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Butyric Acid & Metabolic Health

iStock-1371348207Results of a randomized clinical trial were published in JAMA Network Open in December 2022, the first trial to examine supplementation with butyric acid as a treatment for obesity in children. Butyrate is among the short-chain fatty acids (SCFAs) known to have a role in energy metabolism and which are produced by bacterial fermentation (mostly of plant polysaccharides and resistant starches). Previous research suggests that butyrate specifically may be a link between obesity-related metabolic disease, diet, and the intestinal microbiome. Butyrate has an anti-inflammatory effect; it modulates the intestinal barrier and also influences gene expression in colonocytes. People with diabetes, for example, have been found to have lower levels of butyrate-producing bacteria, and increasing butyrate levels may improve insulin sensitivity.

In the recently published paper, 54 children (aged 5-17) with a BMI greater than the 95th percentile were randomized to receive oral sodium butyrate, at a dose of 20 mg/kg body weight per day for 6 months. A BMI above the 95th percentile (of the CDC 2000 growth charts) is the accepted definition of childhood obesity, a threshold met by ~20% of children in the U.S. This trial was quadruple-blinded, with the blinding of the investigators, children, parents or legal guardians, and data entry researchers. Both the butyrate and placebo groups received Italian standard of care for childhood obesity, which included a Mediterranean diet, 60 minutes per day of aerobic activity, and a reduction in sedentary time. The primary outcome the study was powered for was a reduction in at least 0.25 BMI SD scores, though many secondary outcomes (e.g., lipids, IL-6, microbiome changes, HOMA-IR, etc.) were also included. 

The results of this study suggest that butyrate can not only reduce the BMI of children with obesity, but it can also improve glucose metabolism and reduce inflammation. Comparing only the children that completed the 6-month trial (a small number were lost to follow-up), 96% of those receiving butyrate met the primary objective goals (BMI reduction of 0.25 SD) compared to 52% receiving placebo (note, both groups also received lifestyle recommendations). This corresponded to a “number needed to treat” of 2, an extremely good outcome. Additionally, significant improvements in BMI, fasting insulin, waist circumference, HOMA-IR, ghrelin, micro-RNA221 expression, and IL-6 were also observed, with no differences in serum glucose or lipids. For example, the placebo group’s mean BMI was 29.47 and 28.71 at the onset and conclusion of the trial, respectively, compared to a mean BMI of 29.55 (onset) and 26.53 (conclusion) in the butyrate group. 

Although no major differences in the gut microbiome were observed between groups, an association between the baseline microbiome and the response to butyrate was found. Specifically, in the intervention group, Faecalibacterium prausnitzii was positively associated with a decrease in HOMA-IR, Roseburia faecis was positively associated with a decrease in insulin levels, and Ruminococcus torques had a negative correlation with HOMA-IR. Microbial gene expression was also influenced by butyrate; children receiving butyrate had an increase in gene richness and a decrease in genes involved in branched-chain amino acid biosynthesis. 

Four children in the butyrate group stopped the treatment after the first dose, compared to 2 in the placebo group. Additionally, 2 children receiving butyrate reported mild nausea and headache in the first month of intervention which resolved with no additional treatment, while no such symptoms were described in children receiving placebo. The authors suggest that sodium butyrate has unpleasant features, and that more pleasant forms may improve adherence. 

While mechanisms of action were not established in this study, a paper published in Immunity reviewed many possible ways in which butyrate is tied to metabolic health. It is speculated that the harm of a Western diet may be in part related to decreased synthesis of SCFAs, leading to weakened intestinal permeability and endotoxemia. SCFAs promote the secretion of mucus by gut epithelial cells, they induce Treg cells (reducing inflammation and promoting tolerance), as well as the production of IgA. They limit the production of inflammatory mediators, such as tumor necrosis factor (TNF), IL-6 (as observed in this recent trial), and interferon-γ. F. prausnitzii, the species associated with improved HOMA-IR in the pediatric trial, has been identified as an anti-inflammatory commensal bacteria, in part because it is thought to synthesize butyrate in large amounts. Although not measured in this study, butyrate has also been shown to upregulate leptin levels, likely through the activation of G protein-coupled receptors. Also, treatment with glucagon-like peptide-1 (GLP-1) has been shown to upregulate intestinal levels of butyrate among people with type 2 diabetes, suggesting that increasing butyrate synthesis may partly mediate the beneficial effects of GLP-1 on glucose homeostasis. 

The number of mechanisms by which butyrate or butyrate-upregulating treatments may modulate insulin resistance and improve metabolism is currently a promising and exciting area of obesity research. While most animal and cell-based research has demonstrated positive results, human trials have been limited by small sample sizes, and/or the absence of placebo groups, making this recent trial an important contribution. It’s also worth noting that butyrate has other possible therapeutic benefits. For example, in addition to its metabolic effects, butyrate is an important substrate for colonocytes and has been shown in vitro and in animal models to have several anti-tumor properties, possibly playing a role in the management of colon cancer.

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