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

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, 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.

Sulforaphane Ameliorates Nonalcoholic Fatty Liver Disease Induced by High-Fat and High-Fructose Diet via LPS/TLR4 in the Gut–Liver Axis

“…As shown in Figure 5 A, SFN treatment significantly reduced the LPS level in the liver. The ability to recognize the increased LPS, TLR4 and their downstream pathway has shown dominance in the mechanisms of the microbiota-gut-liver axis [ 42 ]. LPS is a key factor in inducing an inflammatory response in liver tissue and plays an important role in liver injury through the LPS-TLR4 signaling pathway [ 43 ].…”

“…Studies on animals and humans have reported altered gut microbes in NAFLD individuals. Gut microbiota dysbiosis was observed in HFHFr-induced obese rats [ 42 ]. We observed that SFN decreased the F/B ratio and the abundance of Lactobacillus , Lactococcus , Blautia , Dubosiella , and Alistipes at the phylum level in HFHFr mice.…”

Integrated multi-omics analyses reveal effects of empagliflozin on intestinal homeostasis in high-fat-diet mice

“…Intestinal contents contain nonabsorbable food components and complex mixtures of metabolites produced by the host and intestinal microbes. 24 Therefore, intestinal metabolites can reflect the health status of the host. Based on this, we examined the intestinal metabolome of obesity model mice, which consists of a mixture of host-produced and microbiota-produced molecules.…”

The Short-Day Cycle Induces Intestinal Epithelial Purine Metabolism Imbalance and Hepatic Disfunctions in Antibiotic-Mediated Gut Microbiota Perturbation Mice

“…RNA-Seq was performed as described previously before [ 67 ]. Briefly, total RNA for hepatic transcriptome sequencing was isolated and purified using TRIzol reagent (Invitrogen, Carlsbad, CA, USA) following the manufacturer’s procedure.…”