sorafenib uptake by HCC and induces potent ferroptosis is designed. This platform is butyrate-modified nanoparticles separately encapsulated with sorafenib and salinomycin. The multifunctional ligand butyrate interacts with monocarboxylate transporter 1 (MCT-1) to facilitate transcytosis. Specifically, MCT-1 is differentially expressed on the apical and basolateral sides of the intestine, highly expressed on the surface of HCC cells but lowly expressed on normal hepatocytes. After oral administration, this platform is revealed to boost transepithelial transport effectively and continuously in the intestine, drug accumulation in the liver, and HCC cell uptake. Following drug release in cancer cells, sorafenib depletes glutathione peroxidase 4 and glutathione, consequently initiating ferroptosis. Meanwhile, salinomycin enhances intracellular iron and lipid peroxidation, thereby accelerating ferroptosis. In vivo experiments performed on the orthotopic HCC model demonstrate that this combination strategy induces pronounced ferroptosis damage and ignites a robust systemic immune response, leading to the effective elimination of tumors and establishment of systemic immune memory. This work provides a proof-of-concept demonstration that an oral delivery strategy for ferroptosis inducers may be beneficial for HCC treatment.

Gut microbiota-derived short-chain fatty acids regulate gastrointestinal tumor immunity: a novel therapeutic strategy?

Tumor immune microenvironment (TIME), a tumor-derived immune component, is proven to be closely related to the development, metastasis, and recurrence of tumors. Gut microbiota and its fermented-metabolites short-chain fatty acids (SCFAs) play a critical role in maintaining the immune homeostasis of gastrointestinal tumors. Consisting mainly of acetate, propionate, and butyrate, SCFAs can interact with G protein-coupled receptors 43 of T helper 1 cell or restrain histone deacetylases (HDACs) of cytotoxic T lymphocytes to exert immunotherapy effects. Studies have shed light on SCFAs can mediate the differentiation and function of regulatory T cells, as well as cytokine production in TIME. Additionally, SCFAs can alter epigenetic modification of CD8+ T cells by inhibiting HDACs to participate in the immune response process. In gastrointestinal tumors, the abundance of SCFAs and their producing bacteria is significantly reduced. Direct supplementation of dietary fiber and probiotics, or fecal microbiota transplantation to change the structure of gut microbiota can both increase the level of SCFAs and inhibit tumor development. The mechanism by which SCFAs modulate the progression of gastrointestinal tumors has been elucidated in this review, aiming to provide prospects for the development of novel immunotherapeutic strategies.

Characterization of butyrate-metabolism in colorectal cancer to guide clinical treatment.

Colorectal cancer (CRC) is the third most prevalent one in the world among the most common malignant tumors. Numerous studies have shown that butyrate has demonstrated promise as an antitumor agent in a variety of human cancer types. However, butyrate remains understudied in CRC tumorigenesis and progression. In this study, we explored therapeutic strategies to treat CRC by examining the role of butyrate metabolism. First, from the Molecular Signature Database (MSigDB), we identified 348 butyrate metabolism-related genes (BMRGs). Next, we downloaded 473 CRC and 41 standard colorectal tissue samples from The Cancer Genome Atlas (TCGA) database and the transcriptome data of GSE39582 dataset from Gene Expression Omnibus (GEO) database. Then we evaluated the expression patterns of butyrate metabolism-related genes with difference analysis in CRC. Through univariate Cox regression and least absolute shrinkage and selection operator (LASSO) analysis, a prognostic model was constructed based on differentially expressed BMRGs. In addition, we discovered an independent prognostic marker for CRC patients. According to the expression levels and coefficients of identified BMRGs, the risk scores of all CRC samples were calculated. Utilizing differentially expressed genes in the high- and low-risk groups, we also constructed a Protein-Protein Interaction (PPI) network to visualize the interactions between proteins. Through the results of PPI network, we screened out differentially expressed target butyrate metabolism-related genes from ten hub genes. Finally, we performed clinical correlation analysis, immune cell infiltration analysis, and mutation analysis for these target genes. One hundred and seventy three differentially expressed butyrate metabolism-related genes were screened out in all the CRC samples. The prognostic model was established with univariate Cox regression and LASSO regression analysis. CRC patients' overall survival was significantly lower in the high-risk group than in the low-risk group for both training and validation set. Among the ten hub genes identified from the PPI network, four target butyrate metabolism-related genes were identified containing FN1, SERPINE1, THBS2, and COMP, which might provide novel markers or targets for treating CRC patients. Eighteen butyrate metabolism-related genes were used to develop a risk prognostic model that could be helpful for doctors to predict CRC patients' survival rate. Using this model, it is beneficial to forecast the response of CRC patients to immunotherapy and chemotherapy, thus making it easier to custom tailor cancer chemotherapy and immunotherapy to the individual patient.

