How Gut Microbiota Affect Brain Health

Post by Elisa Guma

What is your gut microbiome?

Living inside (and on the skin) of every person are trillions of bacteria, viruses, fungi, and other organisms that collectively make up our microbiome. These microorganisms can coexist with their human hosts, causing no harm, they can have mutualistic relationships with their hosts, providing them benefits, or they can be harmful, producing unwanted metabolites. Many of these metabolites can influence brain structure and function. Although many organs have their own distinct microbial colonies, the gut microbiome has attracted a great deal of attention, particularly because there is bidirectional communication between the gut, its microbiome, and the brain. Our first big dose of microbiota comes from birth (via the vaginal canal and breastfeeding), but its composition continues to evolve throughout the lifespan, influenced by our environment and diet.

The gut-brain axis

Your gut and your brain are in an ongoing dance of bidirectional communication, forming a circuit often referred to as the gut-brain axis. Our central nervous system (i.e., our brain and spinal cord) can influence the composition and function of the gut microbiota via the autonomic nervous system, regulating gastrointestinal motility, mucus secretion and permeability, and luminal release of neurotransmitters. In turn, microbiota in the gut can affect the permeability of the gut and blood-brain-barrier, as well as shape brain development, behaviour, and mood. This bidirectional communication can be neural, i.e. through the vagus nerve. It can also be neuroendocrine or immune, via metabolites and neurotransmitters produced in the gut. Microbiota can produce these signaling molecules from the food we ingest (carbohydrates, amino acids), from our bodily secretions (estrogens), or from chemical substances to which we are exposed (pesticides or medications). Some of these metabolites include (or are precursors for the production of) short-chain fatty acids (for example, butyrate), neurotransmitters (serotonin or γ-aminobutyric acid (GABA)), hormones (for example, cortisol), and immune system modulators (for example, quinolinic acid).

How can diet impact the microbiome?

Diet plays a critical role in shaping the diversity and proportions of microorganisms in our gut. This in turn can modulate brain structure and function through the communication channels discussed above: neuroendocrine, neural, and immune. Importantly, diet intervention has been found to alter both microbiome diversity and inflammatory markers in humans. A recent randomized controlled study found that individuals who ingested diets rich in fermented foods, compared to those who ingested diets rich in fiber, had increased microbiota diversity and decreased inflammation. Although those ingesting high-fiber diets experienced positive effects from their microbiota as well, increased diversity and decreased inflammation were not observed. Thus, fermented foods may be valuable dietary additions, particularly for those dealing with increased inflammation, or decreased microbial diversity (for example, if following a course of antibiotic treatment). In contrast, rodent and human studies have shown that diets rich in high-sugar and high-fat foods can change the bacterial content of the gut rapidly, decreasing diversity, and increasing inflammatory markers.

The gut microbiome and mental health

From anecdotal observations in patients, the association between altered gut-to-brain signaling and anxiety, depression, and autism spectrum disorder (ASD) was first established. Often, these psychiatric conditions were comorbid with another diagnosis of a digestive problem, such as irritable bowel syndrome. Post-mortem studies have also identified increased intestinal permeability and heightened inflammation in individuals with ASD, suggesting a potential link between gut health and inflammation. 

Studies in animal models have shown that the composition of the gut microbiome can modulate the central nervous system and central nervous system-driven behaviours. Initial studies comparing mice with and without microbes in their gut found that the former displayed increased motor activity, decreased anxiety, and altered genes associated with synaptic function in the brain. 

Dysbiosis of the gut has also been identified in patients with major depressive disorder (compared to healthy controls). Microbiome transfer from depressed human individuals into healthy rodents has been found to induce depressive-like behaviours in those mice, which suggests a potential causal role between the microbiota and the depressive symptoms. It is unclear whether these are indirectly mediated through other factors like increased inflammation, which has also been associated with the pathology of numerous psychiatric conditions.

Important links with neurodegenerative diseases have also been made. A strain of Escherichia coli in the gut has been shown to make a protein that is similar to the misfolded alpha-synuclein protein associated with disease progression in Parkinson’s disease. Some researchers hypothesize that these misfolded proteins may travel up the vagus nerve to the brain, providing a “template” for misfolding to the alpha-synuclein protein.

Therapeutic microbes to tackle disease

Given the intriguing interactions between gut microbiota and psychiatric symptoms, many groups are investigating putative therapies aimed at altering the composition of these microbes. Microbial transfer therapy (or fecal transplants) has been successfully used to recolonize the gut of individuals suffering from severe gastrointestinal distress or following complications from antibiotic therapy. Some are starting to investigate its utility in the treatment of autism spectrum disorder. In a recent study, children with autism spectrum disorder who received a microbial transfer from the gut of healthy individuals showed a decreased severity of autistic and gastrointestinal symptoms. In contrast, probiotic treatment of individuals with major depressive disorder or schizophrenia has shown mixed findings, with some individuals showing improvements and others no changes. While targeting gut microbiota in the treatment of mental illness shows great promise, there is much more research to be done to understand the gut-brain axis, and how best to develop therapies to effectively modify the gut microbiome.

References +

Horn et al. Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders. Translational psychiatry (2022).

Neufeld et al. Effects of intestinal microbiota on anxiety-like behaviour. Communicative & Integrative Biology (2011).

Parker et al. Gut microbes and metabolites as modulators of blood-brain-barrier integrity and brain health. Gut Microbes (2020).

Sgritta et al. Mechanisms underlying microbial-mediated changes in social behaviour in mouse models of autism spectrum disorder. Neuron (2019).

Shoubridge et al. The gut microbiome and mental health: advances in research and emerging priorities. Molecular Psychiatry (2022).

Wastyk et al. Gut-microbiota-targeted diets modulate human immune status. Cell (2021).

Willyard. How gut bacteria alter the brain. Nature (2021). Zhu et al. The progress of gut microbiome research related to brain disorders. Journal of Neuroinflammation (2020),