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Short-chain fatty acids (SCFA), formed by microbial fermentation, are believed to be involved in the aetiology of obesity and diabetes. This study investigated the effects of colonic administration of physiologically relevant SCFA mixtures on human substrate and energy metabolism. In this randomized, double-blind, crossover study, twelve normoglycaemic men (BMI 25–35 kg/m 2 ) underwent four investigational days, during which SCFA mixtures (200 mmol/L) high in either acetate (HA), propionate (HP), butyrate (HB) or placebo (PLA) were rectally administered during fasting and postprandial conditions (oral glucose load). Before and for two hours after colonic infusions, indirect calorimetry was performed and blood samples were collected. All three SCFA mixtures increased fasting fat oxidation ( P  < 0.01), whilst resting energy expenditure increased after HA and HP compared with PLA ( P  < 0.05). In addition, all three SCFA mixtures increased fasting and postprandial plasma peptide YY (PYY) concentrations, and attenuated fasting free glycerol concentrations versus PLA ( P  < 0.05). Colonic infusions of SCFA mixtures, in concentrations and ratios reached after fibre intake, increased fat oxidation, energy expenditure and PYY, and decreased lipolysis in overweight/obese men. Human intervention studies are warranted to investigate whether these effects translate into long-term benefits for body weight control and insulin sensitivity in the obese insulin resistant state.

Aims/hypothesisThe pathophysiology of type 1 diabetes has been linked to altered gut microbiota and more specifically to a shortage of intestinal production of the short-chain fatty acid (SCFA) butyrate, which may play key roles in maintaining intestinal epithelial integrity and in human and gut microbial metabolism. Butyrate supplementation can protect against autoimmune diabetes in mouse models. We thus set out to study the effect of oral butyrate vs placebo on glucose regulation and immune variables in human participants with longstanding type 1 diabetes.MethodsWe administered a daily oral dose of 4 g sodium butyrate or placebo for 1 month to 30 individuals with longstanding type 1 diabetes, without comorbidity or medication use, in a randomised (1:1), controlled, double-blind crossover trial, with a washout period of 1 month in between. Participants were randomly allocated to the ‘oral sodium butyrate capsules first’ or ‘oral placebo capsules first’ study arm in blocks of five. The clinical investigator received blinded medication from the clinical trial pharmacy. All participants, people doing measurements or examinations, or people assessing the outcomes were blinded to group assignment. The primary outcome was a change in the innate immune phenotype (monocyte subsets and in vitro cytokine production). Secondary outcomes were changes in blood markers of islet autoimmunity (cell counts, lymphocyte stimulation indices and CD8 quantum dot assays), glucose and lipid metabolism, beta cell function (by mixed-meal test), gut microbiota and faecal SCFA. The data was collected at the Amsterdam University Medical Centers.ResultsAll 30 participants were analysed. Faecal butyrate and propionate levels were significantly affected by oral butyrate supplementation and butyrate treatment was safe. However, this modulation of intestinal SCFAs did not result in any significant changes in adaptive or innate immunity, or in any of the other outcome variables. In our discussion, we elaborate on this important discrepancy with previous animal work.Conclusions/interpretationOral butyrate supplementation does not significantly affect innate or adaptive immunity in humans with longstanding type 1 diabetes.Trial registrationNetherlands Trial Register: NL4832 (www.trialregister.nl).Data availabilityRaw sequencing data are available in the European Nucleotide Archive repository (https://www.ebi.ac.uk/ena/browse) under study PRJEB30292.FundingThe study was funded by a Le Ducq consortium grant, a CVON grant, a personal ZONMW-VIDI grant and a Dutch Heart Foundation grant.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common cause of chronic liver disease and is closely associated with metabolic abnormalities and cardiovascular risks. Butyrate, a short-chain fatty acid produced by gut microbiota, has the potential to enhance liver health by modulating inflammation and supporting gut barrier integrity. This study aimed to investigate and compare the effects of sodium butyrate and calcium butyrate in patients with MASLD. In this single-center, randomized clinical trial, 181 patients with MASLD were enrolled and assigned to receive either sodium butyrate (n = 121) or calcium butyrate (n = 60) supplementation at a daily dose of 1000 mg. The primary endpoint was the change in liver steatosis, measured using the Controlled Attenuation Parameter (CAP) via FibroScan®. Secondary endpoints included liver stiffness, biochemical parameters, hepatic steatosis and fatty liver indices, fecal calprotectin levels, stool short-chain fatty acid levels, and microbiome composition. A subgroup analysis compared responders (a ≥ 5% reduction in CAP) to non-responders. There were no significant changes in CAP values for either group (ΔCAP: sodium butyrate, 0.84; calcium butyrate, −0.23; p = 0.70). Sodium butyrate significantly reduced serum trimethylamine N-oxide and fatty liver index, while calcium butyrate led to a decrease in fecal calprotectin levels. Responders demonstrated a lower body mass index, higher levels of high-sensitivity C-reactive protein and HbA1c, and distinct microbiome profiles, characterized by lower abundance of Subdoligranulum and higher abundance of Catenibacterium. Although butyrate supplementation did not significantly improve liver steatosis as measured by CAP, the differing effects on metabolic and inflammatory markers suggest that there may be potential benefits for specific subgroups of patients with MASLD.

