I gut a feeling!

I bet you don’t think about the 100 trillion microbugs thriving in your gut that much. Neither did I, until I started reading up on the Human Microbiome Project (HMP) at a conference last week. Several fun facts that came out from the project:

• • For every human cell, there are 10-100 times of microbe living in your gut in harmony. Not to mention the skin, nose, mouth and foot dwellers. We’re really more bug than man.
  • People host very different types of microbug (over 1000!); but when you look at the GENES that compose each microbiome, they’re remarkably similar.
  • Along the same lines, an extremely diverse microbe composition can activate the same METABOLIC pathways to help you digest carbs and influence your metabolism - all (normal)microbug roads lead to metabolic Rome.
  • So it’s probably not surprising that aberrant microbug-ecology is involved in Type 2 Diabetes, Inflammatory Bowel Disease and MAYBE cardiovascular disease.
  • There’s tantalizing (but little) evidence that environmental bacteria may get into healthy brains and start colonizing.
  • One for the ladies: we can be “bug typed” into 5 categories, depending on our vaginal microbiome composition. Like blood type.

And finally, most interesting to me, is the emerging brain-bug connection. Microbes rapidly and densely settle in newborns as their brains are still developing. If the bad (pathogenic) ones get in, it may drastically increase a child’s chance of developing schizophrenia and autism. If the “normal” ones don’t get in – well, it seems to influence mood, anxiety and even cognition, at least in mice.

Let me explain.

Since we can’t ethically eliminate normal gut microbes in human newborns, scientists turned to germ-free (GF) mice, or mice without intestinal flora. When tested for anxiety levels, adult GF mice were much bolder than their controls, wandering into terrifying bright fields and cliff-like arms of an elevated maze. This brash behaviour disappeared if they were artificially colonized with gut flora when young, but not once they reached adulthood.

This tells us that –all else the same - gut bugs can impact behavior, depending on whether or not they were present in the “critical period” in development.

"Conv" = gut microbe (poop) transplant. If gut flora settle down & flourish before or during the critical period, germ-free (GF) mice show normal anxiety behaviour. Otherwise they turn into brash adults. Source: below #2

But it’s not just the kids that are susceptible. Giving adult mice a mixture of ANTIbiotics and antifungals for a week reduced their anxiety-like behaviors, which went back to baseline 2 weeks after the treatment stopped. This doesn’t imply gut flora’s bad for mood - a dose of PRObiotics (L. rhamnosus) also made healthy male mice gutsier. So the absolute amount of gut flora may not matter as much as composition in this case.

So HOW are normal bugs in the gut signaling to the brain? Scientists aren’t too sure yet, but peripheral and gut nerves may be involved. Gut bugs may also be generating neurotransmitters from food, which gets delivered to the brain by blood. They could also be communicating with the brain indirectly, by changing global metabolism. Alternatively, a crazier idea is that gut bugs can change protein expression in the brain – at least during early development – and so the brain “sets up” its synapses and circuits differently, eventually changing how stress and mood is processed.

There is some evidence for this. We know that monoamines, like dopamine and serotonin, are involved in mood regulation. Surveying the brains of bug-free GF mice, scientists found increased metabolism of monoamines in the striatum, a brain area important for motivation, motion initiation and reward learning. Zooming further in, at the synapse, the levels of two proteins involved in neurotransmitter shuttling and synapse maturation were changed. So were a cluster of genes related to learning (plasticity) and depression. Remember, the only thing that differed GF and control mice is their lack of gut bugs. When scientists gave young GF mice normal gut flora from a donor (read: poop implant), several synaptic protein levels returned back to normal, as did behaviour.

Proteins involved in anxiety and learning are expressed differently in control (SPF-left) and bug-less (GF-right) mice. For those interested, A is NGF-1A, B is BDNF

So mice microbiome tweaks mice behavior. But what about humans? In one double blind, placebo-controlled 30-day trial, healthy volunteers given probiotics (L. helveticus & B. Longum) reported less psychological distress than controls. In another similarly controlled trial, healthy volunteers were given probiotics or placebo for 3 weeks. Those who scored lowest on depressive moods showed significant improvement after probiotic supplementation compared to control. Finally, in a small pilot study with chronic fatigue syndrome patients, those who took probiotics (L. casei) daily for 2 months showed significantly fewer anxiety symptoms than did the placebo group.

You may think that everything described above sounds a little iffy (Why look at those proteins and genes and brain area? Why use that strain of probiotic? Why do antibiotics and probiotics show similar anti-anxiety effects?). I tend to agree. The gut-brain-behavior field is still in its infancy – what we do know if that the human microbiome is important, in health and disease. Whether they’re good targets for anxiety and depression treatment though, is still an open question. So maybe it's not yet time to drop the Prozac and pick up the probiotics.

I’ll leave you with this: since what we eat heavily affects the composition of gut flora, and gut flora affects our brains, there is some scientific truth in the old saying “you are what you eat”.

Thoughts?

Diaz Heijtz R, Wang S, Anuar F, Qian Y, Björkholm B, Samuelsson A, Hibberd ML, Forssberg H, & Pettersson S (2011). Normal gut microbiota modulates brain development and behavior. Proceedings of the National Academy of Sciences of the United States of America, 108 (7), 3047-52 PMID: 21282636

Foster JA, & McVey Neufeld KA (2013). Gut-brain axis: how the microbiome influences anxiety and depression. Trends in neurosciences, 36 (5), 305-12 PMID: 23384445