Published online May 7, 2022. doi: 10.3748/wjg.v28.i17.1814
Peer-review started: December 30, 2021
First decision: January 27, 2022
Revised: February 4, 2022
Accepted: March 26, 2022
Article in press: March 26, 2022
Published online: May 7, 2022
Gut microbiota can be modified by the dietary composition and play a role in fatty liver pathogenesis through endotoxemia. Peroxisome proliferator-activated receptor (PPAR)-alpha activation has previously rescued the gut–liver axis with anti-steatotic effects in high-fructose-fed mice, whereas a high-dose dipeptidyl peptidase-4 (DPP-4) inhibitor (linagliptin) inhibited hepatic lipogenesis in high-fat-fed mice. The combination of these drugs could restore the gut–liver axis in obese mice.
Nonalcoholic fatty liver disease (NAFLD) is highly prevalent among obese individuals and can evolve into harmful liver diseases. Currently, there is no treatment directly prescribed to counter NAFLD. Herein, we propose a drug combination (PPAR-alpha agonist plus DPP-4 inhibitor) that can alleviate fatty liver by modulating the gut–liver axis with anti-inflammatory properties.
To evaluate the effects of monotherapy with a PPAR-alpha agonist (WY14643) or a DPP-4 inhibitor (linagliptin) and their combined treatment on the gut–liver axis, highlighting the intestinal barrier, endotoxemia, and inflammatory pathways in the livers of high-fat-fed mice. These preclinical insights can help establish new strategies for the treatment of NAFLD.
Mice were fed a control diet (C, 10% of energy as lipids) or a high-fat diet (HF, 50% of energy as lipids) for 12 wk. Then, the HF group was randomly divided into four groups: HF, HF-A (treated with the PPAR-alpha agonist), HFL (treated with the DPP-4 inhibitor), and HFC (treated with the combination of both drugs). The treatments lasted for five weeks. The gut–liver axis was assessed by histological, biochemical, stereological, and molecular techniques.
The HF diet yielded overweightness and oral glucose intolerance, altered gut microbiota composition, and decreased the numerical density of goblet cells and tight junction gene expression, with increased plasma lipopolysaccharide (LPS) concentrations and increased fatty liver. The combined treatment rescued all of these metabolic alterations by restoring the gut microbiota and intestinal barrier markers, resulting in decreased LPS concentrations and fatty liver through anti-inflammatory signals. Further studies may focus on the Proteobacteria phylum, whose alteration can trigger harmful signaling to the liver.
The combination of PPAR-alpha activation with DPP-4 inhibition yielded marked anti-steatotic effects by modulating the gut–liver axis, with reduced endotoxemia and amelioration of the intestinal barrier histology and gene expression. In turn, the livers of obese mice treated with the drug combination benefited from downregulation of the Tlr4 and Nlrp3 pathways and exhibited a hepatic parenchyma similar to that in the C group. Of note, we used stereology to estimate the numerical density of goblet cells in cecum slides stained with Alcian Blue and Periodic Acid-Schiff. This technique can be used to assess the effects of different interventions on the intestinal barrier and leaky gut in further studies.
This study brings novelty to the treatment of NAFLD, which is a challenge to the scientific community. Our results confirm the importance of the gut–liver axis in the pathogenesis of fatty liver and propose a combined treatment that targets the gut microbiota composition, endotoxemia, and intestinal barrier alterations to alleviate fatty liver through local anti-inflammatory effects in HF-fed mice.