We have discussed how a bacterial metabolite called lipopolysaccharide (LPS) can enter the bloodstream and stimulate the immune system, causing inflammation in the body. This inflammation can lead to damage to the blood-brain barrier (BBB) and result in mental health issues like depression and anxiety.
LPS and Blood Brain Barrier
Now, let’s explore how LPS enters the bloodstream and what dietary factors we should be aware of. Our gut contains various types of microbes, including beneficial, pathogenic, and commensal bacteria. When these microbial populations are balanced, they don’t negatively affect our health. However, there is a specific type of bacteria, such as Escherichia coli (E. coli), which is a Gram-negative bacterium, meaning it has a cell wall with LPS as a component. They generate a significant amount of LPS, which is considered an endotoxin.
Numerous studies have confirmed that LPS can stimulate immune cells through specific receptors (TLR receptors), triggering the release of various inflammatory cytokines like TNF-α, IL-1β, and IL-6. [1]
When LPS enters the bloodstream and circulates throughout the body, it can harm the blood-brain barrier, allowing substances that shouldn’t enter the central nervous system to do so, leading to mental health problems. These substances don’t necessarily have to be bacteria or foreign substances; even certain molecules produced by our own body can cause issues when they enter the central nervous system.
Let’s consider an example to understand this better: Over 80% of serotonin in the human body is produced in the gut. However, serotonin cannot pass through a healthy blood-brain barrier, so it remains within the brain, where it functions as a neurotransmitter. If serotonin from the bloodstream, due to a compromised blood-brain barrier, enters the central nervous system, it can disrupt the balance of neurotransmitters, potentially causing mental health issues. Another neurotransmitter, glutamate, which is present in various organs, including the brain, is also tightly regulated by a healthy blood-brain barrier. Excessive glutamate can act as a neurotoxin, so if it enters the central nervous system due to a compromised BBB, it can lead to various mental health problems. Hence, LPS might be one of the root causes, or at least a contributing factor, to mental health issues.
How LPS Enters Systemic Circulation
Now, let’s talk about one of the key factors that allow LPS to enter the bloodstream: Leaky gut. Leaky gut refers to an increased permeability of the intestinal lining, which allows substances that should not normally pass through the gut wall to enter the bloodstream. However, the details of why leaky gut occurs would require another explanation; in this article, we will focus on another factor more directly related to diet – a high-fat diet.
Chylomicrons, a type of lipoprotein, can carry LPS from the intestines into the bloodstream. Chylomicrons are responsible for transporting triglycerides from the intestines to the circulatory system.
When we consume fat and oil in our diet, the cells lining our intestines absorb these fats and oils and convert them into triglycerides and cholesterol, which are then packaged into chylomicrons in the Golgi complex of the cell. These chylomicrons are then released into the lymphatic system and the bloodstream. Since LPS has a high affinity for chylomicrons, any LPS already internalized by intestinal cells can attach to chylomicrons and be released into the bloodstream alongside them. Although this interaction with chylomicrons may reduce the toxicity of LPS and facilitate its metabolism and clearance by the liver, excessive LPS attached to chylomicrons in the bloodstream can still stimulate immune cells, leading to the release of inflammatory cytokines and causing systemic inflammation. Research has shown that even in the absence of leaky gut, long-chain fatty acids in the diet can increase LPS in the bloodstream through their association with chylomicrons. [2]
High-fat Diet Causes Increase of LPS in Our Blood
Several studies have provided insights into the connection between a high-fat diet and increased levels of LPS in the bloodstream. In one clinical study, obese participants were given a high-fat meal, and within three hours, the levels of LPS in their blood significantly increased. This increase in LPS was positively correlated with the increase in triglycerides in the blood, but not significantly related to blood glucose or insulin resistance.[3]
Another randomized crossover trial found that when participants consumed foods with a higher content of palmitic acid (a saturated fatty acid commonly found in animal fats), the inflammatory cytokines (TNF-α) induced by LPS increased, leading to inflammation. On the other hand, foods with higher oleic acid content (a monounsaturated fatty acid commonly found in olive oil) resulted in a decrease in inflammatory cytokines. Therefore, this research suggests that consuming olive oil, which is rich in oleic acid, may not increase LPS levels in the bloodstream, whereas saturated fats can raise LPS levels [4].
Additionally, another small-scale randomized crossover trial in women found that consuming foods high in saturated fats increased the inflammatory cytokines induced by LPS (IL-18, IL-1β). Interestingly, MRI scans of the participants’ brains after consuming high-saturated-fat meals showed changes in brain activity when engaged in tasks requiring short-term memory. The researchers speculated that the brain might be experiencing inflammation due to the impact of LPS-induced cytokines. However, when saturated fats were replaced with oleic acid-rich fats, the brain activity returned to normal [5].
Summary
LPS entering the bloodstream from the gut can trigger an immune response, leading to organ and systemic inflammation.
This inflammation can damage the blood-brain barrier, allowing substances that should not enter the central nervous system to do so, resulting in brain inflammation and various mental health issues, including depression and anxiety.
Dietary fats, particularly saturated fats, play a key role in this process. Reducing the intake of dietary fats, especially saturated fats, can help reduce inflammation and is an important factor in improving symptoms of depression and anxiety.
References:
[1] Panaro, Maria Antonietta et al. (2010). Toll-like Receptor 4 Mediates LPS-Induced Release of Nitric Oxide and Tumor Necrosis Factor-α by Embryonal Cardiomyocytes: Biological Significance and Clinical Implications in Human Pathology. Current pharmaceutical design. 16. 766-74. 10.2174/138161210790883624.
[2] Ghoshal, Sarbani et al. (2008). Chylomicrons promote intestinal absorption of lipopolysaccharides. Journal of lipid research. 50. 90-7. 10.1194/jlr.M800156-JLR200.
[3] Clemente-Postigo, M et al. (2012). Endotoxin increase after fat overload is related to postprandial hypertriglyceridemia in morbidly obese patients. Journal of lipid research. 53. 973-8. 10.1194/jlr.P020909.
[4] Kien, C. et al. (2015). Lipidomic evidence that lowering the typical dietary palmitate to oleate ratio in humans decreases the leukocyte production of proinflammatory cytokines and muscle expression of redox-sensitive genes. The Journal of nutritional biochemistry, 26, 1599-1606. doi: 10.1016/j.jnutbio.2015.07.014
[5] Dumas, Julie et al. (2016). Dietary saturated fat and monounsaturated fat have reversible effects on brain function and the secretion of pro-inflammatory cytokines in young women. Metabolism. 65. 10.1016/j.metabol.2016.08.003.
