The Gut-Brain Axis

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Abstract

The concept of the gut-brain axis (GBA) has existed for more than 3 decades [1]. Gastrointestinal motor and sensory components send messages to the central nervous system (CNS), and the return response to the intestine is the definition of the GBA [2]. Nutrition affects microbiota colonization and gut metabolites, which can influence brain development and function through neural, immunological, and endocrine pathways [3]. The brain is the central component of the GBA and includes connections between the cerebral cortex, the limbic system, the hypothalamic-pituitary axis, and the brain system. The limbic system receives input from other brain regions including the hippocampus, which is responsible for a range of behaviors [4]. The peripheral components of the GBA communicate with the CNS through the enteric, autonomic, and sympathetic nervous systems [5, 6]. The enteric nervous system, which resides within the intestinal wall, communicates with the brain via the vagus nerve, dorsal root, and nodose ganglia [5]. The hypothalamicpituitary axis, the autonomic nervous system, and the sympathetic nervous system are integrated peripheral components of the GBA [7]. The afferent vagus nerve is a major retrograde signaling system from the gut to the brain [8]. The efferent vagus nerve-based cholinergic anti-inflammatory pathway regulates the balance between tumor necrosis factor-α and other cytokines secreted by macrophages in response to stress signals in the gut [9]. This inflammation can result in the loss of intestinal epithelial barrier function, which allows bacterial invasion. Bacterial invasion leads to an increase in intestinal permeability and activation of immune and somatic cells through pathogen-associated molecular patterns including lipopolysaccharides (LPS, endotoxin), which are recognition receptors that trigger inflammation in the gut [6]. Signals sent through the systemic and intestinal immune system via the GBA cause alterations in brain function and disease. During a state of stress, hormone and neuropeptide secretion in the gut ultimately invokes cortisol release from the adrenal gland via signals though the hypothalamus. The GBA influences intestinal immune cells via norepinephrine and neuropeptide messengers, such as vasoactive intestinal peptide, and these modulate the function of dendritic cells and T cells located throughout the wall of the intestine and in secondary lymphoid tissues, such as Peyer’s patches. Regarding the gut microbiome, the ability of the immune system to modulate brain development has been recognized [3], and researchers have proposed a critical window for intestinal microbes to influence developmental programming of long-lasting brain function. Interest-