Sometime in the last ten years I gave up on the idea of truly keeping up with the microbiome field. In graduate school it was more reasonable because I had the luxury of focusing on viruses in the microbiome, but since then my interests have broadened and the size of the field has continued to expand. These days I try to focus on the subset of papers which are telling the story of either gene-level metagenomics, or the specific metabolites which mediate the biological effect of the microbiome on human health. The other day I happened across a paper which did both, and so I thought it might be worth describing it quickly here.
Brown, EM, et al. Bacteroides-Derived Sphingolipids Are Critical for Maintaining Intestinal Homeostasis and Symbiosis. Cell Host & Microbe 2019 25(5) link
As a human, my interest is drawn by stories that confirm my general beliefs about the world, and do so with new specific evidence. Of course this is the fallacy of ascertainment bias, but it’s also an accurate description of why this paper caught my eye.
The larger narrative that I see this paper falling into is the one which says that microbes influence human health largely because they produce a set of specific molecules which interact with human cells. By extension, if you happen to have a set of microbes which cannot produce a certain molecule, then your health will be changed in some way. This narrative is attractive because it implies that if we understand which microbes are making which metabolites (molecules), and how those metabolites act on us, then we can design a therapeutic to improve human health.
Motivating This Study
Jumping into this paper, the authors describe a recently emerging literature (which I was unaware of) on how bacterially-produced sphingolipids have been predicted to influence intestinal inflammation like IBD. Very generally, sphingolipids are a diverse class of molecules that can be found in bacterial cell membranes, but which also can be produced by other organisms, and which also can have a signaling effect on human cells. The gist of the prior evidence going into this paper is that
people with IBD have lower levels of different sphingolipids in their stool, and
genomic analysis of the microbiome of people with IBD predicts that their bacteria are making less sphingolipids
Of course, those observations don’t go very far on their own, mostly because there are a ton of things that are different in the microbiome of people with IBD, and so it’s hard to point to any one bacteria or molecule from the bunch and say that it is having a causal role, and isn’t just a knock-on effect from some other cause.
The Big Deal Here
The hypothesis in this study is that one particular type of bacteria, Bacteroides are producing sphingolipids which reduce inflammation in the host. The experimental system they used were mice that were born completely germ-free, and which were subsequently colonized with strains of Bacteroides that either did or did not have the genes required to make some particular types of sphingolipids. The really cool thing here was that they were able to knock out the gene for sphingolipid production in one specific species of Bacteroides, and so they could see what the effect was of that particular set of genes, while keeping everything else constant. They found a pretty striking result, which is that inflammation was much lower in the mice which were colonized with the strain which was able to make the sphingolipid.
To me, narrowing down the biological effect in an experiment to the difference of a single gene is hugely motivating, and really makes me think that this could plausibly have a role in the overall phenomenon of microbiome-associated inflammation.
The authors rightly point out that sphingolipids might not actually be the molecular messenger having an impact on host physiology — there are a lot of other things different in the sphingolipid-deficient bacteria used here, including carbohydrate metabolism and membrane composition, but it’s certainly a good place to keep looking.
Of course the authors did a bunch of other work in this paper to demonstrate that the experimental system was doing what they said, and they also went on to re-analyze the metabolites from human stool and identify specific sphingolipids that may be produced by these Bacteroides species, but I hope that my short summary gives you an idea of what they are getting at.
All About Those Genes
I think it can be difficult for non-microbiologists to appreciate just how much genetic diversity there is among bacteria. Strains which seem quite similar can have vastly different sets of genes (encoding, for example, a giant harpoon used to kill neighboring cells), and strains which seem quite different may in fact be sharing genes through exotic forms of horizontal gene transfer. With all of this complexity, I find it very comforting when scientists are able to conduct experiments which identify specific molecules and specific genes within the microbiome which have an impact on human health. I think we are moving closer to a world where we are able to use our knowledge of the microbiome to improve human health, and I think studies like this are bringing us closer.