A collaboration between 3 research institutions is examining how the gut microbiome is spatially organized, uncovering a surprising degree of mixing among different bacteria. This work, which is the first to explore the 3-D structure of a diverse array of gut microbes, has uncovered stark differences between the microbial landscape of the gut and those of other areas of the body such as the mouth.
“No one has looked at a complex microbial community in the gut this way before,” said senior author Gary Borisy, PhD, a senior research investigator at the Forsyth Institute in Cambridge, Mass, which is joining the Marine Biological Laboratory of Woods Hole, Mass, and Washington University in St. Louis in the project.
“If we truly want to understand the role of the microbiome, it is not enough to know just which microbes are present. We must also learn what they are doing, who they are talking to, and why. Part of the answer to that problem is to figure out who is next to who and who is next to what,” Borisy said.
The researchers introduced 15 different bacterial species into germ-free mice, creating a humanized model of the gut microbiome. Although it is only a partial representation of the full suite of microbes typically found in the human gut, this simplified microbial community provided a key opportunity to investigate how microbes assemble into distinct neighborhoods, according to the team.
“We used probes that lit up each of the bacterial species with a different color so that we could see exactly how the bacteria were arranged relative to each other and relative to landmarks like food and host tissue,” said Jessica Mark Welch, PhD, first author and associate scientist with the Marine Biological Laboratory.
Based on previous studies of the gut microbiome as well as their own research on the oral microbiome, specifically the plaque that forms on teeth, the researchers expected to see a significant amount of structure.
“At the sites we’ve examined so far in the mouth, we see highly ordered microbial communities, so much so that you might imagine them as multicellular organisms, like a liver or a thymus gland,” said Borisy. “They are made of bacterial cells, of course, but there are many different cell types organized in a highly structured way like a body organ.”
But that isn’t what they found. In the gut, the researchers observed a high degree of mixing among microbes. It wasn’t a completely homogenous mixture, but still highly intermingled.
“We liken it to a bioreactor, where things are stirred around and well mixed,” said Borisy.
While this model gut microbiome lacked a highly organized structure, there were some micro-habitats where bacterial cells tended to congregate. These sites included the tissue lining the interior surface of the gut, or the epithelium, which is typically coated with a layer of mucus. They also included the central space, the lumen, where food and mucus also are collected.
While the microbial populations at these locations varied somewhat in their overall makeup—that is, the relative proportions of the different bacteria may fluctuate—the researchers did not observe any stark differences such as a bacterial species found exclusively at one site and not another.
“We think the host is homogenizing the microbial community, using muscle contractions to mix the contents of the gut and push them up against the gut wall and sloughing mucus and epithelial cells from the wall into the lumen,” said Mark Welch. “It may be that this mixing is what enables a stable relationship between the host and the microbes.”
The researchers used chemical techniques that made it possible to label 15 different microbes; advanced imaging methods that can detect and resolve these labels; cutting-edge microscopy that can slice through tissues optically instead of physically to visualize complex, 3-D specimens; and software that facilitates the analysis and reconstruction of hundreds of biological images. This approach first was applied to the researchers’ studies of the plaque microbiome in 2016.
Most of the Forsyth Institute’s work is in the oral microbiome with a driving goal to better understand microbial communities. In addition to better understanding what the rules are for governing one particular microbiome by studying a variety of sites in the body, it is also possible that microbial communities can interact in ways that influence health, prompting these investigations into the gut microbiome.
Borisy emphasized that this type of microbiome research is in its infancy, though it is essential for developing a deep understanding of microbial function.
“Imagine that you come into Boston and someone hands you a telephone directory of everyone who lives there. That’s great. Now you have a list of who is there,” Borisy said. “But tell me, how much have you learned about Boston as a city?”
The study, “Spatial Organization of a Model 15-Member Human Gut Microbiota Established in Gnotobiotic Mice,” was published in the Proceedings of the National Academy of Sciences.
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