Our previous study showed that heavy
metal lead (Pb)
exposure exacerbates
high-fat-diet (HFD)-induced metabolic damage and significantly depletes
the gut microbiota-derived metabolite short-chain fatty acid (SCFA)
levels. However, it remains unclear whether SCFA is a key metabolite
involved in accelerating adverse consequences after Pb exposure. In
this study, we explored the effects of exogenous supplementation of
acetate, propionate, and butyrate on a metabolic disorder model in
Pb-exposed HFD mice. We found that three SCFA interventions attenuated
glycolipid metabolism disorders and liver damage, with butyrate performing
the best effects in improving obesity-related symptoms. All three
SCFA promoted the abundance of Muribaculaceae and Muribaculum, acetate specifically enriched Christensenellaceae, Blautia, and Ruminococcus, and
butyrate specifically enriched Parasutterella, Rikenella, Prevotellaceae_UCG-001, and Bacteroides, which contributed to the positive promotion
of SCFA production forming a virtuous cycle. Besides, butyrate inhibited
Gram-negative bacteria Escherichia-Shigella. All
of these events alleviated the intestinal Th17/Treg imbalance and
inflammatory response through crosstalk between the G protein-coupled
receptor (GPR)/histone deacetylase 3 (HDAC3) and lipopolysaccharide
(LPS)/toll-like receptors 4 (TLR4)/nuclear factor κ-B (NF-κB)
pathways and ultimately improved the intestinal barrier function.
SCFA further upregulated the monocarboxylate transporter 1 (MCT1)
and GPR43/adenosine 5′-monophosphate-activated protein kinase
(AMPK) pathways to inhibit hepatic lipid accumulation. Overall, SCFA,
especially butyrate, is an effective modulator to improve metabolic
disorders in obese individuals exposed to heavy metals by targeting
gut microecology.