Objectives There is increasing evidence that gut metabolites have a role in the etiology of obesity. This study aimed to investigate the effects of sodium butyrate (NaB) supplementation on the expression of peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1α (PGC-1α), PPAR-α, and uncoupling protein-1 (UCP-1) genes, as well as on the metabolic parameters and anthropometric indices in persons with obesity. Methods In this triple-blind placebo-controlled randomized clinical trial, 50 individuals with obesity were randomly assigned to NaB (600 mg/day) + hypo-caloric diet or placebo group + hypo-caloric diet for 8 weeks. The study measured the participants’ anthropometric characteristics, food consumption, and feelings of hunger in addition to the serum levels of metabolic indices and the mRNA expression of the PGC-1α, PPAR-α, and UCP-1 genes in peripheral blood mononuclear cells (PBMCs). Results PGC-1α and UCP-1 genes expression significantly increased in NaB group compared to the placebo at the endpoint. A significant decrease in weight, BMI, and waist circumference (WC) was observed in NaB group. Among the metabolic factors, NaB significantly decreased fasting blood sugar (FBS) ( P  = 0.04), low-density lipoprotein cholesterol (LDL-C) ( P  = 0.038) and increased high-density lipoprotein cholesterol (HDL-C) ( P  = 0.016). NaB could not significantly change serum GLP-1 level. Conclusions This study unveiled NaB supplementation alone cannot have significant beneficial effects on anthropometric, and biochemical factors. NaB could affect anthropometric and metabolic risk variables associated with obesity only when prescribed, along with calorie restriction. Clinical trial registration This study was registered in the Iranian Registry of Clinical Trials ( https://en.irct.ir/trial/53968 ) on 31 January 2021 (registry number IRCT20190303042905N2).

Purpose Menopause is associated with muscle detriment and physical compromise. However, relevant mechanisms and effective interventions remain elusive. We investigated the therapeutic effects of exogenous butyrate administration on skeletal muscle and physical capacity with relevance to intestinal leak as a potential mechanism in post-menopausal women. Methods We recruited post-menopausal women as placebo (age = 55.4 ± 3.3 years, n  = 76) and butyrate (age = 54 ± 2.8 years, n  = 70) groups, along with pre-menopausal women (age = 42.3 ± 3 years, n  = 75) as controls. The butyrate group received sodium butyrate (570 mg capsules) daily for 12 weeks. We measured plasma biomarkers of intestinal leak (zonulin) and sepsis (lipopolysaccharide-binding protein, LBP) along with handgrip strength (HGS), gait speed, and physical performance (short physical performance battery, SPPB). Results Post-menopausal women had higher zonulin and LBP and lower HGS, gait speed, and SPPB scores than pre-menopausal women (all p  < 0.05). Butyrate reduced plasma zonulin and LBP levels and improved HGS and SPPB scores in post-menopausal women (all p  < 0.05). We found significant correlations of reduction in plasma zonulin and LBP with improvement in HGS and SPPB in the butyrate group (all p  < 0.05). Butyrate also modestly improved respiratory muscle strength and reduced systemic inflammation and oxidative stress in post-menopausal women (all p  < 0.05). Conclusion Collectively, our findings demonstrate the muscle-protective effects of butyrate through intestinal mucosal repair. Future research is warranted to elucidate the underlying mechanisms of butyrate in post-menopausal women.

