Written & Illustrated by Andrew Neff

The Gut Brain Axis

Scientists say gut bacteria are shaping human psychology, but the evidence?

The brain and gut have to work together to carry out basic bodily processes,

for example,

your brain needs to flex internal muscles to push food through the intestines.

On the other end, peripheral nerves surrounding the gut

are studded with mechanical receptors to detect intestinal stretching,

and nutrient receptors responsive to food intake.

There is such a thing called the gut-brain axis,

that is, there is a relationship between your gut and your brain.

 

This is not about that.


This is about what looks like a group of researchers

overinterpreting their research,

both to the public and scientific communities,

either from ignorance,

or more likely,

as a means to gain attention, and bolster their careers.

 

This is about claims made mostly by scientists from the

APC Microbiome Institute at the University College Cork,

who publish scientific papers with catchy headlines like

Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour

and

Transferring the blues: Depression-associated gut microbiota

induces neurobehavioural changes in the rat

 

Who in very highly cited research papers make statements along the lines of

 

“...microbiota within the gut, can greatly influence all aspects of physiology, including ... behaviour

and

[gut bacteria are] poised to control canonical aspects of brain and behaviour in health and disease

(Cryan 2012)

 

And at WIRED conferences posted on youtube,

 

We’re beginning to realize that many aspects of … behavior are determined by the composition of bacteria within our gut

and

These bacteria could be the master puppeteers of our brain

 

This article is about the following question

 

Is variability in human psychology

explained by variability in gut bacteria?

 

That is, high-level human-type psychology,

emotions, thoughts, and complex behaviors.

 

And it’s important because of how casually

a group of very high profile scientists have come to accept the reality of this statement,

and begun a media campaign to promote it’s existence,

despite a lack of supporting evidence.

 

With a background in neuroscience,

and years of research on how nutrition and metabolism impact the brain,

this article takes seriously the evidence for the idea that human psychology is driven by our guts.

Because there are substantial theoretical limitations,

and practical shortcomings

to the experiments scientists are using as confirmation of this claim.

 

All in an effort to set things straight.

 

Because mental health is an huge problem,

and the end really isn’t at all in sight.

If we continue to allow ourselves to be lead down blind alleys like this,

people might start to think they can blame their emotional distress on their gut,

and therefore may focus on sculpting their microbiomes,

which, is not an experimentally validated approach to changing psychology,

rather than scrutinizing their behaviors,

which, is.

And just as important,

convincing scientists that this fact is true

may serve to divert research funding away from

other fields of research that are at least as promising, if not more.

 

In short, we don’t know where this alley leads,

but we need to resist being lead down blind alleys

because while this research could lead to the cure for mental illness,

it also could lead to us getting mugged for

30 million a year on gut-brain-axis research expenditures (see NIH Reporter).

 

So then, our position is pretty clear,

but what is it that makes this research untrustworthy?

And, from the opposite perspective,

what would lead a scientist to the conclusion that

the bacteria in our guts are really in charge?

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You can grow mice in completely sterile laboratory conditions,

meaning they (the mice) have no bacteria, in their gut or anywhere.

These sterile animals are called germ-free mice, and,

maybe as expected,

they have weird brains and do weird things (Sudo, 2004)

They also have very irregular immune systems, different sized organs,

and a bunch of other freakish abnormalities,

but more importantly, germ-free humans don't exist.

 

When it comes to mental health, or neurological disease, or just disease,

there are only two things we care about:

First, why it is that some people get the disease and others don’t,

and second, what leads to the development of a disease, or its cure.

Another way to think about it is,

we care about how people are different from each other,

and how people change over time.

 

There are no germ free humans,

and so in every case, we’re comparing two groups,

both of which have a particular microbiome,

neither of which have no microbiome.

Germ-free

Animals

This mouse likes to be touched

A “probiotic” refers to any bacterial species that is intended for human consumption

and is thought to promote good health.

You see in some placebo-controlled trials, but not all,

people taking probiotics report improvements in their emotional well-being (Mckean, 2017).

Practical Concerns:

 

Small sample sizes

There has been meticulous, well-design, placebo controlled research

on whether probiotics influence emotion,

but none of these studies would be quite enough for approval by the FDA.

The most important piece of evidence missing

is a study that has evaluated a large enough sample.

Much of this research is based on samples of about 30 subjects,

and so while these smaller scale studies may be promising,

they’re not quite enough.

 

Theoretical Issues

Most people aren’t on a prescribed daily probiotic regimen,

so the question that emerges is

whether or not probiotic studies can inform us about a particular species’ natural function.

In other words,

if taking a daily tablet of some bacterial species does X,

does it follow that harboring that bacterial species in your gut,

or harboring more of that species,

mean you have more X?

 

There’s a couple reasons to think that probiotic research doesn’t generalize to natural bacterial function.

 

Genetics dis-similarity:  Probiotics ≠ natural species

The bacteria in your gut are very much your own,

that is, there is substantial genetic variability within individual bacterial species (Kuleshov, 2016).

So much so that some people think the idea of a discrete bacterial “species” doesn’t make sense

in the same way it does for, say, humans vs chimpanzees (see this blog post).

