The human gut is a teeming locus of bacterial enterprise. This ever-changing clump of activity—our gut microbiome—spans the length of the stomach and intestines and is colonized by trillions of microbial residents, more than anywhere else in the human body. 

In the recent decade or so that human gut microbiome research has taken off, scientists have established relationships between different types of bacteria and a variety of physiological outcomes both beneficial and adverse. Most conclusively, a relationship has been identified between imbalances in different bacterial groups and obesity related symptoms. 

However, new research was presented Feb. 13 at the 2015 American Association for the Advancement of Science’s Annual Meeting in San Jose, California suggesting that the relationship between obesity and the kinds of bacteria living in one’s stomach may be a red herring of sorts. 

“It’s a bit complicated,” said Katherine Pollard, a senior investigator at the Gladstone Institutes and a professor at the University of California, San Francisco. “I think a number of variables are at play. The first one is that there is real, biological variability—quite a bit of it—between people’s gut microbiomes.”

Pollard said not only is there great variability between the gut bacteria of different people who live in close proximity to one another, sharing meals and common spaces, but the bacterial content of an individual’s gut can vary from day to day. This shifting array of microscopic guests led Pollard and a team of researchers to perform a systemic review of prior studies that implicated particular strains of bacteria and imbalances between those strains as having a causal link to obesity.

“What we saw when we reanalyzed lots of studies is if you have a background and a lot of variability and then you take a small sample—a handful of individuals who are lean and a handful who are obese—you could find differences just by chance,” Pollard said. “Because people are so different from each other.”

The team has hypothesized that the genetic makeup of the bacteria present in the microbiome, rather than the type or amount of bacteria itself, may play a more causal role in presenting disease outcomes like diabetes.

“There’s really striking evidence [of this] even within the same species,” Pollard said. “You and I could both have what microbiologists would call the same exact species of bacteria but your version could have 30 or 40 percent of their genes be different from my version.”

According to Sean Davies, an assistant professor of pharmacology at Vanderbilt University, although there is a body of scientific research establishing that gut bacteria do contribute to obesity in some way, much of the original research focused on the ratio of two specific phyla, or divisions, of bacteria that appear in the human gut, which is an approach that minimizes the complexity of the microbiome and its inhabitants.

“It’s been apparent for quite a while that in other studies that have been going on, that simple ratio couldn’t possibly be the primer that was the major difference,” Davies said. “There’s all these different species [of bacteria] within the phylum which have many different metabolic properties and make different metabolites. It’s not surprising that in the end, it was too crude of a measure.”

Davies said that in recent years, researchers have attempted to hone in on particular species or metabolic pathways—specific types of chemical reactions—that might help clue them in to how different types of nutrients are processed in the gut. The complexity of the puzzle is compounded by the fact that, similar to the way diseases like obesity are the result of many contributing factors, it is likely that multiple metabolic pathways are involved and may play important roles for some people but not for others. The types of pathways and metabolites that are produced depends on the present bacteria’s genetic profile, according to Pollard.

“Bacteria do a lot more than other organisms,” Pollard said. “The problem with saying, ‘If you have this type of bacteria you’re more likely to be obese,’ is that [there are] factors that make the genomes of bacteria very dynamic. That even knowing that you have a particular species doesn’t tell me for sure what that species can do. We just know it’s there, but we don’t know what it’s doing.”

According to Thomas Sharpton, an assistant professor in the departments of microbiology and statistics at Oregon State University, extracting the DNA from a microbial community and then fragmenting it in order to digitally represent its sequences and reference them against preexisting data can help to determine what biological functions the bacteria might be able to perform.

“For example, we might determine that one particular sequence encodes a gene for which we know something about, given other organisms we studied previously,” Sharpton said. “We may be able to infer the biological function.”

Even with the ability to sequence the bacterial genome to a point where researchers may be able to glean information about the specific functions of certain genetic codes, Pollard said it only takes minor changes in the genome to radically alter how a microbe interacts with its host. 

“I actually do think there is some relationship with obesity, microbiome and diet, it’s just not as straightforward as the percentage of a particular phylum,” Pollard said. “So there are some associations with particular genes and with particular species or strains. It’s just not as simple, unfortunately, as it originally appeared.”