The Brain-Gut Axis and the Gender

The term brain-gut axis depicts an anatomic and functional substrate in which the brain and psychosocial factors influence the GI tract and vice versa. The hardwiring between the brain and gut is mainly, but not solely, represented by a complex integrated circuitry that exchanges information from emotional and cognitive centers of the brain to the peripheral functioning of the GI tract and vice versa [1]. This communication is mainly based on a dense network of neurons connecting the brain and the gut, composed by afferent and efferent components and functioning via the exchange of neurochemical molecules released at the level of neuronal synapses, namely, neurotransmitters. Structurally, there are direct connections between the central nervous system (CNS) and the myenteric plexus, the muscle layers, and other end-organ structures [2]. Other systems take part in the complex process of communication in the brain-gut axis and include immune, endocrine, and microbial factors. The gut microenvironment of the gastrointestinal tract is a rich source of signals for the brain. The gut is particularly enriched with molecules derived from the microbiome (a complex microbial world composed by not only bacteria but also viruses and fungi), enteroendocrine cells (producing 95% of body’s serotonin among other hormonal substances), and a large bulk of immune cells, comprising the largest immune organ of the human body. These substances can communicate with the brain via different modalities. These include a direct signaling of immune, endocrine, and bacterial mediators on specific receptors located on sensory nerve ending conveying information to the brain. Examples of this communication include toll-like receptors located on enteric nerves and sensory afferent fibers sensing substances produced by bacteria (e.g., lipopolysaccharide), viruses, and fungi. Gut microenvironment substances can also communicate to the brain through the bloodstream reaching higher centers through the passage of the blood-brain barrier. This is the case for many food-derived substances but also for microbiota-derived molecules or products deriving from the bacterial fermentation of foods (e.g., short-chain fatty acids). The relevance of the bloodstream pathway and the constant production of gut-derived metabolites, particularly of bacterial origin, with a potential impact on the brain, is clearly revealed in patients with liver failure in whom the normal passage of numerous catabolites produced as a process of bacterial degradation of foods (particularly ammonia) reaches the brain without liver detoxification and generates hepatic encephalopathy of various degrees of severity up to coma. Interestingly, this severe brain dysfunction can be reversed by reducing intestinal bacterial load with laxatives (e.g., lactulose) and nonabsorbable antibiotics (e.g., rifaximin).