The Takeaway Points
To study the link between Ridperidone, the microbiome, and weight gain, the group setup a study in which mice were treated with Risperidone through their drinking water (a common, non-invasive approach for delivering drugs). They started by confirming that Risperidone does in fact increase the body mass of their experimental mice, and they used 16S rRNA gene analysis to show there were differences between the bacterial communities of mice treated with Risperidone and the vehicle control (see the paper for the details).
Flow chart from the manuscript, illustrating the
protocol used for fecal content transplant.
The group went on to evaluate the role of metabolism in weight gain. They found that despite the same amount of food being ingested between groups, the Risperidone treated mice experienced an altered resting metabolic rate. This confirmed an altered metabolism along with an altered microbiome and weight gain in the Risperidone treated mice. This effect was transferable to otherwise healthy mice by transferring the microbes from Risperidone treated mice. This was done as a fecal microbiome transplant, similar to what is done therapeutically for humans.
This is a cool result, but one caveat that comes to mind is whether the drug was present in the fecal contents, and maybe that is what caused the transferred effect, at least in part. Unlike many microbiome studies before them, this group actually did this experiment, and found that there were some residual levels of Risperidone in the donor fecal samples. This means that the healthy mice got both the bacteria, as well as some of the drug. It was not clear to me whether this amount of Risperidone, despite its low level, was enough to elicit a response. It seems like the microbes are playing a role, but this is still something the group will have to look into further to be sure.
The Role of Phages in Weight Gain
Now the coolest result of this paper is saved for last. We know that phages (bacterial viruses) not only kill bacteria, but can also transfer genes between bacteria and affect how they behave. The authors recognized this and tested whether phages were sufficient to cause the observed effect, instead of assuming it is a bacterial response like so many researchers have done before them. They did this by simply purifying the phages from the fecal samples and transferred them to new, healthy mice. Their result was that the phage sample was sufficient for transferring the effect, suggesting the phages, and not the bacteria, are the true players behind the transferred weight gain.
Resulting figure from the manuscript, showing the increase in body weight after
phage treatment (section A).
This is actually an incredibly important finding for the field. As far as I know, this is one of the first pieces of evidence that a phage community from a fecal microbiome transplant is sufficient for transferring a phenotype. Up until now, whole communities have been transferred (including both bacteria and phages), but it was always just assumed that bacteria were the culprits. This sheds some doubt on that previous work, and suggests it could have bee phages the whole time. This result also provides a case for why we need to be studying the virome instead of focusing on the bacterial communities. To truly understand the microbiome, we need to think about all of the members present.
So what is next for this work? As I mentioned above, I think the authors will have to do more to confirm the drug is not present in their phage fraction and causing the observed effect. Other than that, I think it is wide open. It would make sense to sequence the phages to see what sorts of genes might be transferred through the phages. They could also further support the role of the phages, and not any residual drug, by treating germ-free mice with the phage solution. If the germ free mice show weight gain, it might not be an actual phage effect because phages most likely need their hosts to act. And the list goes on and on...
In the end, this is a really cool study, a relatively easy read, and the start of something cool. There is certainly a lot of work to be done, but there are some really cool directions that this research can go into. I am certainly excited to see where they take it, and to see what sorts of publications come out of the lab in the future.
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Bahr, S., Weidemann, B., Castro, A., Walsh, J., deLeon, O., Burnett, C., Pearson, N., Murry, D., Grobe, J., & Kirby, J. (2015). Risperidone-induced weight gain is mediated through shifts in the gut microbiome and suppression of energy expenditure EBioMedicine, 2 (11), 1725-1734 DOI: 10.1016/j.ebiom.2015.10.018