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Scientists have generated a rudimentary map of the human gut microbiome, which shows the spatial organization of different microbial species. The studies are the first to examine the three-dimensional landscape of gut microorganisms, according to researchers at the Forsyth Institute in Cambridge, MA, who led the research. “No one has looked at a complex microbial community in the gut this way before,” says Gary Borisy, Ph.D., a senior research investigator at the Foryth Institute. Their findings indicate that whereas the oral microbiome is made up of organized microbial communities, the gut microbiome is generally much more homogeneous, with just a few, relatively defined microhabitats.

“If we truly want to understand the role of the microbiome, it is not enough to know just which microbes are present,” continues Borisy, who is senior author of the published paper describing the research, which was carried out in collaboration with researchers at the Marine Biological Laboratory (MBL) at Woods Hole, MA, and Washington University in St. Louis, MO. “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."

For their studies, the scientists introduced 15 bacterial species into germ-free mice, effectively generating a humanized model of the gut microbiome. While 15 species represent only a snapshot of true gut microbiota diversity, the approach provided an opportunity to investigate how microbes assemble into distinct neighborhoods, the researchers claim. “…we could see exactly how the bacteria were arranged relative to each other and relative to landmarks like food and host tissue," notes lead author Jessica Mark Welch, Ph.D., associate scientist at the MBL.

The researchers labeled each bacterial species with a different probe and applied advanced imaging techniques to detect and resolve each label. An innovative microscopy technique was used to slice optically, rather than physically, through tissues so that the investigators could visualize complex, three-dimensional architecture. Specialized software enabled the team to analyze and reconstruct hundreds of biological images.

The results showed that highly ordered microbial communities formed at different sites in the mouth, “so much so that you might imagine them as multicellular organs, like a liver or a thymus gland," explained 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."

In contrast, in the gut there was a much higher degree of microbial intermingling and far less structured organization, albeit with some evidence of microhabitats where bacteria tended to congregate. "We liken it to a bioreactor, where things are stirred around and well mixed," Borisy commented.

These microhabitats included the gut epithelium with its mucous layer and the gut lumen. In both of these regions, the microbial populations contained fluctuating proportions of different bacteria, although there was no evidence to suggest that some species were found only exclusively in certain areas. "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," added Dr. Welch. "It may be that this mixing is what enables a stable relationship between the host and the microbes."

Although this type of work to study the gut microbiome is still rudimentary, it will provide key insights into microbiome function, Borisy claims. “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. But tell me, how much have you learned about Boston as a city?"

The research is published in the Proceedings of the National Academy of Sciences (PNAS), in a paper entitled "Spatial Organization of a Model 15-Member Human Gut Microbiota Established in Gnotobiotic Mice." The Forsyth Institute’s work is focused largely on oral microbiota, and the approach used for the gut microbiome study was first used by Borisy’s team to study the plaque microbiome.