A High‐Fat High‐Fructose Diet Dysregulates the Homeostatic Crosstalk Between Gut Microbiome, Metabolome, and Immunity in an Experimental Model of Obesity

Scope Ample evidence supports the prominent role of gut‐liver axis in perpetuating pathological networks of high‐fat high‐fructose (HFF) diet induced metabolic disorders, however, the molecular mechanisms are still not fully understood. Herein, this study aims to present a holistic delineation and scientific explanation for the crosstalk between the gut and liver, including the potential mediators involved in orchestrating the metabolic and immune systems. Methods and Results An experimental obesity‐associated metaflammation rat model is induced with a HFF diet. An integrative multi‐omics analysis is then performed. Following the clues illustrated by the multi‐omics discoveries, putative pathways are subsequently validated by RT‐qPCR and Western blotting. HFF diet leads to obese phenotypes in rats, as well as histopathological changes. Integrated omics analysis shows that there exists a strong interdependence among gut microbiota composition, intestinal metabolites, and innate immunity regulation in the liver. Some carboxylic acids may contribute to gut‐liver communication. Moreover, activation of the hepatic LPS‐TLR4 pathway in obesity is confirmed. Conclusion HFF‐intake disturbs gut flora homeostasis. Crosstalk between gut microbiota and innate immune system mediates hepatic metaflammation in obese rats, associated with LPS‐TLR4 signaling pathway activation. Moreover, α‐hydroxyisobutyric acid and some other organic acids may play a role as messengers in the liver‐gut axis.