Our intestinal tract is a fascinating organ. As the largest mucosal surface in the body, it is home to trillions of microbes — bacteria, fungi, helminths, and viruses — that together comprise the gut microbiota, and 500 million neurons — our “second brain”, the enteric nervous system (ENS). Unsurprisingly then, recent research has unveiled what is commonly dubbed the ‘gut-brain axis’ (GBA): an extensive signaling network between the gut and the brain. With involvement from the microbiota and immune system, the GBA regulates aspects of homeostasis such as satiety, hunger, and inflammation.

Given the popularity of the microbiota in today’s biomedical research culture, studies have indicated crucial roles for our microscopic gut residents in facilitating diseases throughout the body. The microbiota has been implicated in diabetes, colorectal cancer, and lupus, yet its effects on the brain, an organ highly protected from the outside world, are perhaps the most surprising. Perturbations and imbalances of the microbiota have been correlated with several neurodegenerative and psychological disorders, although scientists are still attempting to understand how exactly our gut bugs can have such profound impacts on our brain.

Microbiota: The real master-minds?
Over 20 years ago, antibiotic treatment was shown to significantly improve the conditions of patients with chronic hepatic encephalopathy, a disease characterized by neuropsychological impairment due to gastrointestinal inflammation-induced liver failure. The finding provided the first compelling clinical evidence for microbiota-brain interactions. Today, the microbiota has been implicated in a wide range of brain disorders: Alzheimer’s disease, Parkinson’s disease (PD), multiple sclerosis (MS), and even depression, anxiety, and autism.

The advent of high-throughput sequencing techniques has enabled scientists to identify key members of the microbiota correlating with different neurodegenerative and autoimmune diseases. For example, sequencing of stool samples from both MS patients and autistic children revealed a higher abundance of Akkermansia muciniphila, a species known to preferentially feed on the mucus layer that maintains our gut barrier. Similar to autistic patients, those with PD also have an increased abundance of fecal lactic acid-producing Enterococcae spp., pointing to another microbiota-brain connection. Recently, Belgian researchers correlated the fecal microbiota of over 1,000 people with their quality of life and incidence of depression. People with depression were found to have reduced abundance of Coprococcus and Dialister bacteria, while higher quality of life correlated with the microbiota’s ability to synthesize a specific dopamine-derived product. These correlations, while still nebulous at best, nevertheless provide complementary evidence to clinical observations and suggest microbial metabolic activity may regulate gut and brain function.

Strong clinical correlations have been made between intestinal inflammation, in which the microbiota plays a significant role, and neurological and psychological disorders. For example, several clinical studies have demonstrated a higher incidence of depression in inflammatory bowel disease (IBD) patients, and these psychiatric symptoms worsen during periods of active IBD. Meanwhile, a Danish nationwide cohort study revealed IBD patients have an increased risk of PD. In fact, scientists have recently shown that transplanting fecal microbes of PD patients to mice genetically predisposed to the disease exacerbates motor dysfunction. Autistic individuals typically experience a wide range of gastrointestinal problems, including chronic constipation, diarrhea, and abdominal pain. Finally, premature infants with the gastrointestinal disorder, necrotizing enterocolitis, often co-develop cognitive impairments, suggestive of an early-life microbiota-brain link.

Recent studies have also associated the microbiota with other aspects of human function, including cognition, memory, and social behaviors. For example, neuroscientists have correlated a microbiota comprised of high Bacteroides abundance with higher neural activity in the cerebellum, frontal regions, and hippocampus. Meanwhile, germ-free (GF) mice that lack a microbiota display abnormal activation of the hypothalamus-pituitary-adrenal (HPA) axis, which regulates mood and stress, and reduced levels of brain-derived neurotrophic factor, a protein associated with neuroplasticity, learning, and memory. While the verdict is still out on the mechanisms regulating the GBA, emerging clues point to several pathways by which the microbiota and brain interact.

From gut to brain and back again
The brain is typically separated from bacteria and large hydrophilic molecules in the blood by the blood-brain barrier (BBB). However, microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), can enter the circulation and pass through this barrier into the brain. These SCFAs are crucial for the development of microglia, brain-resident macrophages, which maintain homeostasis and regulate neurogenesis. Other microbial metabolites have also been shown to activate central nervous system (CNS) astrocytes, non-neuronal cells that support the BBB and regulate brain health.

Closer to their proverbial homes, the microbiota can both directly affect the ENS and indirectly regulate the nervous system via modulation of the intestinal immune landscape. B cells, a type of adaptive immune cell, become activated and produce antibodies in response to specific microbial members or their dietary metabolites. These cells and their antibodies can then migrate to the CNS, where they either offer protection or induce inflammation depending on the nature of their microbial priming. For example, in a recent study on experimental autoimmune encephalomyelitis (EAE), a murine model of MS, scientists at the University of Toronto found that certain microbiota compositions can increase the abundance of IgA antibody-producing cells in the gut that offer resistance against EAE. This is in line with clinical observations indicating microbiota dysbiosis in MS patients. Dysbiosis of the microbiota, during which the community becomes ‘unbalanced’ and dysregulated (although it is still unclear what constitutes this state at the species level), causes intestinal inflammation that can have systemic repercussions all the way to the brain.

“Up to 95% of the serotonin in the body is produced in the gut”

The vagus nerve, the longest nerve in the body, connects the ENS to the brain. Through this link, certain microbes, such as Lactobacillus reuteri, can regulate the oxytocin-dopamine reward circuit to influence social behavior in mice. The microbiota can also induce the production of local neurotransmitters; in fact, up to 95% of the serotonin in the body is produced in the gut. Meanwhile, microbial products, including flagellin and lipopolysaccharide, can regulate our circadian rhythms and nutrient uptake via interaction with the intestinal immune system, while SCFAs directly impact the ENS to regulate gut peristalsis.

On the other hand, the nervous system can also regulate microbiota composition, primarily through hormone production via the HPA axis. For example, stress-induced activation of the HPA axis alters intestinal permeability, motility, and mucus production, all of which can affect microbiota composition. HPA-derived glucocorticoids and ENS production of neurotransmitters can also drive the intestinal immune system to either pro- or anti-inflammatory states, resulting in the promotion of certain microbial species and the killing of others.

A tale of two brains
Research on the microbiota has yielded insights into the human body beyond our expectations. Not only does it challenge the notion of what it means to be human (after all, bacteria outnumber our cells both in number and genetic content), it also raises the question of who is actually in charge. Growing evidence suggests an important role for our intestinal microbes in regulating our bodily functions, mental health, and social behaviors. While much more research needs to be done to elucidate the methods of communication in the GBA, we can at least give newfound meaning to the age-old advice to ‘trust your gut feeling’.

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Pailin Chiaranunt

Pailin is a PhD student in the Department of Immunology at the University of Toronto. She works in Dr. Arthur Mortha's laboratory on creating a high-dimensional map of host-microbiome interactions in the intestine. In her spare time, Pailin enjoys traveling, reading philosophy, and dabbling in martial arts and languages.

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