Can engineered microbes help prevent kidney stones?

Kidney stones are small, hard deposits that form - as their name suggests - in our kidneys. They develop when waste substances in urine build up forming crystals. Those who have had them will know that - if bits break off - they can cause severe pain, lead to infections, and in extreme cases could even obstruct urine flow. But scientists in the United States say they may have a solution. One of the commonest types of kidney stone is formed from a build up of the substance oxalic acid, which we pick up from our diet. So what Wes Whitaker, from Novome Biotechnologies and Stanford University School of Medicine, has done is to engineer a species of gut microbe to become much better at breaking down this stuff, before it gets into the body. The idea is to produce a probiotic that can cut the risk of kidney stones forming…

Wes - What we're focused on is a disease called enteric hyperoxaluria. That is when a chemical called oxalate - which is part of a normal healthy diet found in nuts and vegetables - can be overabsorbed in the gut. Then it’s concentrated in the kidneys and combined with calcium to make these calcium oxalate deposits - kidney stones. About 80% of kidney stones are made up of calcium oxalate. There are a number of reasons why that could happen, but one of the common ones is having underlying gastrointestinal disorders, such as Crohn’s disease or gastric bypass. In those cases, for example, fat malabsorption could lead to calcium getting trapped with the fat that doesn’t get absorbed because of these issues in the gut. Normally, the calcium would bind with the oxalate chemical in the gut and sort of form a solid deposit there, and just pass through and be harmless. But when the fat binds the calcium, now the oxalate is free to get absorbed and that’s why it ends up concentrated in the kidneys.

Chris - In essence, then, it's giving an enriched population of microbes that have the genetic and metabolic know-how - I suppose a biochemical knife and fork - that will dismantle oxalate in the gut so that you can't absorb it and turn it into a kidney stone.

Wes - That's exactly right.

Chris - How have you done that, then?

Wes - We started off with very common bacteria in the gut of most people called Phocaeicola vulgatus, and we made three changes to it. The first was to enable our bacteria to colonise the gut well. You can imagine the gut has hundreds of different microbes that our bacteria would be competing with, and they can vary from person to person. So we wanted that to be more reliable. We engineered in the ability of our bacteria to use this polysaccharide - this nutrient called porphyran - which is found in red algae and you won’t find it in terrestrial plants. Most of us don't have any bacteria in our gut that are capable of using that nutrient. So when we feed that nutrient, we're basically feeding just our bacteria, very simple, and that's important for getting it to work well. We also modified our bacteria so that it was really dependent on that porphyran molecule so that genes that are essential for it to be able to grow don't function in the absence of porphyran, so the bacteria won't grow outside of the patient or treatment period. And finally, we engineered the bacteria so that it's able to perform the therapeutic activity. In this case, like you mentioned, it's the ability to break down this oxalate. We added five genes for the breakdown of oxalate, which the bacteria don't normally do, but we were able to get them to be able to rapidly perform that activity.

Chris - But do you absorb oxalic acid - oxalate - from the colon? Because my understanding is that we only pick up water from there. So how can they exert much of a therapeutic effect if your small bowel, which does most of your absorbing heavy lifting, has already got all the oxalate out and into your bloodstream?

Wes - Yes, that's a great question. There was some unknown about whether or not the colon was the primary place to absorb it. We talked to a number of experts and GI doctors, and we think there is a lot of evidence for that. One of the pieces of evidence is that the bacteria - this Oxalobacter - normally breaks down oxalate. Its absence from the colon, as it primarily resides, is a risk factor for this hyperoxaluria disease.

Chris - Ah, so even though some absorption can happen in the small gut, there’s still a lot going on in the big bowel as well. Hence, if you put the microbes in the right place at the right time, they will break it down and reduce the amount you’ve got circulating. Therefore, you make kidney stones less efficiently.

Wes - That’s exactly right.

Chris - And is that what happened? Did you see that people demonstrated lower blood levels and lower kidney levels of oxalic acid when you did this?

Wes - Yes. We saw that in some patients, we lost the ability to break down oxalate, so there’s room for improvement. But we did see a reduction in urine oxalate in patients, which we’re quite happy with, but this was done with a small number of patients. We would need to do this with a much bigger study to be really confident.

Chris - So at the moment, you know that it has the potential to work. There's a bit of tinkering to do to improve the efficiency. But would the reduction in the amount of oxalate in the urine be sufficient to reduce the risk of developing stones? Or is the difference statistically significant, but it wouldn't make a clinical difference?

Wes - The oxalate in the urine reduced about 20-25%. There's some evidence that the concentration of oxalate in the urine is proportional to the frequency of getting kidney stones. So we think it would be helpful for patients that have recurrent kidney stones. There have been some other companies that have come before us looking to treat this disease and have had previous endpoints being a percentage of patients that achieve at least a 20% reduction in urine oxalate, so we do think it would be clinically meaningful.

Chris - We've been familiar with the idea of the ‘transpoosion’ - the idea of giving people, say, colonic washings to deal with problems like Clostridium difficile, the hospital superbug you often get when people take too many antibiotics, and it saves lives, doesn’t it? So you're actually going a step further and adding discrete microbes to solve discrete problems. Is this really, do you think, the beginning of quite a fertile avenue? Are there going to be a range of possible disorders that we could treat by giving people bacteria, paradoxically, to treat a disease?

Wes - Yes, I think you're exactly right. That is our hope, that here we'll establish a really reliable way of adding defined activities to the gut. And then you can imagine swapping out that oxalate degradation pathway with any therapeutic activity. For instance, you could secrete proteins that bind to the toxins of the bacteria as a way of preventing them from being able to cause diseases or go after something like inflammatory bowel disease, where there may be a number of different proteins or pathways you might want to add to be able to influence that disease. We're hoping this is really a platform for being able to take those approaches in the future.