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
Obesity and comorbidities onset encompass gut dysbiosis, altered intestinal permeability, and endotoxemia. Treatments that target gut dysbiosis can cope with obesity and nonalcoholic fatty liver disease (NAFLD) management. Peroxisome proliferator-activated receptor (PPAR)-alpha activation and dipeptidyl-peptidase-4 (DPP-4) inhibition alleviate NAFLD, but the mechanism may involve gut microbiota modulation and merits further investigation.
To address the effects of PPAR-alpha activation and DPP-4 inhibition (isolated or combined) upon the gut-liver axis, emphasizing inflammatory pathways in NAFLD management in high-fat-fed C57BL/6J mice.
Male C57BL/6J mice were fed a control diet (C, 10% of energy as lipids) or a high-fat diet (HFD, 50% of energy as lipids) for 12 wk, when treatments started, forming the groups: C, HF, HFA (HFD + PPAR-alpha agonist WY14643, 2.5 mg/kg body mass), HFL (HFD + DPP-4 inhibitor linagliptin, 15 mg/kg body mass), and HFC (HFD + the combination of WY14643 and linagliptin).
The HFD was obesogenic compared to the C diet. All treatments elicited significant body mass loss, and the HFC group showed similar body mass to the C group. All treatments tackled oral glucose intolerance and raised plasma glucagon-like peptide-1 concentrations. These metabolic benefits restored Bacteroidetes/Firmicutes ratio, resulting in increased goblet cells per area of the large intestine and reduced lipopolysaccharides concentrations in treated groups. At the gene level, treated groups showed higher intestinal Mucin 2, Occludin, and Zo-1 expression than the HFD group. The reduced endotoxemia suppressed inflammasome and macrophage gene expression in the liver of treated animals. These observations complied with the mitigation of liver steatosis and reduced hepatic triacylglycerol, reassuring the role of the proposed treatments on NAFLD mitigation.
PPAR alpha activation and DPP-4 inhibition (isolated or combined) tackled NAFLD in diet-induced obese mice by restoration of gut-liver axis. The reestablishment of the intestinal barrier and the rescued phylogenetic gut bacteria distribution mitigated liver steatosis through anti-inflammatory signals. These results can cope with NAFLD management by providing pre-clinical evidence that drugs used to treat obesity comorbidities can help to alleviate this silent and harmful liver disease.
Core Tip: Chronic high-fat diet (HF) intake alters the phylogenetic microbiota composition, sending harmful proinflammatory signals to the liver that elicit nonalcoholic fatty liver disease in mice. Here, we treated HF diet-induced obese mice with a peroxisome proliferator-activated receptor-alpha agonist (WY14643), a dipeptidyl-peptidase-4 inhibitor (linagliptin), or their combination, focusing on gut–liver axis modulation. The treatments rescued gut dysbiosis and endotoxemia due to increased tight junction gene expression, mucin production, and numerical density of goblet cells in the intestinal crypts. Treated mice benefited from downregulated Tlr4, Cd206, and Nlrp3, alleviating fatty liver through anti-inflammatory signals such as increased IL-10 and IL-13.