The Gut–Liver–Brain Axis: From Head to Feet

Dear Colleagues,

The gastrointestinal tract digests and absorbs food and forms a barrier against harmful agents, but it also is an immune–hormonal system, regulated by an intrinsic network of neuronal ganglia known as the enteric nervous system (ENS). In 2013, the National Institute of Mental Health launched a project focused on exploring the mechanism involved in gut–brain communication; however, the exact mechanisms by which the gut and brain communicate and influence each other are not fully understood.

The ENS provides motor excitatory neurons, which innervate muscle layers, secretory glands, and the lymphatic vascular system. The ENS forms a complete sensory–motor reflex composed of intrinsic primary afferent neurons, interneurons, and motor neurons, differentiated by the expression of neuropeptides. The ENS also features enteroglial cells (EGCs). These produce specific proteins, such as glial fibrillar acid protein (GFAP), vimentin, and S-100, and show receptors for cytokines, neuropeptides, and neurotrophins. The critical interactive communications between the gut and brain are the sympathetic system and the vagus nervus (VN) of the autonomic nervous system, while the site of interactive communication occurs in the spinal cord, proceeding through the tractus solitaires nucleus in the brain stem and the dorsal motor nucleus of VN. The afferent fibers ascend towards the thalamus, enter the gracile nucleus and cuneate nucleus, and project to the thalamus through the lemniscus medialis. These fibers arrive diffusively in the lobus limbicus, which is the insular cortex, through the parabrachial nucleus. Interestingly enough, the VN does not directly interact with the gut luminal content but is indirectly involved in its absorption process through entero-endocrine cells in the gut epithelium; neural communications arrive directly into the brain through glutamatergic transmission. VN fibers are enriched with receptors such as 5-HT3, Toll-like receptor 4, and free fatty acid receptors, and their final projections end in the brain. Substance P (SP), neurokinin A, and neurokinin B are neuromodulators of tachykinin, and the action of SP on neurotransmission occurs in the non-adrenergic/non-cholinergic system, which is directly involved in the perception of painful stimuli. The vasoactive intestinal peptide (VIP) induces vasodilation and modulates mucin secretion and participates in the relaxation of intestinal smooth muscles and modulates functions of the lymphocyte component of the immune system. Cholecystokinin (CCK) is a major mediator of gastrointestinal feedback to the central nervous system through the afferent component of the VN. Histamine and serotonin modulate the function of a variety of intestinal cells, including neurons, EGCs, muscle cells, and the immune system. Somatostatin, which lies behind the regulation of the growth of intestinal cells, inhibits the secretion of gastrin, insulin, glucagon, and cytokines. The liver by itself has been widely related to the brai, through the indirect accumulation of ammonium in so-called hepatic encephalopathy. Nevertheless, more recent data involve the specific medical condition of non-alcoholic fatty liver disease (NAFLD) in a direct general status-related condition. NAFLD is associated with high cardiovascular morbidity and mortality, which is usually considered to be related to cardiac involvement, asymptomatic brain lesions, alterations in cerebral perfusion and activity, cognitive impairment, and brain aging, with increased risk and severity of both ischemic and hemorrhagic stroke. Besides known metabolic risk factors, NAFLD is characterized by a pro-inflammatory state, which contributes to atherosclerosis and microglia activation, endothelial dysfunction, pro-coagulant state, and platelets activation, which, in turn, promote both micro and macrovascular damage. This Special Issue aims to expand knowledge and current findings regarding the inter-relationships between ENS, microbiota, liver, and brain, expanding the modern triad-axis to the entire body system.

Prof. Dr. Rita Moretti
Dr. Mauro Giuffrè
Guest Editors

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