You might take a probiotic labelled as “Bifidobacterium adolescentis”,

but the the genetics of the Bifidobacterium adolescentis in your gut may be vastly different.

 

Unrealistic population dynamics

Probiotics often don’t stick around in the gut for too long.

Whether you get your probiotics from yogurt, or from a capsule,

bacteria tend to travel through your intestines like anything else you eat,

and eventually come out the other end.

All this produces a really big but short lived population spike

that travels like a wave through your digestive tract.

For the bacterial residents in your gut, population fluctuations do occur,

but the guys that live in your gut are much more stable over time,

very different from the short lived, high intensity pulse that follows probiotic consumption.

 

*

 

Probiotic research can tell us about what probiotics can do for us,

assuming we take them (the probiotics) in a prescribed regimen as in the study,

and assuming the study was placebo controlled and conducted on a large enough sample.

But people tend not to take daily probiotic regimens,

and the probiotics we’re taking aren’t always quite the same as the ones in our guts,

and even if this weren’t the case,

the existing studies haven’t been conducted on large samples.

Probiotics

So does this guy

One thing not mentioned yet is correlational evidence.

People with some bowel diseases have higher incidences

of psychiatric illness (Fuller-Thomson, 2015),

and certain personality characteristics correlate with

the abundance of certain types of bacteria (PR Burghardt, unpublished observations).

But, correlation, right?  

We can’t tell which is driving which,

or if both are tied to a separate variable.

 

Which got people to thinking,

if you could extract gut bacteria from a group of people,

say people with obsessive compulsive disorder, OCD,

and transferred that bacterial community

to a new group of people who don’t have OCD,

and observed that the people in the second group, who don’t have OCD,

after receiving a bacterial transplant from the first group,

now have all the symptoms of OCD,

if you did all this,

wouldn't you start to think that bacterial communities are causing OCD in the donor population?

 

Amazingly,

one group of researchers took two groups of animals with distinct behavioral characteristics,

swapped stool samples from each group of animals to each other,

and found that stool-swapping caused each group to start acting a little bit more like the other group (Bercik, 2011).

 

This type of experiment has a substantial advantage over other methodologies

because it tries to look at how a whole, intact, microbiome is impacting an organism.  

But it’s not without its own set of theoretical concerns,

and the studies applying this methodology to human mental illness have substantial practical limitations.

 

Practical Concerns

 

small sample sizes

In addition to the Bercik study cited above,

two additional studies put an interesting spin on this method (Zheng, 2016; Kelly, 2016).

They collected stool samples from humans with major depressive disorder,

transferred those samples into germ free mice,

and found these mice failed all the mice “depression tests”

(see theoretical issues for what a mouse depression test is).

One major shortcoming of both studies is a tiny sample size:

in one study, samples were collected from 5 human subjects,

in the other, samples were from 3.

If that isn’t small enough, these samples were smashed together (pooled)

prior to transplantation into the germ free animals.

Which means, neither of these studies should be

considered as evidence that this effect is generalizable.

(check out this discussion between the people who wrote the Zheng paper,

and the dissenting author of unregistered submissions #1, #3, and #6 )

Fecal

Transplants

The theoretical issues of the fecal transplant are concerning,

but if these studies testing fecal transplants from one group of humans to another group of humans

show that mental illness can be cured with psychologically-balanced-poop,

and they’re conducted in large enough samples and replicated in other labs,

it would be hard to deny that the gut microbiome is driving psychology.

But, this hasn’t happened,

so we’ll just have to wait and see.

lack of experimental control

One last mental health study did perform a human to human fecal transplant,

with donor samples from typically developing children into those with autism,

and lo, autism symptoms diminished (Kang, 2017).

Alas -  no placebo,

and autism symptoms we’re measured based on parents impressions.

There are two major problems with not having a placebo here:

First is, if a scientist tells you, the parent of what is probably a difficult child,

“try this really promising new treatment!”,

you might be inclined to see benefits that aren’t actually occurring,

on account of, say, nothing else having worked so far

but nonetheless desperately wanting to believe that a treatment exists.

Alternatively, your child's behavior may actually change,

but, based on, say, your ardent desire to help the treatment work,

you’ve started interacting with your kid differently than you ordinarily would.

 

Theoretical Issues

 

Fecal non-representation

The intestinal environment is complex,

some bacterial species prefer to live in the small intestine,

others are more at home in the colon (Huttenhower, 2012).

Some species embed themselves in intestinal mucus,

others pass time in the central portion of the gut (Li, 2015).

Microbiome research often relies on stool samples as a representation of the digestive tract,

but these samples can’t capture all the complexity of your insides.

All that is to say,

if we want to know how a “gut bacterial community” is affecting an individual,

we’d want to transfer a “gut bacterial community” from one group to another,

unfortunately, poop just isn’t a complete representation of your insides.

 

Ambiguous causation

People with Major Depressive Disorder have different guts than people without,

but they also have differences in behavior.

What if behavioral changes came before gut changes,

like, say someone changed their diet,

like, sorta by the definition of Major Depressive Disorder (see the DSM diagnosis).

