Limosillactobacillus reuteri C501 modulates tryptophan metabolism and alleviates obesity-induced gut-adipose tissue axis metabolic disorders through AhR and Bmal1/Pparγ signaling

Limosillactobacillus reuteri ( L. reuteri ) is known to play a beneficial role in various aspects of human health, including diabetes, inflammatory bowel disease, and neurological disorders. However, its role in regulating obesity-induced metabolic disorders remains poorly understood. We demonstrate that administering L. reuteri C501 to male mice for 10 weeks significantly alleviates high-fat diet (HFD)-induced obesity and related metabolic disorders. Treatment with L. reuteri C501 led to reduced body weight gain, improved insulin sensitivity, and attenuated inflammatory responses. Moreover, the treatment activated the aryl hydrocarbon receptor (AhR) and the circadian rhythm regulator brain and muscle ARNT-like protein 1 (Bmal1)-two key players in immune function and energy metabolism-thereby influencing lipid metabolism in HFD-fed mice. In addition, L. reuteri C501 modulated gut microbiota composition and enhanced the production of indole derivatives. Supplementation with indole-3-lactic acid (ILA), one such derivative, also improved obesity outcomes in HFD-fed mice. Notably, administering L. reuteri C501 at zeitgeber time 0 (ZT0, the beginning of the light cycle) resulted in stronger therapeutic effects, suggesting that timing of intake may critically influence its efficacy. These findings highlight L. reuteri C501 as a promising probiotic intervention for obesity, with chronobiological factors playing a key role in optimizing its metabolic benefits.