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A key circuitry in this communicatome is provided by efferent vagus nerve fibers and cholinergic signaling. Inflammation and metabolic alterations coexist in many disorders affecting the liver and the gastrointestinal (GI) tract, including obesity, metabolic syndrome, fatty liver disease, liver injury, and liver failure, as well as inflammatory bowel disease. Here, we outline mechanistic insights regarding the role of the vagus nerve and cholinergic signaling in the regulation of inflammation linked to metabolic derangements and the pathogenesis of these disorders in preclinical settings. 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