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Bacteria and Depression: Something to Test

Microbiome, microbiome – you haven’t been able to turn around in this business the last few years without hitting some sort of story about the microbiome. It’s easy to roll your eyes and decide that it’s all hype, but that’s the thing: it really is important. It can’t be dismissed just because we don’t understand what’s going on (and just because there are people lined up trying to sell you things based on the tiny scraps of knowledge we do have). Things are starting to be worked out, and there will be more.

Here’s one. For some years, there have been reports of microbiome effects on depression and mood in humans. Some of that has been junk, but some of it hasn’t, and it’s pointed to some real effect that hasn’t quite been worked out, quite possibly through production of neurotransmitter molecules. Now perhaps it has – this paper reports that the human gut hosts a large number of bacterial species that produce GABA (gamma-amino butyric acid, famous as a neurotransmitter) and another large population of bacteria that actually use it – or outright require it – as a growth factor. There are a lot of thus-far-unculturable bacteria in the gut (and everywhere else, honestly), and one of the most obvious reasons for this is the lack of some key nutrient or growth factor in the culture medium. In this case, the strain KLE1738 was finally cultured in the presence of other gut bacteria (and could not be grown without them), and it turns out that it requires GABA that the others can provide. (Co-culture of KLE1738 with bacteria engineered to produce even more GABA confirmed the effect). This strain is missing a key enzyme in a carbohydrate-handling pathway that makes it require GABA, and that uptake (the bacteria have rigged up their own enhanced transport system) was confirmed by radiolabel studies. Those also suggested a metabolic path for GABA as a nutrient, through 4-hydroxybutyrate and then crotonyl-CoA.

And what’s more, when the team studied 23 individuals with major depressive disorder, their gut microbiota (as monitored by 16S sequencing of fecal samples) showed a negative correlation with the GABA-producing strains. This is not a large study, but it’s very suggestive of further lines of research. Is that (as it would appear at first glance) really the causative order of things? If so, what starts off the imbalance in the GABA-using gut ecosystem? Is there some way to monitor that or prevent it? How long ago did that imbalance occur in patients who eventually are diagnosed with depression (for example, does it affect brain development)? And at what point could one intervene in the microbiota to have a therapeutic effect?

We’re going to have to study more people and more of their bacteria to answer those questions, but there is at least a clear line of inquiry to pursue. That means a lot in a field like this, and there are a lot of field like this: big piles of data, with greater or lesser correlations running through them like bumps or folds in a bedsheet. Does the sheet look like that because there’s something under there? Or was it laid down that way via some other cause? Or it is just an accident or an illusion? Is it that there’s nothing under there at all and no particular reason for it to look that way in the first place? But in this case, we have a place to start looking and a plan for how to look at it. I look forward to seeing how this story plays out!

24 comments on “Bacteria and Depression: Something to Test”

  1. Mike says:

    Current data suggests that GABA doesn’t penetrate the blood brain barrier. You can buy it as a supplement and take grams of it with an effect that isn’t really detectable.

    So if bacteria are producing it in the gut, does that really have an effect?

    I suppose one could argue that the GABA produced enters some sort of metabolic pathway and eventually impacts the CNS. But could you just take these people who don’t have the GABA producing bacteria and supplement them to see if anything changes.

    I agree with Derek that the microbiome undoubtedly has some impact on humans, but what makes me roll my eyes is that’s it’s now apparently the cause of all of our bodily ills…without any real proof.

    1. Spience says:

      One might also argue that the BBB is not part of the equation at all, and that GABA acts on the enteric nervous system, mood disorders being a downstream effect. Theories around microbiome-gut-brain axis are all around and not limited to GABA. Still, one should question what makes the effect of GABA produced by the microbiome any different to swallowing a GABA supplement. I noticed a couple of the 23 said individuals have a laundry list of medications in their systems, one was on 14 different drugs at the time of stool collection! I can imagine that counteracting the effect of the GABA somewhat.

      1. Chrispy says:

        This is insightful. It seems as if we ignore the enteric nervous system.

    2. chimaera says:

      In the last year, studies have been published which tie in to this in an interesting way.

      1. The enteric nervous system has a direct link to the brain, so production of GABA in the gut could have an effect through this route: http://www.sciencemag.org/news/2018/09/your-gut-directly-connected-your-brain-newly-discovered-neuron-circuit

      2. The brain may have its own microbiome: http://www.sciencemag.org/news/2018/11/do-gut-bacteria-make-second-home-our-brains

      1. Vader says:

        So, when someone calls me a sh-thead, that may actually be a good thing?

