Abstract
BackgroundElevations of circulating branched-chain amino acids (BCAA) are observed in humans with obesity and metabolic comorbidities, such as insulin resistance. Although it has been described that microbial metabolism contributes to the circulating pool of these amino acids, studies are still scarce, particularly in pediatric populations. Thus, we aimed to explore whether in early adolescents, gut microbiome was associated to circulating BCAA and in this way to insulin resistance.MethodsShotgun sequencing was performed in DNA from fecal samples of 23 early adolescents (10–12 years old) and amino acid targeted metabolomics analysis was performed by LC–MS/MS in serum samples. By using the HUMAnN2 algorithm we explored microbiome functional profiles to identify whether bacterial metabolism contributed to serum BCAA levels and insulin resistance markers.ResultsWe identified that abundance of genes encoding bacterial BCAA inward transporters were negatively correlated with circulating BCAA and HOMA-IR (P < 0.01). Interestingly, Faecalibacterium prausnitzii contributed to approximately ~ 70% of bacterial BCAA transporters gene count. Moreover, Faecalibacterium prausnitzii abundance was also negatively correlated with circulating BCAA (P = 0.001) and with HOMA-IR (P = 0.018), after adjusting for age, sex and body adiposity. Finally, the association between Faecalibacterium genus and BCAA levels was replicated over an extended data set (N = 124).ConclusionsWe provide evidence that gut bacterial BCAA transport genes, mainly encoded by Faecalibacterium prausnitzii, are associated with lower circulating BCAA and lower insulin resistance. Based on the later, we propose that the relationship between Faecalibacterium prausnitzii and insulin resistance, could be through modulation of BCAA.
Highlights
Elevations of circulating branched-chain amino acids (BCAA) are observed in humans with obesity and metabolic comorbidities, such as insulin resistance
We have previously showed that circulating BCAA as part of an amino acid signature are associated with obesity, insulin resistance and higher serum triglycerides levels in Mexican children, without association with total dietary protein intake (Moran-Ramos et al 2017)
After adjusting for age and sex, higher serum levels of BCAA were significantly associated with greater body fat percentage (P = 3.48 × 10–4, Fig. 1A) and with higher homeostasis model assessment for insulin resistance (HOMA-IR) index (P = 1.98 × 10–3, Fig. 1B) and the latter association remained significant after further adjusting for body fat (P = 0.026)
Summary
Elevations of circulating branched-chain amino acids (BCAA) are observed in humans with obesity and metabolic comorbidities, such as insulin resistance. A couple of interventional studies have shown that a protein restricted or BCAA restricted diet can decrease circulating levels of these amino acids and improve insulin resistance markers (Fontana et al 2016; Karusheva et al 2019). A few studies in humans and animal models have shown that gut microbiota metabolism can contribute to BCAA synthesis, uptake and degradation and to its circulating levels (Liu et al 2017, 2020; Pedersen et al 2016; Ridaura et al 2013). Additional studies are needed to define the contribution of bacterial metabolism to the circulating pool of these metabolites, as well as the species contributing to these functions (White and Newgard 2019)
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