Microbiota, Depression, and Anxiety: What's the Connection?

The field of intestinal microbiota is currently the focus of the most fascinating scientific investigations, as the systemic implications of our intestinal ecosystem are highly significant and diverse, encompassing the brain and the entire neurobehavioral system.

The idea that what happens in the gut stays in the gut is a thing of the past. There are more microorganisms in our gut than human cells in the entire body. It is estimated that we have 100 trillion bacteria for every 10 trillion cells throughout the human body.

This collection of microbes plays a fundamental role in maintaining health through various mechanisms. We will discuss the interaction of the microbiota with the brain – the so-called gut-brain axis – and its contribution to neuropsychiatric symptoms such as anxiety and depression.

Is there evidence to suggest an association between neuropsychiatric disorders and the microbiota?

Several studies demonstrate an effect of gut flora on depression and anxiety, including some that analyzed microbiota-modulating interventions, such as prebiotics and probiotics.

In a particularly interesting study published in 2016, researchers decided to transplant fecal matter from 34 depressed patients into mice. (1) The study included a control arm where fecal transplants were performed from healthy donors. Subsequently, analysis of the mice that had received transplants from depressed donors revealed depressive behaviors, such as anhedonia (lack of pleasure) and increased anxiety. The mice in the control group did not exhibit significant changes in their behavior. This is an animal study, which should never be considered the best scientific evidence, but it is nonetheless fascinating.

Separately, a retrospective study in the United Kingdom sought to relate diagnoses of depression and anxiety with antibiotic prescriptions in the previous year. (2) The objective was to determine whether individuals who took antibiotics would be more likely to be diagnosed with one of the aforementioned disorders. The sample collected was quite substantial (approximately 200,000 patients with depression and 15,000 with anxiety). It was concluded that antibiotic intake contributed to a 25% increased risk of depression diagnosis and a 17% increased risk for anxiety. Repeated courses of antibiotics further increased the risk (up to 50%). As antibiotic use is a disruptive factor for the microbiota, this association suggests a relationship between the variables, although it cannot establish causality.

We can think of the microbiota as a collection of workers inhabiting our intestines, with whom we can establish a symbiotic relationship (where both parties benefit) or a dysbiotic relationship (where there is harm to the host, i.e., us). Regarding the central nervous system, the microbiota can interfere with its functioning through the following pathways:

Certain agents of the gut flora produce substances that tend to activate our immune system and induce the release of inflammatory cytokines (chemical messengers). Acutely, we all feel changes in mood and energy when we are ill. This is precisely due to inflammatory cytokines and can constitute an adaptive and protective mechanism. However, when this stimulation is chronic, even to a lesser degree, it causes persistent activation of the immune system.

A 2011 publication, involving 34 volunteers, studied the effect of LPS (endotoxin) administration on various analytical and subjective parameters. (4) Endotoxin is a substance present in the membrane of Gram-negative bacteria (a type of bacteria present in the gut that can be problematic when in excess). These authors demonstrated that exposure to endotoxin had a temporary effect on the following parameters:

The intestinal epithelium (the inner lining of the intestine) has a fundamental function, as it must allow the passage of nutrients but be as "impermeable" as possible to toxins and microbial antigens. This barrier function depends on several factors, some of which are influenced by the bacteria present in the gut. These bacteria assist in maintaining the integrity of the epithelium through the production of short-chain fatty acids (such as butyrate), regulation of the inflammatory response, and promotion of adequate mucin levels (a mucus layer that protects the epithelium). The more permeable the intestinal epithelium, the greater the entry of bacterial endotoxins into the circulation, and the consequent activation of the immune system.

A study published in 2018, involving 50 patients with depression, demonstrated elevated levels of intestinal permeability markers, such as serum zonulin, when compared to healthy individuals. (5)

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