This caveat provides a layer of nuance to the assertion that

fecal transplants prove bacterial causation.

 

Animal Depression?

Assessing emotion in animals is a really controversial subject.

Practically though, one of the main tests involves dropping an animal into a tank of water,

and measuring how much time they (the animal) spend trying to escape,

and how much time they spend floating (but not sinking),

despairing as they resign themselves to their watery fate (google the “forced swim test”).

Fecal transplants can be done in humans, pretty safely,

and they already are being done for people with incurable intestinal pathogens (Brandt, 2012).

So how about fecal transplants into humans with psychiatric illness?

Stay tuned another year or three for the answer.

Design-Oriented Science Media:

Skeptical Perspectives, Independently Produced.

Some report on what scientists report - we're here for the real thing.  

Support us today on Patreon.

Summary

is variability in human psychology

explained by variability in gut bacteria?

 

As wikipedia puts it:

 

"As of 2018

work on the relationship between gut flora and anxiety disorders and mood disorders,

as well as trying to influence that relationship using probiotics...

was at an early stage,

with insufficient evidence to draw conclusions

about a causal role for gut flora changes in these conditions,

or about the efficacy of any probiotic or prebiotic treatment"​

 

Hypothetically, say you’re wondering why a particular person is acting funny,

It may sound crazy, but maybe you could maybe start by looking

at something like whether this person likes their job,

whether they feel like their contributions to a community are valued,

if they have positive relationships with their family and friends,

if they eat healthy, exercise, or have a way of relieving stress.

Aren’t these some of the first places to look when someone’s having a hard time?

 

Or if you prefer a biological explanation,

what about a person's physical health?

What about cortisol, or inflammation?

What about hyperactive amygdalas and shrinking hippocampuses?

What about serotonin and dopamine and endogenous opioids?

 

To be completely clear,

I’m not endorsing any particular explanation of psychology or mental illness.

A lot of these concepts are probably blind alleys themselves as far as finding treatments goes.

But they need to be brought up because they’re supported

by evidence at least as strong as that for the gut brain axis,

and typically far stronger.

 

All this is to say that even if a scientist showed definitively

that the microbiome is impacting mental health,

which, they haven’t,

it doesn’t necessarily mean that bacteria have a privileged influence over the brain.

Thousands of years of human thinking on psychology,

and centuries of scientific research can’t be neglected.

 

If a scientist can effectively persuade others that everything we once thought was upside down,

that a millennia of thought on human psychology and behavior is unimportant,

that gut microbes aren’t just subtly influencing digestion,

but are somehow deeply important drivers of human emotion and behavior,

they’re gonna get a lot of attention.

 

And I now consider it the responsibility of everyone doing research in this field,

and everyone who comes across these claims in the news,

to take a second look at the evidence.

Because if these gut-brain-axis advocates are right,

and they may be right,

then great, we’ve found the cure for mental illness.

But if they’re wrong,

research funds are going to be diverted away from other similarly or more promising areas,

and people may feel encouraged to eat more yogurt and kimchi rather than think deeply about who they are.

 

In a world where almost everyone is in some way directly touched by mental illness,

either suffering themselves, or knowing someone who has,

these are costs that everyone’s going to have to bear together.

​References

  1. 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.

  2. Brandt, Lawrence J., et al. "Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection." The American journal of gastroenterology 107.7 (2012): 1079.

  3. 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.

  4. Ewaschuk, Julia B., et al. "Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function." American Journal of Physiology-Gastrointestinal and Liver Physiology 295.5 (2008): G1025-G1034.

  5. Fuller-Thomson, Esme, Rusan Lateef, and Joanne Sulman. "Robust association between inflammatory bowel disease and generalized anxiety disorder: findings from a nationally representative Canadian study." Inflammatory bowel diseases 21.10 (2015): 2341-2348.

  6. Huttenhower, Curtis, et al. "Structure, function and diversity of the healthy human microbiome." Nature 486.7402 (2012): 207.

  7. 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.

  8. 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.

  9. Kuleshov, Volodymyr, et al. "Synthetic long-read sequencing reveals intraspecies diversity in the human microbiome." Nature biotechnology 34.1 (2016): 64.

  10. Li, Hai, et al. "The outer mucus layer hosts a distinct intestinal microbial niche." Nature communications 6 (2015): 8292.

  11. 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.

  12. Metges, Cornelia C. "Contribution of microbial amino acids to amino acid homeostasis of the host." The Journal of nutrition 130.7 (2000): 1857S-1864S.

  13. Parvez, S., et al. "Probiotics and their fermented food products are beneficial for health." Journal of applied microbiology 100.6 (2006): 1171-1185.

  14. Petruzzello, Steven J., et al. "A meta-analysis on the anxiety-reducing effects of acute and chronic exercise." Sports medicine 11.3 (1991): 143-182.

  15. Strozzi, G. Paolo, and Luca Mogna. "Quantification of folic acid in human feces after administration of Bifidobacterium probiotic strains." Journal of clinical gastroenterology 42 (2008): S179-S184.

  16. 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.

  17. 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.

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