Page 46 - Read Online

Cui et al. Microbiome Res Rep. 2025;4:31 https://dx.doi.org/10.20517/mrr.2025.25 Page 7 of 14

signaling. Secondary bile acids activate the farnesoid X receptor (FXR) in hepatic tissue to suppress
lipogenesis and engage the GPCR TGR5 in adipose tissue to promote energy expenditure via thyroid
hormone activation [51,52] . Bile acids can bind to TGR5, leading to improved insulin sensitivity, enhanced
glucose tolerance, reduced plasma lipid levels, and alleviation of hepatic steatosis. TGR5 functions mainly
through three pathways. First, it activates cyclic adenosine monophosphate (cAMP), which induces type 2
iodothyronine deiodinase (DIO ); DIO converts inactive thyroid hormone T4 into active T3, thereby
2
2
promoting thermogenesis in adipose tissue . Second, TGR5 activation in intestinal L cells promotes the
[53]
secretion of GLP-1, enhancing insulin secretion and improving glucose homeostasis. Third, TGR5
modulates inflammatory responses by inhibiting the nuclear factor-kappa B (NF-κB) signaling pathway,
[54]
thereby reducing inflammation associated with metabolic disorders . Additionally, it regulates glucose
metabolism and energy balance by releasing GLP-1, inhibits the NF-κB signaling pathway in macrophages,
reduces foam cell formation, lowers fat deposition, and suppresses the development of atherosclerosis .
[55]
Together, these pathways highlight bile acids as critical microbial-derived regulators that orchestrate lipid
metabolism, inflammation, and energy homeostasis.

LPS
Metabolic endotoxemia, characterized by low-grade elevation of plasma LPS, triggers TLR4-NF-κB signaling
in adipocytes and macrophages, driving pro-inflammatory cytokine release, insulin resistance, and adipose
tissue expansion [56,57] . HFDs increase gut permeability, facilitating LPS translocation into the portal
circulation; conversely, prebiotic and probiotic interventions that restore epithelial tight junctions lower
systemic LPS levels and attenuate adipose inflammation and fat gain [57,58] . CD14-deficient mice resist HFD-
induced weight gain and insulin resistance, confirming that LPS-CD14 interactions play a crucial role in
[57]
setting the tone for metabolic inflammation and the development of obesity . LPS triggers pro-
inflammatory cytokine release, immune activation, and chronic inflammation, accelerating atherosclerosis
and plaque formation. It also downregulates ATP-binding cassette transporter A1 (ABCA1) in murine
macrophages, impairing cholesterol efflux. A HFD increases the abundance of LPS-producing gut bacteria,
stimulating tumor necrosis factor-alpha (TNF-α) and NF-κB signaling. Both LPS and TNF-α activate
apoptosis signal-regulating kinase 1 (ASK1), a critical suppressor of adipose tissue browning . These
[59]
findings underscore the pivotal role of microbiota-derived LPS in linking gut barrier dysfunction to
systemic inflammation, lipid dysregulation, and metabolic disease progression.

BCAAs
BCAAs, including leucine, isoleucine, and valine, are metabolized by both host and microbial pathways,
[60]
with dysregulated microbial handling of BCAAs preceding obesity and insulin resistance . Elevated
circulating BCAAs correlate with increased fat deposition, and transplantation of BCAA-enriched
microbiota from obese donors into germ-free mice raises serum BCAA levels and promotes adipocyte lipid
storage [61,62] . The cellular uptake of BCAAs into adipocytes is predominantly regulated by specific amino acid
transporters, including solute carrier family 1 member 5 (SLC1A5), solute carrier family 3 member 2
(Slc3a2), and solute carrier family 7 member 5 (Slc7a5). This complex facilitates an antiport mechanism,
whereby extracellular BCAAs are exchanged for intracellular glutamine and asparagine. Upon cellular
internalization, BCAAs undergo sequential metabolic transformations, culminating in the generation of
intermediate acyl-CoA derivatives, including isovaleryl-CoA and 2-methylbutyryl-CoA . These
[63]
intermediates serve as critical precursors for the biosynthesis of monomethyl branched-chain fatty acids
(mmBCFAs). The mitochondrial export of these acyl-CoA species is mediated by carnitine acetyltransferase,
followed by their cytosolic elongation catalyzed by FAS. This metabolic cascade highlights the dual role of
BCAAs in adipose tissue: not only do they serve as substrates for energy production, but they also
contribute to de novo lipogenesis through the generation of mmBCFAs . This pathway underscores the
[64]
metabolic versatility of adipose tissue in integrating nitrogen and carbon metabolism, further emphasizing