Written by: Dr Ryan Cedarmark, DC, DACNB, RN, BSN, NP Student (Chief Resident, CHC)

Reviewed by: Dr. Brandon Brock, MSN, BSN, RN, NP-C, DCN, DCM, DAAIM, BCIM, DACNB, FICC

Structural content edited by: Tara Brock

Post 1: Do you have the guts to beat depression?


Neurologically speaking, depression is caused by decreased activation or decreased frequency of firing of the frontal lobe and the anterior cingulate gyrus. A good question to ask yourself is what is causing the decrease of activation of the frontal lobe? If the frontal lobe is responsible for beating depression, then why not just exercise your frontal lobe? From a functional neurological perspective, there are several pathways that can be exercised to increase frontal lobe activation. Why not just take anti-depressant medications or supplements to activate the frontal lobe? These may work if there is a true chemical imbalance leading to the cause. The literature shows that depression is a multimodal and very complex problem. The literature also shows that approximately 30-50% of patients that suffer from depression are not responsive to antidepressant management. It is difficult to pinpoint one specific causative factor when it comes to depression.

Keeping in mind that depression is multimodal and complex, I would like to focus on one area that is a contributing factor in the cause of depression: gut health. If you are depressed, a good question to ask yourself is how is my gut health? There is constant communication between the brain and the gut and the gut and the brain, which in this case can be a good and bad thing. If things go bad in the brain, things can go bad in the gut. If things go bad in the gut, things can go bad in the brain. Communication between the brain and the gut comes from the brainstem, specifically the vagal nuclei of the pons. Within the vagal nuclei are a bundle of nerve branches called vagal nerve branches. The front part of the brain communicates with the vagal nuclei to allow the vagal nerve branches to communicate with gut (the enteric nervous system). The cool thing about these vagal nerve branches is that they work in both directions. Messages from the brain can travel along these nerves to the gut and messages from the gut can travel to the brain. There are several different types of signals that travel along this communication pathway. The nerves can talk to the gut to increase gastrointestinal motility, they can tell the gut to release important enzymes, and they can also modulate the flow of blood within the gut.

It is important to note that if there is a decrease in communication between the brain and the gut, things can go awry. From a functional neurological perspective, decreased frequency of firing of this loop or axis will decrease the efficiency or neuronal plasticity, which can cause complications in both the brain and the gut. As mentioned above, the vagal nuclei by way of the vagal nerves activate gut motility and tell the enteric nervous system to release digestive enzymes. If the frontal lobe is not telling the brain stem to communicate with the gut, there will be decreased gut motility and decreased release of digestive enzymes. The combination of decreased digestive enzymes and decreased gut motility can lead to poor digestion. If food is not digested properly, large proteins can form in the gut. A problem with large proteins forming in the gut is that they can challenge the intestinal barrier. The intestinal barrier is set up in such a way that it will recognize and allow passage of different particles such as nutrients, ions and water while restricting foreign invaders and pathogens. Tight junctions within the epithelial lining of the intestines are responsible for this. When large proteins that are undigested challenge the lining of the small intestine, a break down in these tight junctions can occur, thus leading to an increase in the permeability of the intestinal barrier. This is known as “leaky gut.” The more these large proteins hang around, the less a person’s brain is able to activate the brain-gut loop, the greater the permeability in the small intestines will become. Remember, when you eat food, the brain should also tell the brainstem to then tell the intestines to increase blood flow. If there is decreased communication, there is decreased blood flow. So now we have decreased blood flow with decreased digestive enzymes and decreased intestinal motility. These compounding factors now really begin to increase the chances of creating leaky gut. When these large proteins squeeze their way through the tight junctions, the immune system recognizes them as foreign invaders. The recognition of foreign invaders creates an inflammatory response that only creates more disruption in the intestinal barrier.