Airway-delivered short-chain fatty acid acetate boosts antiviral immunity during rhinovirus infection.

BACKGROUND: Microbiota are recognized to play a major role in regulation of immunity through release of immunomodulatory metabolites such as short-chain fatty acids (SCFAs). Rhinoviruses (RVs) induce upper respiratory tract illnesses and precipitate exacerbations of asthma and chronic obstructive pulmonary disease through poorly understood mechanisms. Local interactions between SCFAs and antiviral immune responses in the respiratory tract have not been previously investigated. OBJECTIVE: We sought to investigate whether pulmonary metabolite manipulation through lung-delivered administration of SCFAs can modulate antiviral immunity to RV infection. METHODS: We studied the effects of intranasal administration of the SCFAs acetate, butyrate, and propionate on basal expression of antiviral signatures, and of acetate in a mouse model of RV infection and in RV-infected lung epithelial cell lines. We additionally assessed the effects of acetate, butyrate, and propionate on RV infection in differentiated human primary bronchial epithelial cells. RESULTS: Intranasal acetate administration induced basal upregulation of IFN-ß, an effect not observed with other SCFAs. Butyrate induced RIG-I expression. Intranasal acetate treatment of mice increased interferon-stimulated gene and IFN-λ expression during RV infection and reduced lung virus loads at 8 hours postinfection. Acetate ameliorated virus-induced proinflammatory responses with attenuated pulmonary mucin and IL-6 expression observed at day 4 and 6 postinfection. This interferon-enhancing effect of acetate was confirmed in human bronchial and alveolar epithelial cell lines. In differentiated primary bronchial epithelial cells, butyrate treatment better modulated IFN-ß and IFN-λ gene expression during RV infection. CONCLUSIONS: SCFAs augment antiviral immunity and reduce virus load and proinflammatory responses during RV infection.

Lactiplantibacillus plantarum NKK20 Increases Intestinal Butyrate Production and Inhibits Type 2 Diabetic Kidney Injury through PI3K/Akt Pathway.

Nephropathy injury is a prevalent complication observed in individuals with diabetes, serving as a prominent contributor to end-stage renal disease, and the advanced glycation products (AGEs) are important factors that induce kidney injury in patients with diabetes. Addressing this condition remains a challenging aspect in clinical practice. The aim of this study was to explore the effects of Lactiplantibacillus plantarum NKK20 strain (NKK20) which protects against diabetic kidney disease (DKD) based on animal and cell models. The results showed that the NKK20 can significantly reduce renal inflammatory response, serum oxidative stress response, and AGE concentration in diabetic mice. After treatment with NKK20, the kidney damage of diabetic mice was significantly improved, and more importantly, the concentration of butyrate, a specific anti-inflammatory metabolite of intestinal flora in the stool of diabetic mice, was significantly increased. In addition, nontargeted metabolomics analysis showed a significant difference between the metabolites in the mouse serum contents of the NKK20 administration group and those in the nephropathy injury group, in which a total of 24 different metabolites that were significantly affected by NKK20 were observed, and these metabolites were mainly involved in glycerophospholipid metabolism and arachidonic acid metabolism. Also, the administration of butyrate to human kidney- (HK-) 2 cells that were stimulated by AGEs resulted in a significant upregulation of ZO-1, Occludin, and E-cadherin gene expressions and downregulation of α-SMA gene expression. This means that butyrate can maintain the tight junction structure of HK-2 cells and inhibit fibrosis. Butyrate also significantly inhibited the activation of PI3K/Akt pathway. These results indicate that NKK20 can treat kidney injury in diabetic mice by reducing blood glucose and AGE concentration and increasing butyrate production in the intestine. By inhibiting PI3K pathway activation in HK-2 cells, butyrate maintains a tight junction structure of renal tubule epithelial cells and inhibits renal tissue fibrosis. These results suggest that NKK20 is helpful to prevent and treat the occurrence and aggravation of diabetic kidney injury.

Dendrobium officinale polysaccharide ameliorates polycystic ovary syndrome via regulating butyrate dependent gut-brain-ovary axis mechanism.

