Bacteria and Depression: Something to Test

By Derek Lowe 17 January, 2019

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!