Page 47 - Read Online

Page 8 of 14 Cui et al. Microbiome Res Rep. 2025;4:31 https://dx.doi.org/10.20517/mrr.2025.25

its role in systemic BCAA homeostasis and lipid biosynthesis. Green et al. elucidated the pivotal
[65]
contribution of BCAA degradation to the control of adipocyte differentiation . Their work revealed that
increased expression of BCAA-catabolizing enzymes coincides with elevated peroxisome proliferator-
activated receptor gamma (PPARγ) levels during the initial phases of adipogenesis, implicating BCAA
metabolism in the determination of adipogenic fate. The study further delineated that BCAAs promote
adipocyte maturation by stimulating the mechanistic target of rapamycin complex 1 (mTORC1) pathway,
with ribosomal protein S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E-binding protein 1
[66]
(4E-BP1) serving as key downstream mediators that ultimately regulate PPARγ function . Moreover, the
mitochondrial deacylase SIRT4 was identified as a modulator of BCAA metabolic flux in preadipocytes,
acting through PPARγ upregulation - a finding that reinforces the critical crosstalk between mitochondrial
metabolic regulation and transcriptional programming in early adipogenic commitment . Enhancing
[67]
BCAA catabolism, via dietary modulation or next-generation probiotics, improves glucose homeostasis and
reduces fat mass in rodent obesity models, offering a novel avenue for metabolic health interventions [68,69] .
Altogether, these findings highlight the integral role of BCAA metabolism in adipose tissue development,
energy balance, and the pathogenesis of obesity-related metabolic disorders.

GUT MICROBIOTA IN METABOLIC DISORDERS
Obesity
Obese individuals and HFD rodents exhibit a characteristic shift toward an elevated Firmicutes/
Bacteroidetes ratio, promoting the extraction of additional calories from complex polysaccharides and
increasing fat deposition . Concurrently, depletion of mucin-degrading and barrier-protective taxa such as
[70]
Akkermansia muciniphila correlates with higher body mass index, while supplementation with
A. muciniphila restores tight junction integrity and ameliorates metabolic parameters in overweight
humans . Dysbiosis also underlies metabolic endotoxemia: increased intestinal permeability allows LPS
[71]
translocation into the circulation, activating TLR4-NF-κB signaling in adipose macrophages and adipocytes,
[72]
driving chronic low-grade inflammation and insulin resistance . Moreover, microbial metabolites
modulate host lipid handling: SCFAs bind GPR41/43 to stimulate peptide YY and GLP-1 secretion,
suppressing appetite and improving insulin sensitivity, whereas secondary bile acids generated via microbial
bile salt hydrolase activity activate FXR and TGR5 to inhibit lipogenesis and enhance energy
expenditure [73,74] . Interventions with prebiotics (e.g., inulin) increase microbial diversity and SCFA
production, reducing fat mass in both murine models and clinical cohorts, underscoring therapeutic
potential .
[75]

T2D
T2D diabetes is associated with reduced gut microbial diversity, enrichment of opportunistic pathogens,
and loss of butyrate-producing taxa (e.g., Faecalibacterium prausnitzii), leading to impaired barrier function
[76]
and systemic inflammation . Dysbiosis also diminishes GLP-1 release: under healthy conditions, SCFAs
and secondary bile acids stimulate enteroendocrine L cells to secrete GLP-1, enhancing insulin secretion
and glucose tolerance; in T2D, this axis is blunted, contributing to hyperglycemia . Probiotic and prebiotic
[77]
interventions (e.g., Lactobacillus rhamnosus, dietary fibers) restore SCFA levels, normalize GLP-1 rhythms,
[78]
and improve glycemic control in preclinical and clinical studies . Bariatric surgery further underscores
microbiota’s role: patients undergoing Roux-en-Y gastric bypass exhibit specific microbial shifts that
enhance incretin responses and barrier integrity, correlating with remission of T2D . Next-generation
[79]
approaches, such as FMT from healthy donors and designer consortia, are under investigation to reprogram
dysbiotic communities and reverse insulin resistance [80,81] .