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 potential therapeutic agent for neurodegenerative disorders.

Maintaining an optimum microbial community within the gastrointestinal tract is intricately linked to human metabolic, immune and brain health. Disturbance to these microbial populations perturbs the production of vital bioactive compounds synthesised by the gut microbiome, such as short-chain fatty acids (SCFAs). Of the SCFAs, butyrate is known to be a major source of energy for colonocytes and has valuable effects on the maintenance of intestinal epithelium and blood brain barrier integrity, gut motility and transit, anti-inflammatory effects, and autophagy induction. Inducing endogenous butyrate production is likely to be beneficial for gut-brain homeostasis and for optimal neuronal function. For these reasons, butyrate has gained interest as a potential therapy for not only metabolic and immunological disorders, but also conditions related to the brain, including neurodegenerative diseases. While direct and indirect sources of butyrate, including prebiotics, probiotics, butyrate pro-drugs and glucosidase inhibitors, offer a promising therapeutic avenue, their efficacy and dosage in neurodegenerative conditions remain largely unknown. Here, we review current literature on effects of butyrate relevant to neuronal function, the impact of butyrate in a range of neurodegenerative diseases and related treatments that may have potential for the treatment of neurodegenerative diseases.

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).

Impact of pemafibrate on lipid profile and insulin resistance in hypertriglyceridemic patients with coronary artery disease and metabolic syndrome.

This study examined the effects of pemafibrate, a selective peroxisome proliferator-activated receptor α agonist, on the serum biochemical parameters of male patients with coronary artery disease and metabolic syndrome (MetS). This was a post hoc analysis of a randomized, crossover study that treated hypertriglyceridemia with pemafibrate or bezafibrate for 24 weeks, followed by a crossover of another 24 weeks. Of the 60 patients enrolled in the study, 55 were male. Forty-one of 55 male patients were found to have MetS. In this sub-analysis, male patients with MetS (MetS group, n = 41) and those without MetS (non-MetS group, n = 14) were compared. The primary endpoint was a change in fasting serum triglyceride (TG) levels during pemafibrate therapy, and the secondary endpoints were changes in insulin resistance-related markers and liver function parameters. Serum TG levels significantly decreased (MetS group, from 266.6 to 148.0 mg/dL, p < 0.001; non-MetS group, from 203.9 to 97.6 mg/dL, p < 0.001); however, a percent change (%Change) was not significantly different between the groups (- 44.1% vs. - 51.6%, p = 0.084). Serum insulin levels and homeostasis model assessment of insulin resistance significantly decreased in the MetS group but not in the non-MetS group. %Change in liver enzyme levels was markedly decreased in the MetS group compared with that in the non-MetS group (alanine aminotransferase, - 25.1% vs. - 11.3%, p = 0.027; gamma-glutamyl transferase, - 45.8% vs. - 36.2%, p = 0.020). In conclusion, pemafibrate can effectively decrease TG levels in patients with MetS, and it may be a more efficient drug for improving insulin resistance and liver function in such patients.

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.

The adjuvant treatment role of ω-3 fatty acids by regulating gut microbiota positively in the acne vulgaris.

Objectives:We aimed to explore the potential role of omega-3 (ω-3) fatty acids on acne vulgaris by modulating gut microbiota.Materials and Methods:We randomly divided the untreated acne patients into two groups with or without ω-3 fatty acids intervention for 12 weeks. The Sprague Dawley (SD) rats with acne model were given isotretinoin, ω-3 fatty acids or their combination respectively. Then the colonic contents samples of the drug intervention SD rats were transferred to the pseudo sterile rats with acne model. The severity of the disease was assessed by the Global Acne Grading System (GAGS) score of the patients, and the swelling rate of auricle and the pathological section of the rat with acne model. The 16S rDNA gene sequencing was performed to detect the alteration of the gut microbiota.Results:ω-3 fatty acids could increase the diversity of the gut microbiota and regulate the flora structure positively both in the patients and rats, increase the abundance of butyric acid producing bacteria and GAGS score in the patients, and alleviate the inflammation and comedones of rats.Conclusion:Supplementation of ω-3 fatty acids could alleviate the inflammation of acne vulgaris by increasing the abundance of butyric acid producing bacteria.

Effects of short-chain fatty acids on blood glucose and lipid levels in mouse models of diabetes mellitus: A systematic review and network meta-analysis.

Short-chain fatty acids (SCFAs), the main metabolites of gut microbiota, have been associated with lower blood glucose and lipid levels in diabetic mice. However, a comprehensive summary and comparison of the effects of different SCFA interventions on blood glucose and lipid levels in diabetic mice is currently unavailable. This study aims to compare and rank the effects of different types of SCFAs on blood glucose and lipid levels by collecting relevant animal research. A systematic search through PubMed, Embase, Cochrane Library, and Web of Science database was conducted to identify relevant studies from inception to March 17, 2023. Both pairwise meta-analysis and Bayesian network meta-analysis were used for statistical analyses. In total, 18 relevant studies involving 5 interventions were included after screening 3793 citations and 53 full-text articles. Notably, butyrate therapy (mean difference [MD] = -4.52, 95% confidence interval [-6.29, -2.75]), acetate therapy (MD = -3.12, 95% confidence interval [-5.79, -0.46]), and propionate therapy (MD = -2.96, 95% confidence interval [-5.66, -0.26]) significantly reduced the fasting blood glucose levels compared to the control group; butyrate therapy was probably the most effective intervention, with a surface under the cumulative ranking curve (SUCRA) value of 85.5%. Additionally, acetate plus propionate therapy was probably the most effective intervention for reducing total cholesterol (SUCRA = 85.8%) or triglyceride levels (SUCRA = 88.1%). These findings underscore the potential therapeutic implications of SCFAs for addressing metabolic disorders, particularly in type 2 diabetes mellitus.

