Obesity is increasingly recognized as a disorder of bidirectional communication among the gut microbiota, immune system, and neural circuits controlling energy balance and feeding behavior. This review examines the associations and potential mechanistic links between obesity-associated dysbiosis, chronic low-grade inflammation, and impaired appetite regulation through interconnected peripheral and central pathways. We discuss how these signals reach the central nervous system (CNS), and promote microglial and astrocytic activation, impair leptin and insulin signaling, and disrupt hypothalamic POMC and AgRP/NPY neuronal networks. We also examine how microbial metabolites and structural components influence appetite through enteroendocrine hormones, vagal afferents, blood-brain barrier (BBB) integrity, and direct actions on neural and glial cells. Particular emphasis is placed on short-chain fatty acids, tryptophan-derived metabolites, bile acids, and lipopolysaccharide, as well as their effects on glucagon-like peptide-1 (GLP-1), peptide YY (PYY), serotonergic signaling, and mesolimbic reward pathways. Together, these findings support a bidirectional framework in which diet, microbiota function, immune signaling, and neural regulation may reinforce one another during obesity progression. However, the directionality and causal relevance of many of these relationships, particularly in humans, remain incompletely understood. Clarifying these microbiota-gut-brain interactions may identify new targets for restoring appetite control and interrupting obesity progression.