    3. zero says:

      GABA itself may not meaningfully cross the BBB, but what molecules are being produced by the GABA consumers?

      This has complexity and difficulty at least comparable to ecosystem studies. Network effects are real. Studying individual gut microbe strains in isolation should be a tool, not the whole toolbox.

    4. Michael Striker says:

      I think this is more proof that we can’t say “X is the cause of Y” unless only controlling for levels of “X” proportionately modulates “Y”. But, outside of those definitive circumstances, we can still assume that blanket statements are misleading.

      (We can also assume that those making such statements are either misapplying logic or misguided or acting deliberately. )

  2. ScientistSailor says:

    No comment on the Forma layoffs?

    1. anon3 says:

      You could enlighten us? If its a small layoff, then it wouldn’t make for a blog post…

        1. Passerby says:

          I am genuinely curious to know what Forma has accomplished in terms of actual drug discovery since it was founded.

  3. Scientist says:

    “their gut microbiota (as monitored by 16S sequencing of fecal samples) showed a negative correlation with the GABA-producing strains” doesn’t seem to be strictly what they did based off of the abstract. The 16S provides a readout at the genus level (Bacteroides). Some (most?) species or strains within that genus likely don’t contain the biosynthetic pathway to produce GABA. Since the 16S only insinuates that the biosynthetic pathway is there, I’m curious why they didn’t do some sort of sequencing that actually detects the pathway.

  4. Anonymous says:

    Recently mentioned In The Pipeline was the guy at MGH who is looking at Alzheimer’s, or at least amyloid plaques, as a response to bacteria in the brain: link in handle.

    Working in the field of antibacterial med chem can sometimes be depressing, too. ;-(

  5. I'm no statistician says:

    I will acknowledge that biology has error bars, but if you dropped 2-3 data points on the tail of that regression then I would be more inclined to draw a circle around the ‘cluster’ rather than a line through the ‘trend’.

    I found this amusing.

    https://en.wikipedia.org/wiki/Further_research_is_needed

  6. Emjeff says:

    Is it just me, or is it beginning to look like the majority of human diseases are infectious in nature?

    1. Todd says:

      Either infectious or immune system related. It somewhat makes sense, considering how eukaryotes evolved. Undergrad immunology strikes again!

  7. MMK says:

    What if there is a causative link, but in the other direction? Namely, that depressed people are likely to have seriously screwed GI tracts due to stress.

    1. Derek Lowe says:

      That’s definitely something that current work can’t rule out, I’d say. . .thus the remark about causality.

  8. Barry says:

    Any embryologist will explain that the brain* is just a swelling on our GI tract. But whether a ligand binding there can affect “mind” requires proof.

    *of which humans are so inordinately proud

  9. Nameless says:

    “Co-culture of KLE1738 with bacteria engineered to produce even more GABA confirmed the effect”

    To prove that GABA was the needed nutrient adding it to the culture medium would be the straightforward proof of the dependency? This co-culturing only proves that the other strain produces something, maybe GABA, maybe something unknown, that is required for survival.

    Or am I missing something?

    1. MMK says:

      Again, the links between autism and various GI tract functional abnormalities may be the result of extreme levels of stress and restricted (i.e. usually pretty bad) diet and/or unusual eating habits… This would explain why dietary interventions (like GFCF diet) are not efficacious in reducing ASD symptoms (but that’s already way off topic).

    2. While otherwise wary of assigning causality, there is some plausibility in the “vagus nerve as conduit” theory. Epidemiological studies have hinted that vagotomy (mainly for refractory gastric ulcer) correlates with a lower risk of Parkinson’s disease and one recent large (1.6m patient records) study suggests that appendectomy also reduces PD risk (but only in city dwellers).

      The appendix is a reservoir for abberant forms of α-synuclein similar to those found in the PD brain and which, in vitro, are capable of altering normal α-synuclein. The appendix may play a role in maintaining the gut microbiome and inflammation could result in an increase in “pro-PD” metabolite formers. Fascinating as a hypothesis, but too early to book that elective appendectomy.

      Science News piece here http://tinyurl.com/yagm7sx8.

  10. Simon says:

    But with this gut metagenomics links I always wonder what is cause and what is effect.
    I mean, it is clearly established that mood, stress etc. affects the digestive tract – motility, contractions, pain reception … Couldn’t the altered bacterial communities be a consequence of depression rather than the cause?

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