Background Microencapsulated sodium butyrate (MSB) has been previously associated with anti-inflammatory and regenerative properties regarding large bowel mucosa. We aimed to examine a role of MSB in patients with diverticulosis, hypothesizing its potential for reduction of diverticulitis episodes and diverticulitis prevention. Methods Seventy-three patients with diverticulosis (diagnosed in colonoscopy or/and barium enema or/and CT colography) were recruited for the study and randomized. The investigated group was administered MSB 300 mg daily; the control group was administered placebo. After 12 months, a total of 52 patients completed the study and were subject to analysis (30 subjects and 22 controls). During the study, the number of episodes of diverticulitis (symptomatic diagnosis with acute pain, fever, and leukocytosis), hospitalizations, and surgery performed for diverticulitis were recorded. Additionally, a question regarding subjective improvement of symptoms reflected changes in quality of life during the analysis. Results After 12 months, the study group noted a significantly decreased number of diverticulitis episodes in comparison to the control group. The subjective quality of life in the study group was higher than in the control group. There were no side effects of the MSB during the therapy. Conclusions MSB reduces the frequency of diverticulitis episodes, is safe, and improves the quality of life. It can play a role in the prevention of diverticulitis.

Emerging evidence suggests that the intestinal microbiota is a source of sleep-promoting signals. Bacterial metabolites and components of the bacterial cell wall are likely to provide important links between the intestinal commensal flora and sleep-generating mechanisms in the brain. Butyrate is a short-chain fatty acid produced by the intestinal bacteria by the fermentation of nondigestible polysaccharides. We tested the hypothesis that butyrate may serve as a bacterial-derived sleep-promoting signal. Oral gavage administration of tributyrin, a butyrate pro-drug, elicited an almost 50% increase in non-rapid-eye movement sleep (NREMS) in mice for 4 hours after the treatment. Similarly, intraportal injection of butyrate led to prompt and robust increases in NREMS in rats. In the first 6 hours after the butyrate injection, NREMS increased by 70%. Both the oral and intraportal administration of butyrate led to a significant drop in body temperature. Systemic subcutaneous or intraperitoneal injection of butyrate did not have any significant effect on sleep or body temperature. The results suggest that the sleep-inducing effects of butyrate are mediated by a sensory mechanism located in the liver and/or in the portal vein wall. Hepatoportal butyrate-sensitive mechanisms may play a role in sleep modulation by the intestinal microbiota.

This study evaluates the effects of lactic, propionic and butyric acids, along with their salts, as natural antibiotic alternatives and growth promoters in broiler diets. Three hundred one-day-old Cobb broiler chicks ( n  = 60 per group), with six replicates of 10 birds each, were randomly allocated to five dietary treatments for 35 days: T1 (control, basal diet); T2 (basal diet + lactic acid and lactate, 0.5 g/kg each); T3 (basal diet + propionic acid and propionate, 0.5 g/kg each); T4 (basal diet + butyric acid and butyrate, 0.5 g/kg each); and T5 (basal diet + a mixture of lactic, propionic, and butyric acids and their salts, 0.17 g/kg each; total ≈ 1 g/kg). Growth performance, blood biochemistry, antioxidant indicators, thyroid hormones, carcass characteristics, intestinal microbiota, and humoral immune responses were assessed. The findings indicate that the blend of organic acids and their salts significantly improved ( p  ≤ 0.05) productive performance during the grower, finisher, and overall periods. Serum antioxidant indices (TAC, CAT) and RBC enzymatic activities (SOD, CAT) exhibited significant increases ( p  ≤ 0.05), whereas MDA levels were significantly decreased ( p  ≤ 0.05). T4 hormone levels increased ( p  ≤ 0.05) in the treated groups without affecting liver and kidney functions. The intestinal microbiota exhibited elevated ( p  ≤ 0.05) Lactobacillus levels and inhibited E. coli proliferation. Humoral immunity exhibited significantly higher ( p  ≤ 0.05) HI titers against avian influenza viruses (H9 and H5) than the control group. Overall, supplementation with organic acids and their salts offers a suitable natural growth promoter that enhances broiler productive performance, immunity, and antioxidant status without adversely affecting physiological functions.

