Evidence For A Gut Brain Connection

Written by Andrew Neff

Edited by Maisha Razzaque

June 2019

When research turns to shit

A personal encounter with the theory that human psychology is driven by gut microbes.

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Walking into a recent psychiatry grand rounds meeting, I found on the projection screen a person with intestines where their brain should be. Some time before, I watched a youtube video in which gut bacteria are said to be dictating human behavior - the Gepetto to our Pinocchio. Again, this time in the pages of The Psychologist, I discovered more puppet-based metaphors, more assertions of gut bacterial control over the human mind.

The claim that human psychological variability is driven by gut microbes is provocative. If it’s true, we’re living in a biologically deterministic world, with little room for everyday psychological explanations. The nature of our upbringing, our socioeconomic environment, the quality of our relationships, our twitter follower count (@neuroscience_fu) — the more influential gut microbes are, the less important traditional explanations can be.

My wife is a social worker, which means that over dinner we regularly violate HIPAA privacy rules as we discuss her troubled clientele. As a kid, one client witnessed their dad physically assault their mom. After years of bad grades and disruptive classroom behavior, the client was expelled from high school. At 18, this person is imagining a future with little to no job prospects, no real family support, and potentially even homelessness. To suggest that this clients anxiety over his future can be explained by which bacteria are in his gut, rather than his fear of living through a Michigan winter on the streets, would not contribute to dinner table harmony.

To be sure, it’s possible that behaviorists are seeing patterns where there aren’t any. Maybe this clients abusive father, absent mother, and general failure to succeed in society isn’t the real explanation for his psychological turmoil. But, maybe, and to some, probably, people really are comprehensible in the context of their experiences.

As a graduate student I came to the so-called gut-brain-axis by accident. Studying microbes offered me a way to remain in neuroscience while still learning how to use the incredibly interesting new tools of molecular biology. My mentor always had a balanced perspective on the role of microbes in psychology, as did most scientists, so I went along with.

This balanced perspective, however, was not shared by everyone. An affirmative tweet under #gutbrain or a casually accepting comment from a friend could be forgiven. Slightly more troubling was the endorsement by the popular media, where attitudes ranged from enthusiastic to outright accepting. More scientists were coming to believe in the promise of gut bacterial diagnostics and therapeutics, as researchers from my institution began probing my thoughts on how the gut microbiome relates to their mental illness of interest. Couldn’t we take a step back and ask whether bacteria were doing anything in the first place?

But the field was taking off, over the five years I spent in graduate school, the number of neuroscience or psychology papers referencing gut bacteria doubled, and the National Institute of Health is now spending some thirty million dollars annually on this type of research. National conferences in psychiatry were holding special workshops on the idea, in which generally credulous scientists presented data that generally didn’t seem to support an attitude of credulity. And then there was one scientist, probably the most highly cited and visible in the field, who was giving talks and writing about how we’re not so unlike Pinocchio, passively responsive to our gut microbial puppet-masters.

One hundred fifty plus years we’ve been trying to treat mental illness from a biological perspective; EEG, fMRI, blood-based biomarkers - almost none of it is making an impact on people’s lives, but we’re confident the answers we’ve been waiting for are in our stool?

Whatever your bias is, we could just test the idea, and to some extent, we have. If we manipulate our gut microbiomes, can we produce results that look like a human response to trauma? Can microbial alterations trigger prolonged periods of depression or anxiety? In this article; a critical take on the four lines of evidence used to support the idea that human psychological variability is driven by gut microbes.

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Correlations

There are correlations between which bacteria are found in people’s guts and an individuals mental health status. These associations are interesting, but could be easily explained by behavioral, possibly nutritional differences between people with varying mental health conditions. After all, some mental illnesses, Major Depressive Disorder for example, include changes in appetite as a part of the diagnostic criteria.

Digestive System, Circulatory System, Nervous system

Germ-free Animals

Proponents of the theory often note that animals raised without any bacteria have abnormal brains and act kinda weird. These studies offer compelling information on what it means to be human, and how important it is to have bacteria in the first place. The thing is though, we all have bacteria, every one of us. But not every one of us has a mental illness, and few of us are psychiatrically ill all the time. Knowing that germ-free mice have altered behavior can’t help us understand why some people are resilient to stress while others go on to develop mental illness. Nor can it explain why someone develops or overcomes a particular psychological ailment. Germ-free mice tell us nothing about human variability, which is arguably the only thing psychologists really care about.

Probiotics

Another approach, and a way to look at what makes us different, has been to ask how individual bacterial species are impacting us. The old way of thinking about bacteria is as disease causing, to be avoided if possible. But some bacteria are thought to promote good health, these are called probiotics, and they’re growing in popularity at grocery stores all over. It’s a fraught field, surrounded by controversy and skepticism. But when the research is done right, some think that probiotic studies helps us understand the contribution of individual bacterial species to human psychology. And convincingly, some high-quality scientific evidence supports the idea that some species of bacteria can reduce feelings of anxiety.

