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Mental Illness: Brain Disease or Gut Disease?

A guide to the gut-brain axis and mental health.

Almost 30 years ago, the U.S National Institute of Health declared the 1990s "the decade of the brain." Since then, considerable funding has been devoted to psychiatric research exploring various aspects of brain science.

Some scholars have argued that this was a nodal point in the history of psychiatry, marking a reorientation from a biopsychosocial model to a "bio-bio-bio model," which remains dominant today. This emphasizes three factors: neuroscience, psychiatric genetics and psychopharmacology.

This led to groundbreaking new knowledge in areas such as neuroplasticity, brain architecture and molecular genetics. That said, subsequent research offered inconclusive evidence for popular hypotheses regarding the "chemical imbalance" theory of mental illness.

For example, "the dopamine hypothesis" of schizophrenia and "the serotonin hypothesis" of depression remain unproven, and there are still no validated diagnostic biomarkers for any mental illness.

This led the respected psychiatrist Dr. Ron Pies to caustically declare that "The legend of the 'chemical imbalance' should be consigned to the dustbin of ill-informed and malicious caricatures."

Beyond the Brain

Given this situation, some mental health researchers have refocused their activity beyond the brain to examine an unlikely organ: the gut. This was prompted, in part, by epidemiological research indicating a high degree of co-morbidity between gastrointestinal illnesses and mental illnesses.

For example, both irritable bowel syndrome and ulcerative colitis are highly co-morbid with major depression. This raises the possibility of a common factor affecting both gut and brain health.

As such, there is a growing research interest in "the gut-brain axis" and gut microbiota in particular, and their possible causal role in mental illnesses.

The Gut-Brain Axis

The human gut is extremely rich in a diversity of bacteria and other microorganisms, known collectively as gut microbiota (or gut flora). There is a delicate balance between this diversity of gut microbiota, which have a variety of vital biological functions.

Importantly, research indicates considerable bi-directional "cross-talk" between the gastro-intestinal system and the brain, with both organs influencing the other. This can occur through the nervous system (mainly via the vagus nerve) or through the vascular system.

In other words, brain activity can influence gut activity, and gut activity can influence brain activity, through intense bidirectional cross-talk in this "gut-brain axis" (GBA).

Could this mean that gut activity affects mental health and mental illness?

Gut Microbiota and Mental Illness

Much research indicates that the distribution of gut microbiota varies between individuals. Interestingly, a small but growing number of studies indicate that people with a range of mental illnesses tend to have different gut microbiota patterns (or "signatures") compared to healthy controls

For example, two studies published in February this year independently found that people with schizophrenia had a much lower diversity of gut microbiota compared to healthy controls. Other studies indicate that people with depression and autism spectrum disorder also have different patterns of gut microbiota compared to healthy controls.

This is concerning as related studies indicate that specific gut microbiota play a formative role in the production and regulation of neurotransmitters and metabolites implicated in mental illness. This includes serotonin, dopamine and gamma-aminobutyric acid (GABA).

Similarly, harmful gut microbiota can produce neuroactive substances than can cross the blood-brain barrier, affecting both cognition and emotion.

All this points towards plausible mechanisms and preliminary evidence for an association between gut microbiota signatures and mental health.

What Causes an Unhealthy Gut?

Some research indicates that both chronic and temporary stress can affect the distribution of gut bacteria. Likewise, rodent studies indicate that in utero stress and maternal separation can upset the equilibrium of gut microbiota with a knock-on effect on mental health.

Other studies indicate that exposure to maternal microbiota is important to the development of a healthy and diverse gut in offspring. This can be achieved through vaginal birth, skin contact and breast-feeding.

Interestingly, one 2019 study introduced fecal microbial transplants from people with schizophrenia into sterile germ-free mice, finding that these mice subsequently "displayed schizophrenia relevant behaviours."

Likewise, another study indicated that administering probiotics to rodents with depression-like traits can diminish these traits, restoring the rodents to baseline behaviours. All this suggests that external manipulation of gut microbiota has the potential for new mental health treatments.

Diagnosis and Treatment

The emerging corpus of research on the gut-brain axis has produced exciting new knowledge about the possible etiology of mental illness. Moreover, this line of research contains much promise and potential for both diagnosis and treatment.

Understanding the relationship between specific gut microbial signatures and specific mental illnesses could aid in the ongoing quest for diagnostic biomarkers. Additionally, ongoing findings could have implications for targeted treatment and personalized therapies.

For example, probiotics can provide healthy gut bacteria, while antibiotics can destroy harmful gut bacteria. Likewise, fecal microbial transplants could be used to transfer healthy and diverse gut bacteria to those lacking. Some have begun to speculate that these could be used to treat mental illness.

A Note of Caution

It should be noted that most studies on mental illness and the gut-brain axis have been on rodents, and University of California expert Clair Martin and colleagues rightly state that "evidence for causality remains sparse."

Indeed, there is an absence of double-blind randomized longitudinal studies examining the impact of probiotics, antibiotics, or fecal microbial transplants on recovery from mental illness. Likewise, the problem of reverse causation has not been adequately addressed.

For example, lifestyle factors associated with mental illness (e.g. poor diet) and medication side-effects could cause a disturbance and disequilibrium in the gut microbiota. In other words, variations in the distribution of microbiota could be a consequence, rather than cause, of mental illness.


As such, it is too early to state that mental illnesses are "gut diseases," and we should be wary of replacing simplistic notions of "chemical imbalance" with equally simplistic notions of "gut imbalance."

That said, this line of research does hold promise and potential, and the upcoming 2020s may very well be the "decade of the gut" when it comes to breakthroughs in psychiatric diagnosis and treatment. Only time will tell.

More from Rob Whitley, Ph.D.
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