Pathways of the Gut-Brain Axis

Dr. David Wiss

September 17, 2021

Gut Health

Most people understand the idea that what you eat affects how you feel. Less people, however, are aware of the bi-directional communication between their gut and brain, known as the “gut-brain axis”. In the past fifteen years, thousands of studies on the microbiome (the collective genome of all microorganisms living in us and on us) have led researchers to conclude that the gut should be considered a “second brain.” How is that even possible? What exactly is it? In this article, we dive into the various pathways and make connections to certain presentations of depression. 

Once upon a time, most people thought of bacteria primarily as threatening agents of infection, but evidence suggests many species are actually “friends with benefits” [1]. Several pounds of bacteria that live inside our gastrointestinal tract are sufficiently active enough to be considered a separate organ (albeit one invisible to the human eye). Fascinating right?

Bacteria are partially responsible for the established links between the gut and the brain, though other important pathways exist. The gut-brain axis is a bidirectional link between the central nervous system (which includes the brain and spinal cord) and the enteric nervous system (which governs the function of the gastrointestinal [GI] tract and is part of the autonomic nervous system). The gut-brain axis involves complex crosstalk across several systems:

Autonomic Nervous System (ANS)

The ANS includes a sympathetic arm (known for its role in “fight or flight”) and a parasympathetic arm (known for its role in “rest and digest”). The vagus nerve is the longest nerve in the ANS and the most direct route between the gut and the brain. It is involved in the parasympathetic arm via afferent (transmits impulses from peripheral organs to the central nervous system) and efferent (communicates the opposite way) signaling pathways, creating a complex bidirectional communication network along nerve cells.

The enteric nervous system governs the function of the GI tract and is part of the ANS. Scientific advances in our understanding of the enteric nervous system are partially responsible for the development of the term “second brain” around 2010.

Neuroendocrine System

The hypothalamic-pituitary-adrenal [HPA] axis coordinates adaptive responses against stress, including activation of memory and emotional centers in the brain, and finally impacting cortisol output from the adrenals (which sit right above the kidneys). This process feeds back into the brain to create an ongoing self-surveillance network important for various stress-related disorders (and may help explain stress eating).

Other neuroendocrine pathways include the production of neurotransmitters such as serotonin (via tryptophan metabolism) and dopamine (via tyrosine metabolism) by gut bacteria. Such neurotransmitters modulate processes in the brain and communicate with the other systems on the gut-brain axis. Investigators are exploring how such modulation can impact gut-brain axis diseases such as anxiety and depression [2]. This data has contributed to the emerging field of Nutritional Psychiatry. 

Immune System

Inflammatory mediators (such as cytokines, including interleukins and tumor necrosis factors) can become activated through processes that begin in the gut and eventually travel to the brain (in some cases leading to neuroinflammation). In the opposite direction, neuro-immuno-endocrine mediators allow the brain to influence intestinal function, creating a bottom-up and top-down bidirectional communication network. This has led to the development of a field called “psychoneuroimmunology,” which bridges gaps in various areas, including social science and nutrition, all linking back to the immune system [3–5].

It has become increasingly clear that inflammation is important for some presentations of depression. Using a lifestyle medicine approach based on the tenets of the Mediterranean Diet, one can begin eating more good-mood foods for depression, which helps by decreasing intestinal permeability and reducing the passing of inflammatory cytokines through the blood-brain barrier. This doesn’t happen overnight and could take several months of ongoing effort. 

Short-Chain Fatty Acids

The production of other metabolites (now referred to as “postbiotics” [6]) such as short-chain fatty acids (SCFAs) by colonic bacteria appear to have local effects such as the maintenance of intestinal barrier integrity and peripheral effects such as the production of hormones relayed to the brain [7]. SCFAs are the main products of anaerobic fermentation of indigestible polysaccharides such as dietary fiber and resistant starch (found in various whole grains, beans, nuts, seeds, and fruits and vegetables).  


According to many experts, diet is one of the most critical modifying factors of the microbiota-gut-brain axis [6,8,9]. Feeding time and dietary composition are primary drivers of gut microbiota structure and function, which have important implications for energy homeostasis [10]. The best fiber for gut health is soluble fiber which is one ingredient in the best diet for depression. The other ingredient may be omega-3 fatty acids.   

The gut-brain axis is involved in controlling food intake through various hormones related to hunger and satiety. Emerging data suggest that gut bacteria may also regulate the reward processes that underly various addictions [11]. This area of research along with the others mentioned above highlights the importance of the food we eat in our mental health, which is the focus here at Wise Mind Nutrition! Are you looking for a nutritionist for mental health symptoms?


Several systems connect the gut to the brain and the brain to the gut. These systems work alongside multiple communication networks that include non-human life forms (i.e., bacteria) that profoundly impact our health and health behaviors. There are growing numbers of individuals reporting gut-brain dysfunction, including an inability to assess hunger and fullness properly. Many components of the gut-brain can be altered through specific nutritional modalities. Since everyone is different, it is critical to determine which steps are indicated, beginning with a comprehensive assessment through the Wise Mind Nutrition program.

When you start paying attention to your eating habits and gradually increase fiber intake (both soluble and insoluble fiber), there are many evidence-based health benefits such as reducing symptoms of depression. The mechanisms are along the various bidirectional pathways linking the gut and brain. While more research is needed to unpack additional pathways, the evidence is strong enough to support integrated nutrition into the current health care model.  


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