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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.

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).

Background Diabetic retinopathy (DR) development is associated with disturbances in the gut microbiota and related metabolites. Butyric acid is one of the short-chain fatty acids (SCFAs), which has been found to possess a potential antidiabetic effect. However, whether butyrate has a role in DR remains elusive. This study aimed to investigate the effect and mechanism of sodium butyrate supplementation on DR. Methods C57BL/6J mice were divided into three groups: Control group, diabetic group, and diabetic with butyrate supplementation group. Type 1 diabetic mouse model was induced by streptozotocin. Sodium butyrate was administered by gavage to the experimental group daily for 12 weeks. Optic coherence tomography, hematoxylin–eosin, and immunostaining of whole-mount retina were used to value the changes in retinal structure. Electroretinography was performed to assess the retinal visual function. The tight junction proteins in intestinal tissue were evaluated using immunohistochemistry. 16S rRNA sequencing and LC–MS/MS were performed to determine the alteration and correlation of the gut microbiota and systemic SCFAs. Results Butyrate decreased blood glucose, food, and water consumption. Meanwhile, it alleviated retinal thinning and activated microglial cells but improved electroretinography visual function. Additionally, butyrate effectively enhanced the expression of ZO-1 and Occludin proteins in the small intestine. Crucially, only butyric acid, 4-methylvaleric acid, and caproic acid were significantly decreased in the plasma of diabetic mice and improved after butyrate supplementation. The deeper correlation analysis revealed nine genera strongly positively or negatively correlated with the above three SCFAs. Of note, all three positively correlated genera, including norank_f_Muribaculaceae , Ileibacterium , and Dubosiella , were significantly decreased in the diabetic mice with or without butyrate treatment. Interestingly, among the six negatively correlated genera, Escherichia-Shigella and Enterococcus were increased, while Lactobacillus , Bifidobacterium , Lachnospiraceae_NK4A136_group , and unclassified_f_Lachnospiraceae were decreased after butyrate supplementation. Conclusion Together, these findings demonstrate the microbiota regulating and diabetic therapeutic effects of butyrate, which can be used as a potential food supplement alternative to DR medicine.

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.

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.

Microbiome dysbiosis resulting in altered metabolite profiles may be associated with certain diseases, including inflammatory bowel diseases (IBD), which are characterized by active intestinal inflammation. Several studies have indicated the beneficial anti-inflammatory effect of metabolites from gut microbiota, such as short-chain fatty acids (SCFAs) and/or D-amino acids in IBD therapy, through orally administered dietary supplements. In the present study, the potential gut protective effects of d-methionine (D-Met) and/or butyric acid (BA) have been investigated in an IBD mouse model. We have also built an IBD mouse model, which was cost-effectively induced with low molecular weight DSS and kappa-carrageenan. Our findings revealed that D-Met and/or BA supplementation resulted in the attenuation of the disease condition as well as the suppression of several inflammation-related gene expressions in the IBD mouse model. The data shown here may suggest a promising therapeutic potential for improving symptoms of gut inflammation with an impact on IBD therapy. However, molecular metabolisms need to be further explored.

• Indole-3-acetic acid (IAA) is a predominant form of active auxin in plants. In addition to de novo biosynthesis and release from its conjugate forms, IAA can be converted from its precursor indole-3-butyric acid (IBA). • The IBA-derived IAA may help drive root hair elongation in Arabidopsis thaliana seedlings, but how the IBA-to-IAA conversion is regulated and affects IAA function requires further investigation. • In this study, HOMEOBOX PROTEIN 24 (HB24), a transcription factor in the zinc finger-homeodomain family (ZF-HD family) of proteins, was identified. With loss of HB24 function, defective growth occurred in root hairs. INDOLE-3-BUTYRIC ACID RESPONSE 1 (IBR1), which encodes an enzyme involved in the IBA-to-IAA conversion, was identified as a direct target of HB24 for the control of root hair elongation. The exogenous IAA or auxin analogue 1-naphthalene acetic acid (NAA) both rescued the root hair growth phenotype of hb24 mutants, but IBA did not, suggesting a role for HB24 in the IBA-to-IAA conversion. • Therefore, HB24 participates in root hair elongation by upregulating the expression of IBR1 and subsequently promoting the IBA-to-IAA conversion. Moreover, IAA also elevated the expression of HB24, suggesting a feedback loop is involved in IBA-to-IAA conversion-mediated root hair elongation.

The potential for mitigating intestinal inflammation through the gut-bone axis in the treatment of osteoporosis is significant. While various gut-derived postbiotics or bacterial metabolites have been created as dietary supplements to prevent or reverse bone loss, their efficacy and safety still need improvement. Herein, a colon-targeted drug delivery system is developed using surface engineering of polyvinyl butyrate nanoparticles by shellac resin to achieve sustained release of postbiotics butyric acid at the colorectal site. These engineered postbiotics nanoparticles can effectively suppress macrophage inflammatory activation, modulate the redox balance, and regulate the composition of the gut microbiota, thereby restoring epithelial barriers, inhibiting bacterial invasion, and down-regulating pro-inflammatory responses. As a result, the remission of systemic inflammation is accompanied by a rebalancing of osteoblast and osteoclast activity, alleviating inflammatory bowel disease-related and post-menopausal bone loss. Specifically, the treatment of engineered postbiotics nanoparticles can also improve the quality and quantity of bone with restoration of deteriorative mechanical properties, which indicating a therapeutic potential on fracture prevention. This study provides valuable insights into the gut-bone axis and establishes a promising and safe therapeutic strategy for osteoporosis. Gut inflammation and bone loss have previously been linked. Here, the authors show colon-targeted engineered postbiotics can protect the gut and reduce systemic inflammation, which rebalances inflammation disturbed osteoblast-osteoclast levels restoring bone homeostasis.

Gamma-amino butyric acid (GABA) is marketed in the U.S. as a dietary supplement. USP conducted a comprehensive safety evaluation of GABA by assessing clinical studies, adverse event information, and toxicology data. Clinical studies investigated the effect of pure GABA as a dietary supplement or as a natural constituent of fermented milk or soy matrices. Data showed no serious adverse events associated with GABA at intakes up to 18 g/d for 4 days and in longer studies at intakes of 120 mg/d for 12 weeks. Some studies showed that GABA was associated with a transient and moderate drop in blood pressure (<10% change). No studies were available on effects of GABA during pregnancy and lactation, and no case reports or spontaneous adverse events associated with GABA were found. Chronic administration of GABA to rats and dogs at doses up to 1 g/kg/day showed no signs of toxicity. Because some studies showed that GABA was associated with decreases in blood pressure, it is conceivable that concurrent use of GABA with anti-hypertensive medications could increase risk of hypotension. Caution is advised for pregnant and lactating women since GABA can affect neurotransmitters and the endocrine system, i.e., increases in growth hormone and prolactin levels.