Rurgo, Sara (2026) MODULATION OF THE MICROBIOTA–GUT BARRIER AXIS AND IMMUNOMETABOLIC PATHWAYS IN OBESITY: FROM ALIAMIDE-BASED PHARMACOLOGY TO MICROBIOTA-ENGINEERED THERAPEUTIC STRATEGIES. [Tesi di dottorato]

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Abstract

Obesity represents a major global health challenge, characterized by excessive adipose tissue accumulation and associated with metabolic, cardiovascular, and neurobehavioral disorders. Beyond the classical paradigm of energy imbalance, increasing evidence identifies the intestine as a central regulatory hub in the pathophysiology of obesity, where gut microbiota dysbiosis, epithelial barrier dysfunction, and altered neuroendocrine signaling converge to promote low-grade inflammation and metabolic impairment. High-fat diet (HFD)-induced dysbiosis disrupts intestinal homeostasis, leading to increased permeability, activation of innate immune pathways, and impairment of gut–brain axis communication. Within this complex network, intestinal regulatory systems—including the enteric nervous system (ENS), enteroendocrine cells (EECs), and lipid-derived mediators—play a key role in integrating nutritional, immune, and neural signals. Among these, N-acylethanolamides of the ALIAmide family have emerged as crucial modulators of inflammation, barrier integrity, and energy balance. In this context, the present doctoral thesis investigates integrated pharmacological and microbiota-based strategies aimed at restoring intestinal homeostasis and modulating ALIAmide signaling. First, the anti-inflammatory and barrier-protective effects of N-palmitoyl-D-glucosamine (PGA) were demonstrated in a murine model of intestinal inflammation, where PGA reduced disease severity and inhibited TLR-4/NLRP3/iNOS signaling through a PPAR-α-dependent mechanism. Second, Adelmidrol administration was shown to enhance endogenous palmitoylethanolamide (PEA) levels in the intestine, supporting a novel strategy based on the modulation of ALIAmide tone through PPAR-γ-independent pathways. Third, a microbiota-based biotechnological approach was developed using an engineered strain of Lactobacillus paracasei F19 capable of producing oleoylethanolamide (OEA) in situ. This strategy improved metabolic and behavioral alterations in HFD-induced obesity, restoring intestinal barrier integrity, modulating microbiota composition, and reinforcing gut–brain axis communication. Finally, a comprehensive review of ALIAmides highlights their multi-target therapeutic potential in metabolic syndrome, emphasizing their ability to modulate inflammation, lipid metabolism, and intestinal signaling networks. Collectively, these findings support a novel integrative framework in which the modulation of intestinal homeostasis—through both pharmacological compounds and engineered microbial systems—emerges as a promising multi-target strategy for the prevention and treatment of obesity and its associated metabolic and neurobehavioral disorders.

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