Sodium butyrate and tributyrin are known to enhance broiler chicken performance. In this study, 1,000 Arbor Acres broiler chicks were assigned to four dietary treatments (250 birds each; six replicates of 40–42 birds): a control basal diet (CON), or the same diet supplemented with either 500 g/ton tributyrin (40%) + copper + essential oils (TB-500), 300 g/ton di- and tri-butyrin (60%) (TB-300), or 500 g/ton coated sodium butyrate (40%) (SB-500). Weekly growth parameters were recorded, and on Day 35, carcass traits, serum biochemistry, immunity, gene expression ( mTOR, TLR4, NBN ), intestinal morphology, caecal microbiota, and litter hygiene were assessed. TB-300 improved body weight (+ 4.6%, P  = 0.014), FCR (− 5.2%, P  = 0.032), and European Production Efficiency Factor (EPEF) (+ 14.9%, P  = 0.006). SB-500 significantly reduced litter Clostridia ( P  < 0.0001) and aerobic bacteria ( P  = 0.026) counts, while all butyrate treatments lowered caecal aerobic bacterial levels ( P  = 0.041). TB-300 and SB-500 enhanced duodenal villi height ( P  < 0.0001) and crypt-villus ratio ( P  < 0.001); TB-500 had the deepest duodenal crypts ( P  = 0.003). Jejunal and ileal morphology improved with most of the supplements, particularly TB-500 ( P  < 0.0001; P  = 0.050). All butyrate treatments increased serum total proteins ( P  = 0.015) and digestive enzymes (lipase, P  < 0.0001; protease, P  = 0.001). TB-300 and SB-500 significantly lowered serum lipids ( P  = 0.024), urea ( P  = 0.018), and aspartate aminotransferase (AST) ( P  = 0.027), while enhancing mTOR and NBN gene expression ( P  < 0.0001). TLR4 expression was upregulated in all butyrate-treated groups ( P  < 0.0001). Each form of butyrate supplementation exerts distinct beneficial effects on growth, gut health, and physiological performance in broiler chickens.

Sodium butyrate is well-known for its immune-modulatory properties. Studies until now only focused on the in vitro effects of butyrate or assessed local effects in the gut upon butyrate administration. In this trial, we studied the systemic anti-inflammatory effects induced by sodium butyrate supplementation in humans. Nine healthy (Lean) and ten obese (metabolic syndrome group, MetSyn) males were given 4 grams sodium butyrate daily for 4 weeks. PBMCs were isolated before and after supplementation for direct stimulation experiments and induction of trained immunity by oxidized low-density lipoprotein (oxLDL), β-glucan, or Bacillus Calmette-Guérin vaccine (BCG). Butyrate supplementation moderately affected some of the cytokine responses in the MetSyn group. In the direct stimulation setup, effects of butyrate supplementation were limited. Interestingly, butyrate supplementation decreased oxLDL-induced trained immunity in the MetSyn group for LPS-induced IL-6 responses and Pam3CSK4-induced TNF-α responses. Induction of trained immunity by β-glucan was decreased by butyrate in the MetSyn group for Pam3CSK4-induced IL-10 production. In this study, while having only limited effects on the direct stimulation of cytokine production, butyrate supplementation significantly affected trained immunity in monocytes of obese individuals with metabolic complications. Therefore, oral butyrate supplementation may be beneficial in reducing the overall inflammatory status of circulating monocytes in patients with metabolic syndrome.