Research Article
A high-fat High-fructose Diet Dysregulates the Homeostatic Crosstalk Between Gut Microbiome, Metabolome and Immunity in an Experimental Model of Obesity
Kun-Ping Li, Min Yuan, Yong-Lin Wu, Miguel Pineda, Chu-Mei Zhang, Yan-Fen Chen, Zhi-quan Chen, Xiang-Lu Rong, Jeremy E. Turnbull, Jiao Guo
First published: 24 January 2022
https://doi.org/10.1002/mnfr.202100950
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as https://doi.org/10.1002/mnfr.202100950


Abstract
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, we aim 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: An experimental obesity associated metaflammation rat model was induced with a HFF diet. An integrative multi-omics analysis was then performed. Following the clues illustrated by the multi-omics discoveries, putative pathways were subsequently validated by RT-qPCR and Western blotting.

Results: HFF diet led to obese phenotypes in rats, as well as histopathological changes. Integrated omics analysis showed there existed a strong interdependence among gut microbiota composition, intestinal metabolites and innate immunity regulation in the liver. Some carboxylic acids might contribute to gut-liver communication. Moreover, activation of the hepatic LPS-TLR4 pathway in obesity was confirmed.

Conclusions: HFF-intake disturbs gut flora homeostasis. Crosstalk between gut microbiota and innate immune system mediated 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.

High-fat high-fructose diet (HFF) induces obesity associated chronic inflammation;

HFF dysregulates the rat intestinal metabolome and gut microbiota composition;

HFF impacts hepatic expression of genes involved in innate immunity;

Modulation of gut microbiota composition and innate immunity are connected partly via TLR4 signalling;

Small molecular carboxylic acids are potential mediators of gut-liver axis communication in chronic obesity.