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Background An increasing body of evidence implicates the resident gut microbiota as playing a critical role in type 2 diabetes (T2D) pathogenesis. We previously reported significant improvement in postprandial glucose control in human participants with T2D following 12-week administration of a 5-strain novel probiotic formulation (‘WBF-011’) in a double-blind, randomized, placebo controlled setting (NCT03893422). While the clinical endpoints were encouraging, additional exploratory measurements were needed in order to link the motivating mechanistic hypothesis - increased short-chain fatty acids - with markers of disease. Results Here we report targeted and untargeted metabolomic measurements on fasting plasma ( n  = 104) collected at baseline and end of intervention. Butyrate and ursodeoxycholate increased among participants randomized to WBF-011, along with compelling trends between butyrate and glycated haemoglobin (HbA1c). In vitro monoculture experiments demonstrated that the formulation’s C. butyricum strain efficiently synthesizes ursodeoxycholate from the primary bile acid chenodeoxycholate during butyrogenic growth. Untargeted metabolomics also revealed coordinated decreases in intermediates of fatty acid oxidation and bilirubin, potential secondary signatures for metabolic improvement. Finally, improvement in HbA1c was limited almost entirely to participants not using sulfonylurea drugs. We show that these drugs can inhibit growth of formulation strains in vitro. Conclusion To our knowledge, this is the first description of an increase in circulating butyrate or ursodeoxycholate following a probiotic intervention in humans with T2D, adding support for the possibility of a targeted microbiome-based approach to assist in the management of T2D. The efficient synthesis of UDCA by C. butyricum is also likely of interest to investigators of its use as a probiotic in other disease settings. The potential for inhibitory interaction between sulfonylurea drugs and gut microbiota should be considered carefully in the design of future studies.

Background Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvβ6) integrin inhibitor, in participants with IPF. Methods This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvβ6-specific ligand, [ 18 F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (V T ), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in V T  > 0%) of ≥80%. Results Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected V T at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: − 9 to 42%). The posterior probability that the true % reduction in V T  > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination. Conclusions This study demonstrated engagement of the αvβ6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug. Trial registration clinicaltrials.gov: NCT03069989 ; date of registration: 3 March 2017.

Hypertriglyceridemia has emerged as an independent risk factor for cardiovascular events, despite low-density lipoprotein-cholesterol (LDL-C) well-controlled with statins. We pooled data from the first 12 weeks of six randomized double-blind placebo-controlled studies of pemafibrate in Japan and investigated its efficacy and safety with and without statins, particularly focusing on patients with renal dysfunction. Subjects were 1253 patients (677 in the “with-statin” group and 576 in the “without-statin” group). At Week 12 (last observation carried forward), triglyceride (TG) was significantly reduced at all pemafibrate doses (0.1, 0.2, and 0.4 mg/day), both with and without statin, compared to placebo (p < 0.001 vs. placebo for all groups). In the “with-statin” group, the estimated percent change from baseline was −2.0% for placebo and −45.1%, −48.5%, and −50.0%, respectively, for the pemafibrate groups. Findings for both groups showed significant decreases in TG-rich lipoproteins and atherogenic lipid parameters compared to placebo. The incidence of adverse events was similar between the pemafibrate and placebo groups and was also similar for patients with and without renal dysfunction in the “with-statin” group. Pemafibrate lowered TG and improved atherogenic dyslipidemia without a significant increase in adverse events in comparison to the placebo, even among “with-statin” patients who had renal dysfunction.

The gut microbiota and its metabolic products interact with the host in many different ways, influencing gut homoeostasis and health outcomes. The species composition of the gut microbiota has been shown to respond to dietary change, determined by competition for substrates and by tolerance of gut conditions. Meanwhile, the metabolic outputs of the microbiota, such as SCFA, are influenced both by the supply of dietary components and via diet-mediated changes in microbiota composition. There has been significant progress in identifying the phylogenetic distribution of pathways responsible for formation of particular metabolites among human colonic bacteria, based on combining cultural microbiology and sequence-based approaches. Formation of butyrate and propionate from hexose sugars, for example, can be ascribed to different bacterial groups, although propionate can be formed via alternative pathways from deoxy-sugars and from lactate by a few species. Lactate, which is produced by many gut bacteria in pure culture, can also be utilised by certain Firmicutes to form butyrate, and its consumption may be important for maintaining a stable community. Predicting the impact of diet upon such a complex and interactive system as the human gut microbiota not only requires more information on the component groups involved but, increasingly, the integration of such information through modelling approaches.

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 short-chain 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 protein-coupled 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.

Background and objective: Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a chronic inflammatory disorder characterized by aberrant immune responses and compromised barrier function in the gastrointestinal tract. IBD is associated with altered gut microbiota and their metabolites in the colon. Butyrate, a gut microbial metabolite, plays a crucial role in regulating immune function, epithelial barrier function, and intestinal homeostasis. In this review, we aim to present an overview of butyrate synthesis and metabolism and the mechanism of action of butyrate in maintaining intestinal homeostasis and to discuss the therapeutic implications of butyrate in IBD. Methods: We searched the literature up to March 2023 through PubMed, Web of Science, and other sources using search terms such as butyrate, inflammation, IBD, Crohn’s disease, and ulcerative colitis. Clinical studies in patients and preclinical studies in rodent models of IBD were included in the summary of the therapeutic implications of butyrate. Results: Research in the last two decades has shown the beneficial effects of butyrate on gut immune function and epithelial barrier function. Most of the preclinical and clinical studies have shown the positive effect of butyrate oral supplements in reducing inflammation and maintaining remission in colitis animal models and IBD patients. However, butyrate enema showed mixed effects. Butyrogenic diets, including germinated barley foodstuff and oat bran, are found to increase fecal butyrate concentrations and reduce the disease activity index in both animal models and IBD patients. Conclusions: The current literature suggests that butyrate is a potential add-on therapy to reduce inflammation and maintain IBD remission. Further clinical studies are needed to determine if butyrate administration alone is an effective therapeutic treatment for IBD.

