Could we use bacteria to fight disease?

While efforts continue to identify more specific microbial contributions to certain diseases, it is important we have a way of (1) being able to test whether these bacteria and the products they make are actually involved in causing or contributing to disease and (2) if it turns out that they are, that we have a way to effectively deliver therapies to the gut in a targeted manner. Amir Zarrinpar, gastroenterologist at UC San Diego, believes he has found a way to do this using a modified form of the common bowel bacterium E.coli. We often regard E.coli as pathogen, but hundreds of strains have been identified - and many are more friend than foe. Amir explains why some of the current approaches for targeting the gut microbiome are challenging…

Amir - Microbiome is constantly fluctuating with the times of day with seasons. And it's hard to imagine what a therapy would look like that would work on all these different landscapes. What we noticed also was that each individual's microbiome seemed to be very well adapted to that person. And then this made us think that a lot of the approaches that people are taking to treat diseases with the microbiome use probiotics or bacteria that have never lived inside of a host. And we're asking that these bacteria now go into an environment in which they will have a great deal of surviving.

Julia - Yeah. And have you found a way to get around this then?

Amir - Yeah. So the way that we went around it was that instead of using a bacteria that never lived in the host, we went to in this case, a mouse and identified a bacteria that was already part of the microbiome of the mouse. And then we engineered that bacteria to express a gene that was potentially therapeutic or beneficial to the mouse to eventually affect the physiology of the mouse and even alleviate disease in these mice. And what was perhaps most remarkable was that these bacterias stayed in these mice for the rest of their life and were able to affect this change for months after this initial treatment.

Julia - And how did this expression of a new gene in a bacteria impact the health of the animals?

Amir - So we had done a lot of studies before where we were looking at the relationship between microbiome and obesity and diabetes. And we had come up with a list of bacterial genes that we had wished that we could always knock in to see whether it was correlational in terms of its relationship with animals' weight and blood glucose, or did it actually play a role in affecting these things? The first gene that we knocked in was a gene called bile salt hydrolase, which is a gene that changes the bile acids in the gut lumen. And what we found was that when these bacteria overexpressed this gene and actually modified the bile acids, they led to a decrease in blood sugars. And it seemed to show that insulin sensitivity of these mice improved. And this was just in regular normal mice on a regular diet. So we decided to then test this in a type two diabetes mouse model. So a mouse that eats so much that it becomes obese and diabetic. And in those mice, we saw a great reduction in blood glucose months after the mice had received this therapeutic bacteria.

Julia - Do you think that this type of bacterial tool could be used in other diseases as well? You know, say for example, in Parkinson's disease where there's been this potential relationship seen between certain bacterial species in the gut and individuals with the disease, can we use this tool to test if something is actually causal?

Amir - Absolutely. When we were thinking of this tool, we were thinking of it as, as I said, a tool so that individuals who are interested in the gut microbiome can actually knock in functions and determine whether things that they were observing in these multi omic studies that people do affect the host in the way that they think it does. But I think there's another potential science fiction version of what this bacteria could be used for, which is that many of our drugs are produced by E coli in labs and giant vats. And one of the things that we can do with these bacteria is engineer them to sense whether there is inflammation in the gut and thus express an anti-inflammatory whenever they sense inflammation, or perhaps if they can sense different things that are going on within our body, they can then express a therapeutic and create a world in which we don't really have to take drugs anymore because many of these drugs are produced by the bacteria in our gut.

Julia - And do you think then we could make these bacteria specific to different diseases? So if you found a relationship between a microbe in IBS and then you could then express the genetic component of whatever that microbe was doing to help people who didn't have IBS, you could then take that and express it in the E coli and then give it to the person with IBS.

Amir - Exactly. Now there are big questions as to what this would look like, whether it has to be a bacteria from that individual that is given back to that same individual, or whether there is a bacteria that we have found from a single individual that can then go to other individuals that have IBS. But that is exactly the kind of things that we were thinking. So for example, with IBS, there are many people who have been outstanding studies who have looked at the role of the gut microbiome, but before some of these synthetic biology experiments, including ours, there was usually only one way to change a person's gut microbiome effectively. And that was with fecal transplant, which may not last a very long time for someone with IBS who has a chronic disease. So the question here is will something like engineering and individual's native bacteria be able to affect a chronic disease on a much longer time scale, essentially functionally curing diseases. And that is the hope that we're striving towards.