Pharmacological modulation of the gut microbiota and epithelial barrier: new therapeutic perspectives in obesity

Obesity represents one of the major health challenges of the twenty-first century, having reached epidemic proportions and profoundly impacting both health and the global economy. It is characterized by excessive adipose tissue (AT) accumulation and constitutes a risk factor for the development of metabolic syndrome, cardiovascular diseases, and neuropsychiatric disorders. Its etiology is multifactorial, but the westernized environment, characterized by easily accessible high-calorie foods and sedentary lifestyles, represents a major contributor to the chronic imbalance between energy intake and expenditure that underlies it. Chronic exposure to high-fat diets (HFD) induces gut dysbiosis, characterized by a loss of intestinal microbiota diversity and low-grade inflammation, which compromises epithelial barrier integrity and promotes the so-called “leaky gut syndrome.” These alterations disrupt neuroepithelial circuits responsible for maintaining energy homeostasis along the gut-brain axis. In this context, the enteroendocrine system plays a pivotal role, as hormones such as leptin, insulin, ghrelin, and peptide YY (PYY) regulate appetite and energy metabolism. However, their secretion and sensitivity are influenced by dysbiosis and impaired intestinal barrier function. The coordinated disruption of microbial, metabolic, and endocrine pathways, therefore, contributes to the onset and maintenance of the obese state. Therefore, the increasing global prevalence of obesity has underscored the urgent need for novel therapeutic strategies. In this framework, the present doctoral thesis explored innovative probiotic approaches capable of modulating the intestinal microbiota and neuroendocrine signaling to counteract metabolic and behavioral dysfunctions associated with obesity. In the first study, an engineered strain of Lactobacillus paracasei F19 was developed to produce in situ oleoylethanolamide (OEA), an endogenous lipid with anorexigenic and anti-inflammatory properties. This approach improved metabolic and behavioral profiles in HFD-fed mice, preserving barrier function and gut-brain axis communication. In the second study, attention was focused on the human intestinal bacterium Phascolarctobacterium faecium, whose administration reduced caloric intake by stimulating early PYY secretion and limiting adiposity, in part by enhancing intestinal transit and lowering lipid absorption. Overall, these results demonstrate that the use of gut bacteria, either native or engineered, can selectively modulate host physiology by influencing the secretion of metabolites and hormones involved in appetite regulation, metabolism, and energy homeostasis. This opens new perspectives for the development of innovative probiotic strategies in the prevention and treatment of obesity and its associated metabolic and neurobehavioral complications.