In a recent study published in the journal Cell Host & Microbe, a team of researchers from the University of Oregon (UO) discovered that strength in numbers does not hold true for intestinal microbes, and that, in fact, a minority population of the right type might hold the key to regulating a good health.
An implicit assumption of microbiome profiling for diagnostic purposes is that the proportional representation of different taxa determine host phenotypes. To test this hypothesis, in the study titled “Individual Members of the Microbiota Disproportionately Modulate Host Innate Immune Responses,” Annah S. Rolig, study lead author and a postdoctoral researcher in the UO’s Institute of Molecular Biology, and colleagues colonized gnotobiotic zebrafish (zebrafish that are either germ-free or have only certain strains of microorganisms) with zebrafish-derived bacterial isolates. They then measured bacterial abundance and host neutrophil immune response.
The team reported that one particular bacterial species, called Vibrio, drew numerous neutrophils, indicating a rapid inflammatory response. Shewanella, conversely, was found to barely trigger an immune response when inserted into a second germ-free fish. And when both species were introduced into a third germ-free fish, in a ratio of 90% Vibrio to 10% Shewanella, its inflammatory response was found to be entirely controlled by the low-abundance species.
According to Dr. Rolig, the findings open a path to study the function of each bacterial species in the gut and to eventually, perhaps, predict and prevent disease.
“Until now, we’ve only been able to capture proportional information, like you’d see displayed in a pie graph, of the makeup of various microbiota, in percentages of their abundance,” Dr. Rolig said in a recent news release. “Biologists in this field have typically assumed an equal contribution based on that makeup.”
Low counts of a bacterial species have typically been disregarded as unimportant, while slight ratio shifts in abundant microbe populations have been thought to play a role in such diseases as diabetes, obesity, and in inflammatory bowel conditions like Crohn’s disease. This thinking is now changing, Dr. Rolig said. “The contribution of each bacterium is not equal. There is a per-capita effect that needs to be considered.”
The keystone — a vital participant that functions in the regulation of a healthy microbiota — may dwell in low-abundant species of bacteria. The team further discovered that these bacterial species secreted molecules — yet unknown — that permitted them to reduce the immune response to the entire population.
“Now we’ve shown that these minor members can have a major impact. If we can identify these keystone species, and find that in a disease state one species may be missing, we might be able to go in with a specific probiotic to restore healthy functioning,” explained Dr. Rolig, who is also a scientist in the National Institutes of Health-funded Microbial Ecology and Theory of Animals Center for Systems Biology, known as the META Center, at the UO.
To create a model that captures per-capita contributions of microbes in a particular population, Dr. Rolig and colleagues turned to UO physicist Raghuveer Parthasarathy. Parthasarathy’s math-driven model, specified in the article, provides formulas that are able to predict collective inflammatory responses of bacteria combinations.
“I’m really proud of this paper because it exemplifies an achievement of one of the major goals of the META Center for Systems Biology, namely to provide a predictive model of how host-microbe systems function,” said Dr. Karen Guillemin, biologist and director of the META Center. “This experimental and modeling framework could be readily generalized to more complex systems such as humans, for example to predict disease severity in individuals with inflammatory bowel disease based on the pro-inflammatory capacity of their gut microbes as assayed in cell culture.”