Cytokine-mediated communication pathways from the immune system and the brain have been hypothesized to be involved in the development of depression. If the aforementioned scenario takes place in the gut, inflammation is bound to occur. The peripheral immune system will activate macrophages and neutrophils. Macrophages and neutrophils will release cytokines that send a signal to the central immune system. The central immune system is dominated by microglial cells. Upregulation of microglial cell activity and dysregulation between the peripheral and central immune systems has been thought to create biochemical changes associated with depression. In the peripheral immune response, cytokines are produced by the immune system’s ability to recognize pathogenassociated molecular patterns (PAMPs). Lipopolysaccarides (LPS) are a common endotoxic PAMP that are a component of bacterial cell walls (gram-negative bacteria to be exact). These LPS are recognized by pro- inflammatory cytokines such as IL-1alpha and IL-1beta which communicate and stimulate other pro-inflammatory cytokines such as TNF-alpha and IL-6 to participate in the immune response. It is important to note that cytokines are large molecules but they usually do not cross the blood-brain barrier (BBB). Our BBB is made to protect our brains from inflammatory markers in the periphery. If there is a will, there is a way. Cytokines have the ability to beat the system. Cytokines can cross the BBB in three different ways. One important pathway is afferent nerves from the periphery that are innervating the site of inflammation. These cytokines can hop a ride on the afferent pathway to the CNS. An interesting and postulating theory is that once arriving in the central nervous system, proinflammatory cytokines can stimulate indoleamine 2,3 dioxygenase (IDO), which is an enzyme associated with the conversion of tryptophan, an important amino acid for the production of serotonin (a very important neurotransmitter, which oddly enough has 90% of it’s production in the gut!!) to kynurenine which is then transformed into a neurotoxic acid (not good!) This neurotoxic acid (called quinolinic acid) binds to N-methyl-D-aspartate (NMDA) receptors while simultaneously depleting serotonin levels and increasing glutamatergic activity (hang tight for cellular excitotoxicity). If we do not stop for a few minutes to talk about the role of disruption of the NMDA receptor and it’s relationship to the energy-linked excitotoxic model of neurodegeneration, then this article will not be awesome. A process called mitochondrial oxidative phosphorylation helps make sufficient ATP at the cellular level. ATP is important in maintaining the health of what is called the transmembrane potential of a neuron. When all is good and healthy in the neurons environment, the NMDA receptor is plugged by a magnesium ion. Receptors known as alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid receptors (or AMPA) are usually surrounding the NMDA receptor (in a way, they are communicating to the NMDA receptors about the extracellular environment). These AMPA receptors tell the NMDA receptors to allow calcium into the cell (in a good way) to activate a gene response and to build proteins. Proteins go through the golgi apparatus in the cell to serve their purpose, create synapses and create neuroplasticity). This is important because when you have a healthy neuronal transmembrane potential, the AMPA receptors and the NMDA receptor will not allow excitatory cytokines or neurotransmitters to open the magnesium plug. This allows the cell to function in a healthy manner and to once again create neuroplasticity (from a functional neurology point of view, this is epigenetics). All is happy and all is well. Inflammation on the other hand can cause uncoupling of mitochondrial OxPhos. This in turn down-regulates the neuronal transmembrane potential, making it easier for excitatory neurotransmitters and cytokines to “convince” the NMDA receptor to release it’s magnesium plug and allow the influx of calcium into the body of the cell. From the incidence of infiltration of calcium comes a series of events that eventually leads to further mitochondrial destruction, decreased ATP production, changes in cellular membrane potentials and eventually cellular death.

This is a really important concept when understanding gut dysfunction and depression. To review, if gut dysfunction such as decreased motility, decreased blood flow, or decreased digestive enzyme production leaves large proteins in the gut that cause increased intestinal permeability and inflammation in the gut, there will be inflammation in the brain. If pro-inflammatory cytokines enter the brain (this is referred to as the cytokine model of depression) and create mitochondrial uncoupling leading to neuronal death, then peripheral (or gut) inflammation has successfully created central or brain inflammation. The inflammation in the brain can turn into a vicious cycle of continued cellular death, decreased neuronal cell signaling, decreased neuronal conduction and decreased functioning of the brain. Decreased functioning of the brain correlates to decreased frequency of firing. A decreased frequency of firing of the frontal lobe will not be able to communicate to the brainstem to tell the gut to function appropriately.

It is a vicious cycle, so where does one begin to fix depression? Based on the literature, looking into ways to heal the gut and reduce peripheral inflammation should allow central inflammation to begin to calm down. Combining this with appropriate frontal lobe exercises targeted at activating the vagal nuclei in the pontine area of the brainstem may in fact help relieve symptoms. Remember, this is just ONE of the many contributing factors that may be linked to inflammation and depression. In part 2 I would like to look into sugar dysregulation and it’s impact on peripheral and central inflammation leading to symptoms of depression.


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