Bacterial butyrate mediates the anti-atherosclerotic effect of silybin.

Silybin (SIL) is a versatile bioactive compound used for improving liver damage and lipid disorders and is also thought to be beneficial for atherosclerosis (AS). The goal of this study was to investigate the efficacy of SIL in the treatment of AS in ApoE-/-mice fed a high-fat diet and explore the mechanism underlying treatment outcomes. We found that SIL significantly alleviated AS-related parameters, including the extent of aortic plaque formation, hyperlipidemia, and adhesion molecule secretion in the vascular endothelium. 16 S rRNA gene sequencing analysis, together with the application of antibiotics, showed that intestinal butyrate-producing bacteria mediated the ameliorative effect of SIL on AS. Further analysis revealed that SIL facilitated butyrate production by increasing the level of butyryl-CoA: acetate CoA-transferase (BUT). The increased expression of monocarboxylic acid transporter-1 (MCT1) induced by butyrate and MCT4 induced by SIL in the apical and basolateral membranes of colonocytes, respectively, resulted in enhanced absorption of intestinal butyrate into the circulation, leading to the alleviation of arterial endothelium dysfunction. Moreover, the SIL-mediated increase in intestinal butyrate levels restored gut integrity by upregulating the expression of tight junction proteins and promoting gut immunity, thus inhibiting the AS-induced inflammatory response. This is the first study to show that SIL can alleviate AS by modulating the production of bacterial butyrate and its subsequent absorption.

Butyrate alleviates renal fibrosis in CKD by regulating NLRP3-mediated pyroptosis via the STING/NF-κB/p65 pathway.

Chronic kidney disease (CKD) is a serious and irreversible disease primarily characterized by chronic inflammation and renal fibrosis. Recent studies have suggested that gut microbiota-related metabolites, particularly short-chain fatty acids (SCFAs) are significantly associated with kidney diseases. Notably, butyrate, a type of SCFAs, plays a crucial role in this correlation. However, the effect of butyrate on renal fibrosis in patients with CKD and its potential mechanisms remain unclear. In this study, we demonstrated that butyrate levels are reduced as CKD progresses using a CKD C57BL/6 mouse model established by a 0.2% adenine diet. Exogenous supplementation of butyrate effectively alleviated renal fibrosis and repressed the levels of proteins associated with NLRP3-mediated pyroptosis (NLRP3, IL-1ß, caspase-1, and GSDMD). Additionally, we conducted an in vitro experiment using HK-2 cells, which also confirmed that the elevated levels of NLRP3-mediated pyroptosis proteins in TGF-ß1-stimulated HK-2 cells are reversed by butyrate intervention. Further, butyrate mitigated the activity of the STING/NF-κB/p65 pathway, and STING overexpression impaired the protective function of butyrate in CKD. Hence, we suggest that butyrate may have a renoprotective role in CKD, alleviating renal fibrosis possibly by regulating NLRP3-mediated pyroptosis via the STING/NF-κB/p65 pathway.

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.

Ketogenic Diet Exacerbates L-Arginine-Induced Acute Pancreatitis and Reveals the Therapeutic Potential of Butyrate.

The ketogenic diet (KD) has emerged as a popular weight-loss regimen in recent years. However, it has been confirmed to elicit a mild inflammatory response in the intestinal epithelium and exacerbate various digestive disorders. The severity of acute pancreatitis (AP) is closely associated with the permeability of the intestinal epithelium and gut microbiota, yet the impact of KD on acute pancreatitis remains unclear. In this study, we induced acute pancreatitis using L-arginine in mice fed with KD. The consumption of KD resulted in an elevation of lipopolysaccharide-binding protein (LBP), accompanied by upregulated cytokines (IL-1a, IL-5, IL-12, MIP-1a, and Rantes) and dysfunction of the intestinal barrier both in control and AP groups. The bloom of Lachnospirales and Erysipelotrichales was observed as a specific profile of gut microbiota in KD-fed mice with AP, along with downregulation of carbohydrate metabolism and depletion of short-chain fatty acids (SCFAs). Antibiotic decontamination reduced the cytokine storm and tissue necrosis but did not significantly improve the integrity of the intestinal barrier in KD-fed mice with AP. The overgrowth of Mycoplasmatales in feces and Enterobacterales in colonic tissue appears to explain the limitation of antibiotic treatment to aggravate acute pancreatitis. Butyrate supplementation attenuated the depletion of SCFAs, promoted the intestinal barrier, and reduced the necrotic area in AP mice. The bloom of Bacteroidales and the correlated increase in tryptophan metabolism explain the therapeutic potential of butyrate supplements for acute pancreatitis. In conclusion, our findings suggest that the ketogenic diet exacerbates acute pancreatitis through its impact on the gut microbiota and subsequent disruption of the intestinal barrier, while butyrate supplementation reverses this effect.

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.