Microbiota-accessible carbohydrates (MACs) exert health-promoting effects, but how each MAC impacts gut microbiota and regulates host physiology remains unclear. Here, we show that L-arabinose and sucrose cooperatively act on gut microbiota and exert anti-obesogenic effects. Specifically, L-arabinose, a monosaccharide that is poorly absorbed in the gut and inhibits intestinal sucrase, suppresses diet-induced obesity in mice in the presence of sucrose. Additionally, the suppressive effect of L-arabinose on adiposity is abrogated in mice lacking the short-chain fatty acid (SCFA) receptors GPR43 and GPR41. Mechanistically, L-arabinose increases the relative abundance of acetate and propionate producers (e.g., Bacteroides), while sucrose enhances SCFA production. Furthermore, L-arabinose and sucrose activate the glycolytic and pentose phosphate pathways of Bacteroides, respectively, indicating that they synergistically promote acetate production through distinct pathways. These findings suggest that each MAC has a unique property and thus may serve as a precision gut-microbiota modulator to promote host homeostasis.
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