Therapeutic Effects of Butyrate on Pediatric Obesity: A Randomized Clinical Trial.

Serena Coppola, Rita Nocerino, Lorella Paparo, Giorgio Bedogni, Antonio Calignano, Carmen Di Scala, Anna Fiorenza de Giovanni di Santa Severina, Francesca De Filippis, Danilo Ercolini, Roberto Berni Canani

Journal: JAMA network open 2022;5(12):e2244912

PMID: 36469320

Free Full Text on PubMed Central View on PubMed

Plain Language Summary

Gut microbiome (GM) could play a role in obesity. A metabolically healthy GM is maintained by a diet rich in fibre. Plant foods are fermented by the gut microbiome to produce the antiobesogenic short-chain fatty acid butyrate. The aim of this study was to evaluate whether butyrate supplementation can be effective in paediatric obesity treatment. This study was a randomised, quadruple-blind, parallel-group, placebo-controlled trial. Children were randomly assigned to the treatment group or placebo in a 1:1 ratio. Results showed that in children with obesity, oral butyrate supplementation produced a reduction of body mass index and exerted beneficial effects on glucose metabolism and inflammation. In fact, butyrate supplementation decreased homeostatic model assessment of insulin resistance [HOMA-IR] and fasting insulin levels in children with obesity. Additionally, the GM analysis supported the role of butyrate in glucose metabolism, as suggested by a more positive response in children with a higher abundance of butyrate-producing bacteria at baseline. Authors conclude that their findings support the importance of the GM-derived metabolite butyrate as a protective factor against obesity, highlighting the central role of a healthy diet and GM function to achieve an optimal endogenous production of butyrate.

Abstract

IMPORTANCE

The pediatric obesity disease burden imposes the necessity of new effective strategies.

OBJECTIVE

To determine whether oral butyrate supplementation as an adjunct to standard care is effective in the treatment of pediatric obesity.

DESIGN, SETTING, AND PARTICIPANTS

A randomized, quadruple-blind, placebo-controlled trial was performed from November 1, 2020, to December 31, 2021, at the Tertiary Center for Pediatric Nutrition, Department of Translational Medical Science, University of Naples Federico II, Naples, Italy. Participants included children aged 5 to 17 years with body mass index (BMI) greater than the 95th percentile.

INTERVENTIONS

Standard care for pediatric obesity supplemented with oral sodium butyrate, 20 mg/kg body weight per day, or placebo for 6 months was administered.

MAIN OUTCOMES AND MEASURES

The main outcome was the decrease of at least 0.25 BMI SD scores at 6 months. The secondary outcomes were changes in waist circumference; fasting glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, ghrelin, microRNA-221, and interleukin-6 levels; homeostatic model assessment of insulin resistance (HOMA-IR); dietary and lifestyle habits; and gut microbiome structure. Intention-to-treat analysis was conducted.

RESULTS

Fifty-four children with obesity (31 girls [57%], mean [SD] age, 11 [2.91] years) were randomized into the butyrate and placebo groups; 4 were lost to follow-up after receiving the intervention in the butyrate group and 2 in the placebo group. At intention-to-treat analysis (n = 54), children treated with butyrate had a higher rate of BMI decrease greater than or equal to 0.25 SD scores at 6 months (96% vs 56%, absolute benefit increase, 40%; 95% CI, 21% to 61%; P < .01). At per-protocol analysis (n = 48), the butyrate group showed the following changes as compared with the placebo group: waist circumference, -5.07 cm (95% CI, -7.68 to -2.46 cm; P < .001); insulin level, -5.41 μU/mL (95% CI, -10.49 to -0.34 μU/mL; P = .03); HOMA-IR, -1.14 (95% CI, -2.13 to -0.15; P = .02); ghrelin level, -47.89 μg/mL (95% CI, -91.80 to -3.98 μg/mL; P < .001); microRNA221 relative expression, -2.17 (95% CI, -3.35 to -0.99; P < .001); and IL-6 level, -4.81 pg/mL (95% CI, -7.74 to -1.88 pg/mL; P < .001). Similar patterns of adherence to standard care were observed in the 2 groups. Baseline gut microbiome signatures predictable of the therapeutic response were identified. Adverse effects included transient mild nausea and headache reported by 2 patients during the first month of butyrate intervention.

CONCLUSIONS AND RELEVANCE

Oral butyrate supplementation may be effective in the treatment of pediatric obesity.

TRIAL REGISTRATION

ClinicalTrials.gov Identifier: NCT04620057.

Address: Department of Translational Medical Science, University of Naples "Federico II," Naples, Italy.; ImmunoNutritionLab, CEINGE-Advanced Biotechnologies, University of Naples "Federico II," Naples, Italy.; Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.; Department of Primary Health Care, Internal Medicine Unit Addressed to Frailty and Aging, S Maria delle Croci Hospital, AUSL Romagna, Ravenna, Italy.; Department of Pharmacy, University of Naples "Federico II," Naples, Italy.; Task Force on Microbiome Studies, University of Naples "Federico II," Naples, Italy.; Department of Agricultural Sciences, University of Naples "Federico II," Naples, Italy.; European Laboratory for the Investigation of Food-Induced Diseases, University of Naples "Federico II," Naples, Italy.

DOI: 10.1001/jamanetworkopen.2022.44912