Mechanisms along the gut-brain axis

The gut-brain axis is a bidirectional communication network between the central nervous system (CNS) and the enteric nervous system, linking emotional and cognitive centers of the brain with peripheral intestinal functions. Both neural and hormonal routes of communication allow the brain to influence intestinal activities, including activity of functional effector cells (i.e., immune cells, epithelial cells, enteric neurons, smooth muscle cells, interstitial cells, etc.). Simultaneously, these cells are under the direct influence of the gut microbiota,¹ leading some to refer to the network by the longer name “microbiota-gut-brain axis.” 

As these immune, endocrine, and neural pathways are increasingly detailed in the medical literature, linkages are being established between emotional and cognitive centers of the brain and peripheral intestinal functions, modulated by the gut microbiota.² Evidence now makes clear that psychological state (e.g., stress) directly affects the composition of the gut microbiota and, conversely, that the microbiota is involved in controlling mood-related behaviors.^3-7 

Mechanisms of the gut-brain axis

The following provides a summary of some of the more widely acknowledged mechanisms facilitating this bidirectional communication. 

“Emotional Motor System” 

Evidence now makes clear that psychological state (e.g., stress) directly affects the composition of the gut microbiota and, conversely, that the microbiota is involved in controlling mood-related behaviors.^3-7

The concept of emotional influence over bodily functions was suggested by Holstege in 1996 as a way to explain seemingly connected phenomena, such as emotion-associated immune changes in the gut.⁸ According to this model, several systems operate in parallel to mediate the effect of emotional states on bodily systems, including the autonomic nervous system (ANS) (sympathetic and parasympathetic branches), HPA axis, and various pain pathways. Consider the role of the ANS in controlling GI mucus secretion. This mucus layer is a habitat where the majority of the enteric microbiota reside within the secreted matrix of biofilm, and under periods of increased stress, mucus secretion is reduced.⁹ The ANS also influences immune activation in the gut, for example by directly modulating macrophage and mast cell responses to luminal bacteria. In the other direction, the intestinal microbiota is necessary for normal excitability of gut sensory neurons and are a likely mechanism for information transfer to the nervous system.¹⁰ 

Stimulation of signaling molecules 

Gut microbes communicate with each other through a system known as quorum sensing, a chemical signaling dictated by cell-population density. The microbiota is also able to sense chemical signals directly from nearby gut epithelial cells and immune cells called enterochromaffin cells that line the gut lumen and secrete signaling molecules including cytokines, catecholamines, serotonin, and opioid peptides. Research suggests enterochromaffin cells, which are activated by the vagus nerve, play a critical role in GI regulation, especially intestinal motility and secretion. The CNS also plays a major role in stimulating and governing the release of these molecules. Serotonin secretion into the stomach lumen, for example, is modulated, at least in part, by a thyrotropin-releasing hormone, a central mediator of the stress response to cold temperatures.^11,12 Both norepinephrine and dynorphins are thought to be released into the gut lumen when gut homeostasis is disrupted.¹³

Epithelial barrier function

Although long suspected, recent research now confirms that periods of increased emotional or physical stress leads to increased permeability of the intestinal epithelium. Mechanisms that control the degree of resultant permeability are complex and likely influenced by a combination of genetic and environmentally-led factors. Sometimes referred to as “Leaky Gut,” this alteration in the gut barrier allows bacterial antigens and lipopolysaccharides to leak into the circulation and stimulate immune responses in the intestinal mucosa and beyond.^14-18 In a study assessing stress-related changes in colonocytes, acute stress induced a three-day delayed increase in colonic paracellular permeability and colonocyte differentiation was reduced.¹⁹ Resultant intestinal permeability is thought to influence systemic inflammation metabolism often seen in times of stress and mood disruption.²⁰

Inflammation metabolism

People experiencing low mood frequently exhibit increased expression of proinflammatory cytokines, such as IL-1β, IL-6, TNF-α, as well as interferon gamma (IFN-γ), and C-reactive protein (CRP).^21-23 Mood and inflammation metabolism may be linked due to alterations in neurotransmitter metabolism that reduce the availability of neurotransmitter precursors and, as a result, activate the HPA axis.²⁴ Intestinal permeability is thought to be a cause for this change in inflammation metabolism. In addition, gut-derived endotoxins called lipopolysaccharides (LPS), which originate from the outer membranes of gram-negative bacteria, trigger immune activation through toll-like receptor 4 (TLR4).²⁵ Optimizing gut permeability and inflammation metabolism of this origin may thus promote healthy HPA axis and neurotransmitter activity.

The serotonergic system

Interestingly, and likely not coincidentally in the context of this subject, serotonin plays important roles in both the CNS and GI tract. In the CNS, serotonin regulates stress and emotions, appetite, and sleep. In the GI tract, this chemical modulates intestinal secretions and gastrointestinal motility, among other critical functions. New research now demonstrates serotonin as a clear link between brain and gut, where changes to the gut microbiome have been shown to profoundly influence the release of serotonin in both the peripheral and central nervous systems. It is hypothesized that beneficial bacteria in the GI tract support mood by increasing production of free tryptophan, and in turn increasing serotonin availability.²⁴ In this way, serotonin is itself a bidirectional communicator within the gut-brain axis. As a related note, probiotic supplementation may then be a way to support CNS function by increasing production of free tryptophan, and in turn, increasing serotonin availability.^† 

Given all that we currently understand about the microbiota-gut-brain axis, many questions remain about how bacteria signal the brain. We currently lack a definitively demonstrated microbiome-endocrine-based mechanism that can account for the influence of gut microbiota on behavior. These questions and others are all yet to be answered through current and future research.