Research has shown that dendrobium officinale polysaccharide (DOP) can promote follicular development and inhibit the apoptosis of ovarian granular cells in PCOS rats. However, DOP cannot be absorbed directly by the stomach and small intestine but is degraded into short-chain fatty acids by gut microbiota in the large intestine and regulates the composition of gut microbiota. How DOP improved ovarian function in PCOS rats through the blood-brain barrier is unclear. In this study, we generated letrozole-induced PCOS rat models and studied the therapeutic effect and mechanism of DOP. 16S rRNA amplicon sequencing analysis, GC-MS short-chain fatty acid detection, and Gene Expression Omnibus database searching were conducted to screen the significantly changed pathways, and a series of experiments, such as enzyme-linked immunosorbent assay, RT-qPCR, Western blot, and immunohistochemistry, were performed. We found that DOP treatment could improve ovarian morphology and endocrine disorders, restore the normal estrus cycle, increase gut microbiota α diversity, and alter ß diversity and enrichment of butyrate-producing bacterium in PCOS rats. In addition, compared with PCOS rats, those treated with DOP exhibited higher butyrate and polypeptide YY levels, possibly due to the regulation of G protein-coupled receptor 41 expression. These results indicated that DOP relieved the symptoms of PCOS rats which may be related to the mechanism of butyrate dependent gut-brain-ovary axis protection.

Cytotoxic effect of metformin on butyrate-resistant PMF-K014 colorectal cancer spheroid cells.

Three-dimensional (3D) cell culture models are used in cancer research because they mimic physiological responses in vivo compared with two-dimensional (2D) culture systems. Recently, cross-resistance of butyrate-resistant (BR) cells and chemoresistance in colorectal cancer (CRC) cells have been reported; however, effective treatments for BR cells have not been identified. In this study, we investigated the cytotoxicity of metformin (MET), an anti-diabetic drug, on BR CRC cells in a 3D spheroid culture model. The results demonstrate that MET decreases spheroid size, migration, and spheroid viability, while it increases spheroid death. The molecular mechanism revealed that AMP-activated protein kinase (AMPK) and Akt serine/threonine kinase 1(Akt) were significantly upregulated, whereas the acetyl-CoA-carboxylase (ACC) and mammalian target of rapamycin (mTOR) were downregulated, which led to caspase activation and apoptosis. Our findings show the potential cytotoxicity of MET on CRC-BR cells. The combination of MET and conventional chemotherapeutic drugs should be addressed in further studies to reduce the side effects of standard chemotherapy for CRC.

Glyceryl butyrate attenuates enterotoxigenic Escherichia coli-induced intestinal inflammation in piglets by inhibiting the NF-κB/MAPK pathways and modulating the gut microbiota.

The aims of this study were to evaluate whether a diet supplemented with glyceryl butyrate could attenuate the immune-inflammatory response in piglets challenged with enterotoxigenic Escherichia coli (ETEC), and to explore the mechanisms of its regulation. Eighteen weaning piglets were assigned to three diets: basal diet (CON), antibiotics diet (ATB), and 0.5% glyceryl butyrate diet (GB group). Significantly lower concentrations of IL-1ß, IL-6 and TNF-α in the jejunum and IL-6 in the ileum were observed in the GB group than that in the CON group (P < 0.05). Moreover, a decreasing trend of IL-1ß (P = 0.075) and TNF-α (P = 0.070) was observed in the ileum in the GB group. Correspondingly, the GB group had significantly increased mRNA expression of porcine beta defensins (pBDs) in the jejunum (pBD1, pBD2, pBD114 and pBD129) and ileum (pBD2, pBD3, pBD114 and pBD129) (P < 0.05), and protein abundance of Claudin 1, Occludin, and ZO-1 in the jejunum and ileum (P < 0.05). Further research results showed that the improvement of beta defensins and tight junctions in the GB group was related to the decreased phosphorylation of the NFκB/MAPK pathway. In addition, the results of 16S rDNA sequencing showed that glycerol butyrate supplementation altered the ileal microbiota composition of piglets, increasing the relative abundance of Lactobacillus reuteri, Lactobacillus salivarius, and Lactobacillus agrilis. In summary, glyceryl butyrate attenuated the immune-inflammatory response in piglets challenged with ETEC by inhibiting the NF-κB/MAPK pathways and modulating the gut microbiota, and thus improved piglet intestinal health.

Butyrate, a postbiotic of intestinal bacteria, affects pancreatic cancer and gemcitabine response in in vitro and in vivo models.

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.

Potential Clinical Applications of the Postbiotic Butyrate in Human Skin Diseases.

Human skin is the largest organ and the most external interface between the environment and the body. Vast communities of viruses, bacteria, archaea, fungi, and mites, collectively named the skin microbiome (SM), cover the skin surface and connected structures. Skin-resident microorganisms contribute to the establishment of cutaneous homeostasis and can modulate host inflammatory responses. Imbalances in the SM structure and function (dysbiosis) are associated with several skin conditions. Therefore, novel target for the skincare field could be represented by strategies, which restore or preserve the SM natural/individual balance. Several of the beneficial effects exerted by the SM are aroused by the microbial metabolite butyrate. Since butyrate exerts a pivotal role in preserving skin health, it could be used as a postbiotic strategy for preventing or treating skin diseases. Herein, we describe and share perspectives of the potential clinical applications of therapeutic strategies using the postbiotic butyrate against human skin diseases.