Xanthohumol and its non-estrogenic derivatives link to the gut-liver-brain axis to improve cognition in mice with diet-induced obesity.

Obesity-associated cognitive decline represents a growing public health concern, yet the mechanisms linking high-fat diet (HFD) to neurological impairment remain incompletely understood. Xanthohumol (XN) and its non-estrogenic derivatives, tetrahydroxanthohumol (TXN) and α,β-dihydro-xanthohumol (DXN), improve metabolic dysfunction and cognitive impairment associated with diet-induced obesity. The mechanisms underlying these cognitive benefits remain poorly defined, but all three compounds improve glucose tolerance, spatial learning and memory in obese C57BL/6J mice. We hypothesized that the gut-liver-brain axis associates with these effects through modulation of gut microbial functional capacity and host ceramide metabolism. To test this, we integrated shotgun metagenomes with lipidomic and behavioral data from male C57BL/6J mice fed a HFD supplemented with XN, TXN, or DXN to determine (1) whether supplementation differentially alters gut metagenome functional capacity, (2) whether variation in the gut metagenome links to cognitive outcomes, and (3) whether supplementation-induced variation in the gut metagenome is associated with alterations in ceramide and bile acid levels in the liver and hippocampus. We found that microbial gene abundance was associated with spatial learning outcomes across all treatment groups, including genes involved in tryptophan metabolism. Gut microbiome composition was also linked to ceramide levels in both hepatic and hippocampal tissues, with C22 ceramide emerging as a shared biomarker. TXN supplementation additionally reduced secondary bile acids HDCA and a DCA-isomer, extending prior 16S rRNA-based findings to the level of microbial gene function. Collectively, these results are consistent with a model in which XN and its derivatives act upon the gut-liver-brain axis to improve cognition in obese mice in association with changes to gut microbial functional capacity (most notably in bile acid and ceramide metabolism, with tryptophan metabolism as a secondary observation).