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We know from evolutionary history that life progressed from simple single-celled organisms to the complex eukaryotes that form the plant and animal worlds. From that perspective, it is clear that nervous systems must have evolved in the presence of microbes. Some investigators have even theorized that interactions of human ancestors with their colonizing microbes helped drive the evolution of the human brain in certain ways (Stilling et al., 2014). Within this context, it is not so surprising that the gut microbiome communicates with the brain and that each has a regulatory effect on the other.
Colonization of the gut by microbes begins at birth as the newborn is exposed during the birth process either to the mother’s vaginal microbiome (vaginal delivery) or her skin microbiome (delivery by cesarean section). Although the infant’s gut microbiome initially differs as a function of type of delivery, this difference gradually disappears. However, in adulthood the composition of the gut microbiome (i.e., relative numbers of different bacterial species) can be altered by diet (Wu et al., 2011), stress (Molina-Torres et al., 2019), and aerobic exercise (Dalton et al., 2019). Changes in the gut–brain axis, therefore, represent one of the means by which these factors can influence our mood and behavior.
Communication between the gut and the brain encompasses four domains: neural, immune, endocrine, and metabolic (Figure 1). The neural pathway involves the vagus nerve, an important component of the parasympathetic branch of the autonomic nervous system. The major portion of this nerve consists of afferent fibers innervating the intestinal wall, including cells of the enteric nervous system. These afferents possess chemoreceptors (chemical sensors) responsible for relaying information about the state of the gut (Bonaz et al., 2018). This sensory information is transmitted by the vagus nerve to the brainstem, where it is integrated with other physiological input to regulate the homeostatic state of the organism. The vagus nerve also contains efferent fibers that release ACh when activated (not shown in the figure). The released ACh has dual beneficial effects on the gut: it inhibits gut inflammation and it reduces permeability of the intestinal wall, thus preventing microbial toxins from leaking out of the intestine.
Figure 1 Communication pathways between the gut and the brain The gut–brain axis consists of neural, immune, endocrine, and metabolic (including neuroactive) pathways of bidirectional communication between the intestines and the brain. All of these pathways are influenced by intestinal microbiota (i.e., the gut microbiome), which highlights the importance of understanding the role of these microbes in mental health and disease. (After Cryan et al., 2020.)
Immune signaling within the gut–brain axis is mediated by the release of cytokines (signaling molecules of the immune system) into the bloodstream from immune cells located near the intestines. Like the vagus nerve, these immune cells are sensitive to substances released from intestinal microbes, thereby resulting in cytokine release. The cytokines not only feed back to the intestines but also, when they reach the brain, exert significant effects on mood and behavior. Indeed, the ability of cytokines to influence our mental state can be seen when we experience so-called sickness behaviors (e.g., feelings of fatigue, lack of motivation, and decreased appetite) in response to an infection.
Endocrine communication from the brain to the gut is mediated by cortisol, a hormone released from the adrenal gland in response to upstream activation by adrenocorticotropic hormone from the pituitary gland and corticotropin-releasing factor from the hypothalamus (see Section 3.3). Cortisol exerts multiple actions on immune cells (altering cytokine release), the intestinal wall (increasing intestinal permeability), and the gut microbes themselves (altering microbial populations). Since cortisol secretion is increased by stress, these represent major mechanisms by which acute and especially chronic stress can alter gut function and, thus, signaling within the gut–brain axis (Tetel et al., 2018). Endocrine communication from the gut to the brain is mediated by gut hormones secreted into the bloodstream by enteroendocrine cells located in the intestinal wall.
The figure additionally illustrates several pathways of metabolic signaling from the gut to the brain. One pathway consists of short-chain fatty acids and other microbial byproducts that diffuse into the bloodstream and subsequently reach the brain. A second metabolic pathway involves microbial metabolism of tryptophan, the amino acid precursor to the neurotransmitter 5-HT. Conversion of gut tryptophan to various circulating metabolites could affect the brain either indirectly by reducing tryptophan availability for 5-HT synthesis (see Chapter 6) or directly if any of these metabolites is neuroactive itself. Most interestingly, gut bacteria have been shown to synthesize a number of different neurotransmitters, including DA, NE, 5-HT, ACh, GABA, and histamine (Strandwitz, 2018). Upon entering the bloodstream, such transmitters or their metabolites could exert signaling effects at synapses in either the peripheral or central nervous system (listed in the figure as the “Neuroactive pathway”). Alternative, neurotransmitters could act locally to signal through pathways that connect the gut to the brain, such as the abovementioned vagus nerve.
Most of the research that has (1) conclusively demonstrated communication between the gut and the brain and (2) elucidated the mechanisms underlying such communication has been performed using experimental animal models (for details, see Cryan and Dinan, 2012; Bastiaanssen et al., 2019). Nevertheless, many studies investigating the relevance of the gut–brain axis for human health and disease are currently under way. These studies fall within three main themes. The first theme is investigating a potential role for the gut–brain axis in neuropsychiatric disorders, such as depression (Kelly et al., 2019; Yang et al., 2020), schizophrenia (Kelly et al., 2020), attention-deficit/hyperactivity disorder (Dam et al., 2019; Mathee et al., 2020), autism spectrum disorder (Pulikkan et al., 2019; Cryan et al., 2020), and substance use disorders (Meckel and Kiraly, 2019). Also being investigated are neurological disorders like multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease (Cryan et al., 2020). The second theme is related to the first; that is, if a disordered gut may contribute to the development of neuropsychiatric disorders, perhaps there are bacteria-derived substances (sometimes called psychobiotics) that can help treat such disorders by improving the health of the gut microbiome (Sarkar et al., 2016; Smith et al., 2019). While such research is still in its infancy, there is sufficient promise that several startup companies have been formed specifically to develop psychobiotic medications. Third, psychopharmacologists have begun to recognize that many standard drugs used in clinical practice exert effects on the gut microbiome, which raises questions about whether any of the therapeutic or side effects of these medications can be traced to the gut–brain axis (Cussotto et al., 2019; Leprun and Clarke, 2019).
Finally, research on the gut–brain axis has shown us that even in health, it is important to take good care of our gut microbiome. Many people seek to accomplish this by regularly ingesting probiotics, live microorganisms (typically bacteria) that aim to maintain and/or restore a healthy population of gut microbiota. It is especially important to consume probiotics if you have been on a course of antibiotics to treat an infection, since antibiotics not only kill the targeted bacteria but also wreak havoc with your normal gut microbiome.
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