But while these results are important, the study design is artificial, and may not be able to tell us about natural bacterial variability. For example, the bacteria you find in grocery stores are generic, one-size-fits-all species. The bacteria you find in your gut, on the other hand, are highly individualized, custom evolved to your personal intestinal environment. Second, the probiotics we take often don’t make it through the stomach alive, while those that do, tend not to stick around after you stop taking the supplement; in other words, most probiotics need to be constantly replenished. The inability of most probiotics to establish a long-term presence suggests that these bacteria may be functionally distinct from the bacteria naturally living in the human gut (which, do establish a long-term presence). Well-controlled probiotic interventions provide us with important information about probiotic interventions, but it’s unclear the extent to which they can tell us about natural human variability.

Fecal Transplants

Now the gold-standard type of experiment, that lets us look at what makes people different, and is thought to be really representative of our natural gut environment, is the fecal transplant. In one study, researchers started with two strains of mice, each with a unique set of behavioral characteristics; one tended to act more hesitant, the other more brazen. Researchers then had each strain swap stools with a partner from the other strain (basically), and incredibly, each strain started behaving a little bit more like the other. In subsequent versions, fecal samples from human subjects with mental illness have been collected and transferred into germ-free mice, who, as predicted, started behaving differently. Fecal transplants have even been attempted in humans; in one experiment, researchers successfully reduced autistic behaviors by performing a fecal transplant with stools collected from non-autistic subjects. At first glance, it’s all kind of amazing, swapping microbiomes changes minds.

However, these studies each have some really important limitations. For one, the human-to-animal-transplant studies have only been performed on really small sample sizes, and, only assess rodent behavior. And in the one human trial, there was no placebo used - a critical element for a behavioral intervention where parents and teachers, who are fully aware of the intervention, are the ones rating behavioral symptoms.

As of writing this, clinical trials are actively recruiting human subjects with mental illness to take part in preliminary studies on the effectiveness of fecal transplants for reducing the symptoms of mental illness. The efforts of these researchers need to be very carefully watched, because if the findings are positive, and are reaffirmed with subsequent replications, this would represent really compelling evidence that natural variability in gut bacteria are driving psychological outcomes. Until then, there is no published evidence, using a placebo control, in humans, demonstrating that fecal transplants can elicit the psychological characteristics of their donors. Which means that if we’re anywhere, we not much beyond step one on the journey of scientific fact-proving.

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When I began looking into the research, I was certain there would be no convincing evidence that bacteria are impacting the brain and behavior. Humans were just too complex and variable, and most importantly, when scrutinized enough, comprehensible in psychological terms. But it’s clear that in many cases, purely biological factors can have a major impact on our minds. In many cases, things like genetics, or the use of psychiatric meds can have subtle effects on general psychological domains, slightly boosting or dampening the likelihood of one outcome or another. The prevailing attitude, even among the more outspoken proponents of the theory (most, at least), is that if gut microbes are playing a role in psychology, they are one influence among many, subtly coloring the way in which we perceive and interact with our world. That is, IF they’re playing a role.

Maybe, one day, we’ll be able to replace the admittedly imperfect Cognitive Behavioral Therapy and Mindfulness Meditation with a spoonful of yogurt and a bowl of fermented cabbage. Or perhaps we’ll have a clinical rationale for requesting a stool from our most psychologically balanced friends. Or maybe we won’t. In a world where almost everyone is impacted by mental illness, either suffering themselves or knowing someone who does, it’s understandable that we’re craving answers. But until we see the results from well-controlled human experiments, and are faced with independent replication of these studies, we might need to accept that we just don’t know.

References

Bercik, Premysl, et al. "The intestinal microbiota affect central levels of brain-derived neurotrophic factor and behavior in mice." Gastroenterology 141.2 (2011): 599-609.
Cryan, John F., and Timothy G. Dinan. "Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour." Nature reviews neuroscience 13.10 (2012): 701.
Kang, Dae-Wook, et al. "Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study." Microbiome 5.1 (2017): 10.
Kelly, John R., et al. "Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat." Journal of psychiatric research 82 (2016): 109-118.
Kuleshov, Volodymyr, et al. "Synthetic long-read sequencing reveals intraspecies diversity in the human microbiome." Nature biotechnology 34.1 (2016): 64.
McKean, Jennifer, et al. "Probiotics and subclinical psychological symptoms in healthy participants: a systematic review and meta-analysis." The Journal of Alternative and Complementary Medicine 23.4 (2017): 249-258.
Metges, Cornelia C. "Contribution of microbial amino acids to amino acid homeostasis of the host." The Journal of nutrition
Sudo, Nobuyuki, et al. "Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice." The Journal of physiology 558.1 (2004): 263-275.
Zheng, P., et al. "Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism." Molecular psychiatry 21.6 (2016): 786.