Background: African Americans (AA) are disproportionally affected by hypertension (HTN). Gut microbiome metabolites (e.g., butyrate) may mediate the relationship between the microbiome and blood pressure (BP). Previous research reports a consistent indirect relationship between gut butyrate, a product of gut microbial nutrient fermentation, and BP. Thus, this study assessed the relationship between individual diet intake on BP changes after a butyrate treatment. Methods: AA aged 30–50 with HTN underwent treatment with a blinded placebo (5 mmol) and butyrate enema (80 mmol) with a one-week washout period. Ambulatory BP monitors collected measures up to 24 h post-enema. The Nutrition Data System for Research was used to assess diet and Healthy Eating Index (HEI-2015) scores from diet records. Paired t-tests and Kendall’s correlation tests determined group differences and relationships between variables (p < 0.05). Results: Positive correlations were found between other vegetables and 24 h diastolic BP (r = 0.64), daytime diastolic BP (r = 0.68), and MAP (r = 0.72). Positive correlations were also found between 24 h systolic BP and HEI-2015 greens and beans sub-scores (r = 0.64) and 24 h DBP and total vegetables (r = 0.64). Negative correlations were found between nighttime arterial stiffness and total grain intake (r = −0.71). Conclusion: These data suggest diet impacts BP measures in response to acutely increasing gut butyrate. These results provide preliminary evidence linking food groups, not individual nutrients, with BP outcomes and gut butyrate availability.

Cross-feeding is an important metabolic interaction mechanism of bacterial groups inhabiting the human colon and includes features such as the utilization of acetate by butyrate-producing bacteria as may occur between Bifidobacterium and Faecalibacterium genera. In this study, we assessed the utilization of different carbon sources (glucose, starch, inulin and fructooligosaccharides) by strains of both genera and selected the best suited combinations for evidencing this cross-feeding phenomenon. Co-cultures of Bifidobacterium adolescentis L2–32 with Faecalibacterium prausnitzii S3/L3 with fructooligosaccharides as carbon source, as well as with F. prausnitzii A2–165 in starch, were carried out and the production of short-chain fatty acids was determined. In both co-cultures, acetate levels decreased between 8 and 24 h of incubation and were lower than in the corresponding B. adolescentis monocultures. In contrast, butyrate concentrations were higher in co-cultures as compared to the respective F. prausnitzii monocultures, indicating enhanced formation of butyrate by F. prausnitzii in the presence of the bifidobacteria. Variations in the levels of acetate and butyrate were more pronounced in the co-culture with fructooligosaccharides than with starch. Our results provide a clear demonstration of cross-feeding between B. adolescentis and F. prausnitzii. The article provides the first experimental demonstration of enhanced butyrate formation by a cross feeding mechanisms betweeen Faecalibacterium prausnitzii, a comensal bacteria of the human colon, with Bifidobacterium adolescentis, one of the most abundant bifidobacteria from the adult's intestinal microbiota.

Abstract Butyrate-producing bacteria play a key role in colonic health in humans. This review provides an overview of the current knowledge of the diversity, metabolism and microbial ecology of this functionally important group of bacteria. Human colonic butyrate producers are Gram-positive firmicutes, but are phylogenetically diverse, with the two most abundant groups related to Eubacterium rectale/Roseburia spp. and to Faecalibacterium prausnitzii. Five different arrangements have been identified for the genes of the central pathway involved in butyrate synthesis, while in most cases butyryl-CoA : acetate CoA-transferase, rather than butyrate kinase, appears to perform the final step in butyrate synthesis. Mechanisms have been proposed recently in non-gut Clostridium spp. whereby butyrate synthesis can result in energy generation via both substrate-level phosphorylation and proton gradients. Here we suggest that these mechanisms also apply to the majority of butyrate producers from the human colon. The roles of these bacteria in the gut community and their influence on health are now being uncovered, taking advantage of the availability of cultured isolates and molecular methodologies. Populations of F. prausnitzii are reported to be decreased in Crohn's disease, for example, while populations of Roseburia relatives appear to be particularly sensitive to the diet composition in human volunteer studies.

Increased dietary fiber consumption has been associated with many beneficial effects, including amelioration of obesity and insulin resistance. These effects may be due to the increased production of short chain fatty acids, including propionate, acetate and butyrate, during fermentation of the dietary fiber in the colon. Indeed, oral and dietary supplementation of butyrate alone has been shown to prevent high fat-diet induced obesity and insulin resistance. This review focuses on sources of short chain fatty acids, with emphasis on sources of butyrate, mechanisms of fiber and butyrate metabolism in the gut and its protective effects on colon cancer and the peripheral effects of butyrate supplementation in peripheral tissues in the prevention and reversal of obesity and insulin resistance.