Depression and Anxiety: Understanding the Impact of Gut Microbiota and Inflammation

Modern medicine is highly specialized, and when it comes to conditions like depression and anxiety, it’s common knowledge to seek help from a psychiatrist or psychologist rather than a gastroenterologist. It doesn’t make sense to go to a digestive specialist for a problem in our head, right? It goes against what we generally understand. In this blog, I aim to share multiple research studies that explore the connection between “treating the head by treating the gut” and how dietary choices and nutritional supplements can alleviate symptoms of emotional issues.

Gut-brain-axis and Blood Brain Barrier

The communication between the gut and the central nervous system happens through various methods, and what occurs in the gut can have a significant impact on the central nervous system. Today, we will focus on one particular communication method known as the gut-brain axis, specifically involving immune cell cytokines.

Let’s start by examining an animal experiment that investigates the connection between diet and mental health. In a study conducted in 2016 [1], mice were fed a refined starch diet for 12 weeks, while another group of mice was fed a regular diet for comparison. The researchers found that even though the mice consuming the refined carbohydrate diet did not gain weight, they had a higher body fat percentage compared to the mice on the regular diet. In behavioral tests, the mice fed the high-carbohydrate diet displayed anxiety and depressive behaviors after experiencing stress. However, the researchers couldn’t determine precisely how the consumption of highly refined starch affected the mice’s anxiety and depressive behaviors.

In another animal experiment conducted in 2019 [2], mice were fed a high-fat diet. After 9 weeks, the mice had gained weight, and in behavioral tests, those consuming the high-fat diet displayed memory decline and anxiety-like behaviors. The researchers analyzed the mice and found a decrease in brain-derived neurotrophic factor (BDNF), an increase in lipopolysaccharide (LPS) in the bloodstream (which indicates increased inflammation), and significant differences in the gut microbiota compared to mice on a regular diet. To neutralize the immune system’s stimulation caused by LPS, the researchers injected LPS antibodies into the mice, which resulted in an improvement in anxiety-like behaviors. This study demonstrated that the impact of a high-fat diet on the mouse brain and anxiety-like behaviors was mediated through the alteration of gut microbiota, leading to an increase in LPS in the bloodstream.

Therefore, whether it’s a refined carbohydrate diet or a high-fat diet, both have an impact on mental health. From the studies mentioned above, it is evident that foods that stress the gut can potentially affect the gut microbiota, leading to an increase in lipopolysaccharides (LPS) in the circulatory system, which in turn stimulates the immune system. However, the central nervous system is highly guarded and not everything can penetrate it. The protective “gateway” of the central nervous system is called the blood-brain barrier, which consists of tightly connected cells, similar to the tight connections in the gut. Many substances in the bloodstream cannot pass through a healthy blood-brain barrier, except for nutrients and certain substances required by the central nervous system, such as lipid-soluble substances.

Lipopolysaccharides (LPS) are components of the cell walls of certain bacteria. The metabolism of bacteria in the human gut generates a significant amount of LPS. In cases of intestinal permeability, LPS can enter the circulatory system and travel to different organs and tissues of the body. As LPS is not a substance familiar to the human immune system, it can easily trigger an overactive immune response, leading to various issues. For instance, molecular mimicry occurs when certain cells in the body resemble substances that the immune system intends to attack. In such cases, the immune system not only attacks the intended target but also attacks the body’s own cells, resulting in autoimmune diseases.

In a study conducted in 2013 [3], mice were injected with LPS (derived from Escherichia coli), and it was observed that within 6 hours of LPS administration, the permeability of the blood-brain barrier continuously increased. This demonstrated that LPS can disrupt the blood-brain barrier and allow substances that shouldn’t normally enter the central nervous system to pass through. It’s worth mentioning that many individuals with sleep difficulties or bipolar disorder take a supplement called GABA, which promotes relaxation and aids in sleep. GABA is a neurotransmitter in the central nervous system and is naturally produced by the body. When taken in appropriate amounts, there are no safety concerns. However, most neurotransmitters in the central nervous system (whether administered orally or intravenously) cannot pass through a healthy blood-brain barrier. If you feel relaxed after taking GABA, it may indicate an issue with your blood-brain barrier. Functional medicine doctors in the United States propose the GABA Challenge as a simple method to assess the integrity of the blood-brain barrier. If you feel no effect after taking GABA, it suggests that your blood-brain barrier is intact. However, if you feel relaxed and drowsy after taking GABA, it may indicate a problem with your blood-brain barrier. I will discuss GABA and other neurotransmitters in a separate article in the future.

Similar findings to the aforementioned animal experiments have also been observed in clinical studies involving humans. In a double-blind, crossover clinical trial conducted in 2001 [4], 20 healthy participants underwent testing with Salmonella endotoxin (a bacterial metabolite similar to lipopolysaccharides). It was found that endotoxin stimulated the immune system to secrete inflammatory cytokines. Most of the participants’ overall health indicators remained unaffected (except for a rise in cortisol levels), but subsequent tests revealed significant memory decline, increased feelings of anxiety, and depressive symptoms. The researchers concluded that whether due to infection or autoimmune issues, even if sometimes subtle, immune system stimulation leading to the secretion of inflammatory cytokines can result in memory decline and mood-related health problems.

Therefore, a diet that is unfriendly to the gut microbiota can disrupt the balance of gut bacteria, leading to intestinal permeability (leaky gut). This allows bacterial endotoxins to enter the bloodstream, triggering immune cells to secrete inflammatory cytokines. The tight connections of the blood-brain barrier become compromised due to inflammation, resulting in the entry of substances into the central nervous system that shouldn’t be there. Various mental health issues can occur when the blood-brain barrier fails. This is one important pathway through which food influences mental health.

Summary

The gut-brain axis serves as a bidirectional channel of communication between the central nervous system and the digestive system. Diet impacts health through the gut-brain axis, and once lipopolysaccharides (LPS) in the gut enter the bloodstream, they stimulate the immune system, leading to systemic inflammation in the body. They also increase the permeability of the blood-brain barrier, causing brain inflammation. Ultimately, this can result in various mental health issues, including depression and anxiety.