Plastic Changes of the Second Brain of the Human Body

Dr. Roberto De Giorgio. Dipartmento di Medicina Clinica / Malattie dell'Apparato Digerente e Medicina Interna, Università di Bologna e Policlinico S.Orsola-Malpighi, Bologna, Italy

Years of research have shed lights on the evidence that the human body has a second brain in the gut. How is that possible ? Is the mere gut provided with a such a highly organized network such as that of a brain with myriads of neuronal pathways and related synapses ? The explanation to those questions comes from both experimental and clinical evidence.

The research level: the brain-in-the-gut and the enteric microenvironment. The function of the gastrointestinal tract is controlled by a dynamic interaction between different cell types that interact either directly or through a large number of signaling molecules. Enteric neural integrity is essential for normal gastrointestinal motility, as is a constant communication between the enteric and the central nervous system. Enteric neurons (organized in the enteric nervous system, ENS, the actual brain-in-the-gut) are classified into functionally distinct classes including intrinsic primary afferent neurons (IPANs), interneurons, motor neurons, and intestinofugal neurons. A fourth class of enteric neurons, intestinofugal afferent neurons (IFANs), have their cell bodies within the myenteric plexus but send their processes out of the gut wall. Smooth muscle cells form an electrical syncytium within the gut and are innervated, directly or indirectly through interstitial cells of Cajal (ICC) by neurons. Not only are smooth muscle cells the final effector cells that result in gastrointestinal motility, they also have an active role in the control of motility through mechanosensitive ion channels. The basic electrical rhythm of the gut, the slow wave, originates from a complex network of ICCs which generate and propagate the slow wave, control the membrane potential gradient of the smooth muscle, are mechanosensors and are required for cholinergic and nitrergic neurotransmission. Other cellular elements, e.g. the immune system and enteric glia, are now increasingly understood to be actively involved in the modulation of intestinal function. In summary, complex interactions between these cell types result in an effective coordination of motility, secretion and blood flow in the gastrointestinal tract. Much progress has been made in recent years on the understanding of these complex interacting networks. Loss of subsets of enteric nerves, of ICC, malfunction of smooth muscle and alteration in immune cells have been identified as the basis of many gastrointestinal (functional) disorders.

The clinical scenario: the brain-in-the-gut (and related cells) gets sick. Functional gastrointestinal disorders are highly prevalent conditions affecting about 30-40% of the general population in Western Countries. These disorders are characterized by symptoms suggestive of upper or lower gut impairment not associated with detectable structural and/or biochemical alterations. Most of these patients usually experience mild-to-moderate symptoms, whereas, in few cases the functional impairment of digestive function is so important to markedly compromise the patient quality of life in severe gut dysmotility observable in achalasia, gastroparesis, intestinal pseudo-obstruction and (slow transit) constipation. Disturbances of digestive motility are the result of several abnormalities affecting, alone or in combination, the main control systems present in the enteric microenvironment i.e. smooth muscle layer, ICCs, and the innervation supplying the gastrointestinal tract, either extrinsic or intrinsic (i.e the ENS). Any noxa/damage to the ENS circuitries may result in neuropathies leading to digestive disorders.

Enteric neuropathies are characterized by a progressive impairment of the integrity and function of the ENS leading to abnormalities of gastrointestinal function, including motility. Although rare, enteric neuropathies are of primary importance for gastroenterologists and clinicians in general because they markedly affect the patient quality of life and they may be so severe to threat the life of affected patients. A better understanding of the pathophysiological mechanisms underlying enteric neuropathies is pivotal to develop effective and targeted therapeutic strategies.