Obesity is a non-communicable and multifactorial disease that may have a genetic component. However, the main causes of obesity are related to poor eating habits including consumption of high amounts of saturated fat and sugar and a sedentary lifestyle. These habits can lead to pathologies associated to obesity such as overweight, hypertension and type 2 diabetes, increased cholesterol, heart and liver diseases and an increased risk of suffering some types of cancer. Furthermore, changes in the composition of the intestinal microbiota, largely defined by diet, can cause differences in nutrients bioavailability and even in their metabolization, affecting the metabolic state of the individual.
Obesity leads to an increase in the basal inflammatory state due to the consumption of saturated fat. This brings the breaking of the “tight junctions” that maintain the integrity of the intestinal barrier, allowing components of the diet or the lipopolysaccharide (LPS) of the bacterial wall to reach the bloodstream, causing the activation of the immune system. In this sense, inflammation is a protective mechanism of the body that involves lipid mediators synthesis, generically called oxylipins (OXLs). OXLs can be pro-inflammatory, anti-inflammatory or pro-resolving in nature. When an inflammatory process begins, the predominant OXLs are those derived from arachidonic acid (ARA) giving rise to leukotrienes (LTs), thromboxanes (TXs) and prostaglandins (PGs). However, once an inflammation threshold is reached, lipoxins (LXs) are synthesized from LTs, which have a pro-resolutive role. Furthermore, the human body can synthesize anti-inflammatory OXLs (resolvins, maresins, protectins and lipoxins) from dietary omega-3 acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). For this reason, in an obesogenic context, there is a higher basal inflammatory state than in a non-obese individual.
In this context, we have carried out a study in 8-week-old male Wistar rats, fed a standard diet or cafeteria diet (CAF), which better simulates the high-fat and high-sugar diet in humans in comparison with a commercial pellet for 5 weeks. Four experimental groups were established, two groups were fed the standard diets and another two groups fed the CAF. Besides, one of each group mentioned received a cocktail of antibiotics (ABX) during the last two weeks to generate a dysbiosis of the microbiota. After this time, saphenous vein blood samples were taken for the metabolomic study of circulating lipid mediators and stool samples for intestinal microbiota determination.
The model was validated by evaluating body weight gain and an oral glucose tolerance test, observing significant differences between both diets. The diversity of the microbiota was lower in those groups treated with ABX, regardless to diet. It was observed that both treatments with ABX and diet caused changes in the composition of microbiota, where ABX was the most relevant parameter. The Principal Component Analysis (PCA) study evaluates the OXLs profile that each animal shows with respect to 64 OXLs studied by metabolomics. This parameter showed a clear difference in the OXLs profile according to the diet. Correlations were made to know if there was a relationship between the composition of the microbiota and the presence of certain OXLs in blood, and it was concluded that there is a clear relationship between the changes in the microbiota and the profile of these OXLs in blood, which may explain the remarkable role of the microbiota in the inflammatory process. Furthermore, these findings may lead to the development of new obesity markers based on the OXLs profile associated with a microbiota profile. However, more studies are necessary to establish the specific action mechanisms responsible of this association.
Empagliflozin Improves Metabolic and Hepatic Outcomes in a Non-Diabetic Obese Biopsy-Proven Mouse Model of Advanced NASH
