Are there general laws governing the gut microbiome? This is an important question if we’re to make sense of how the microbial ecosystem inside each of us influences health and disease, without being overwhelmed by its diversity and complexity. It’s also the question that, almost verbatim, starts off a recent paper from my lab, that gets at a small but surprising piece of the answer. The paper is:
Brandon H Schlomann*, Travis J Wiles*, Elena S Wall, Karen Guillemin, and Raghuveer Parthasarathy, “Bacterial cohesion predicts spatial distribution in the larval zebrafish intestine.” Biophysical Journal 115: 1-7 (2018).
and here’s a summary:
As I’ve written before (e.g. this), one of the main goals of my research group is to understand the spatial organization of the microbial communities of the vertebrate gut, especially how the interplay between the behaviors of bacteria and the physical properties of the gut environment. We make use of larval zebrafish as a model vertebrate organism, and light sheet fluorescence microscopy as a tool for 3D imaging inside the live fish.
Thanks to our wonderful collaborators (esp. Travis Wiles, Elena Wall, and Karen Guillemin), and some great new molecular biology tools they’ve developed, we have a “zoo” of several bacterial species native to the zebrafish gut, each engineered with fluorescent proteins.
We’ve known for years, since we first started imaging gut microbes, that some species can be very individualistic, zooming around the gut like a swarm of bees. I’ve posted this movie before; it’s one of my favorites:
We also know that some species tend to aggregate, forming dense clusters.
Furthermore, we know that some species are located mostly in the front (anterior) part of the gut, and some species are more posterior.
We can imagine, therefore, graphing the fraction of the bacterial population that are un-aggregated individuals (the “planktonic fraction”) versus the average (center of mass) position along the gut axis, where “0” means all at the front and “1” means all at the back. Each species would contribute one point to such a graph. We might imagine the graph would look something like this, with a variety of points indicating a variety of possible gut bacterial lifestyles:
What does the graph actually look like? We — more precisely the amazing duo of Brandon Schlomann and Travis Wiles — examined seven different zebrafish gut bacterial species, each imaged in isolation inside fish, without other species present. They found the following:
We were shocked! Rather than a random bunch of points, the datapoints all lie on a line, indicating a general relationship that transcends the peculiarities of particular bacteria. There are other trends describing the sizes of aggregates, etc., that we mapped out in the paper.
What’s the cause of this relationship? In a rough sense, we believe that the link between aggregation and position is forged from the interplay of peristaltic transport (the periodic “squeezing” motion of intestines), gut geometry, and bacterial growth dynamics. Oversimplifying: aggregates are pushed downstream. We’re presently making progress on a more quantitative understanding that, it turns out, is helping us understand other exciting experiments on the effects of antibiotics on gut microbes. (Stay tuned for that story…) Brandon is driving this work; see here for an amazing paper from him.
Even without a full understanding, I’m very happy about what we’ve uncovered. Most of us would consider our guts to be a dauntingly messy system, and to find robust relationships is not only deeply satisfying, but it suggests that manipulating “local” features like how bacteria stick to each other can alter “global” features like species range — potentially useful for intentionally engineering the microbiome.
More deeply, where we’re at reminds me of much more important work from long ago. In the early 17th century, Johannes Kepler realized that data on planetary motions could be described by elliptical orbits. This empirical relationship had to wait until the late 17th century for an explanation, when Isaac Newton showed that it is a consequence of gravity decaying as the inverse-square of distance. This understanding of planetary orbits is a canonical example of the power of physics to understand a mechanical universe, but it’s worth remembering that it was neither obvious nor rapid. The challenge for present-day Newtons to make sense of the gut microbiome, and other complex systems. Perhaps these will become the canonical models of predictability in the textbooks of the future!
A leaf, because it’s still Fall. I based it on a piece in a book on botanical illustration, but I can’t remember which one.
— Raghuveer Parthasarathy. December 14, 2018