Probiotics for Kidney Stones?

The Problem with Oxalobacter

Kidney stones are nasty business. About one in ten people get one in their lifetime, and I’ve heard that, between being shot and passing a kidney stone, most people would take the gunshot.

They come in a few different flavors, the most common one being calcium oxalate; these form when a molecule of oxalic acid, which is abundant in leafy greens, meets up with an atom of calcium somewhere in your tubes and forms an insoluble compound which crystallizes out.

This goes on largely unnoticed for a few years, until one day something dislodges it, and suddenly you’re the guy rolling on the ground screaming in pain on the exit platform of Big Thunder Mountain Railroad.

A lot of thought has been put into trying to solve this problem, likely because it’s difficult to think about anything else when you’re trying to force a medieval hand-to-hand combat weapon out of your urethra.

But many years ago, someone had a brilliant insight that went something like:
“huh, cows spend all day eating high-oxalate grasses, and I’ve never seen a cow with a kidney stone’’.

And indeed, it turns out it’s not about how much oxalate you eat: you can put a person with kidney stones on an identical diet to a non-stone-former. The stone-former will still have calcium oxalate in their urine, the non-stone-former won’t. What’s more, putting people on a low-oxalate diet actually seems to increase the body’s propensity to excrete calcium oxalate in the urine.

So people got very excited when some clever scientists discovered the existence of Oxalobacter formigenes. It’s a gut bacterium that’s fully dependent on oxalic acid for growth; it eats oxalate! And it can’t eat anything else.

Here, suddenly, was a nice, clean, simple story: “Some people—and probably all cows—have Oxalobacter or something similar in their guts. And if you’re one of these people, the bacteria intercept the oxalate in your diet and break it down, preventing it from forming stones!”
Bob, as the brits would say, ‘syour uncle.

Unfortunately, it’s not true. Kidney stone formers are just as likely to have Oxalobacter in their guts as non-stone-formers.

You drop nineteen citations in a row when you want to make it clear that a hypothesis is not only dead, but has been autopsied, embalmed, placed in an ornate coffin, and entombed forever in a crypt with an inscription over the door that says “Would’ve been nice if it was true.”

I love when you can see the humanity shine through in a scientific paper. This is an author who feels personally wronged by the Oxalobacter hypothesis, probably because they either
a) Wasted several years pursuing it, or
b) Have spent several years telling everyone pursuing it that they were wrong, and now they get to claim smug vindication.

I don’t have answers yet about what you can do to prevent stones if you’re one of the unlucky ones, but the research has made a few things clear. There is something going on here with the microbiome, but it’s at least a little more complicated than presence/absence of oxalate-eaters intercepting it from the diet. For one, your body actually produces oxalate on its own—more than you get from the diet, unless you’re a several-cups-of-spinach-a-day kind of person.

I mentioned earlier that Oxalobacter has roughly equal prevalence in the guts of stone-formers vs. non-stone-formers, but there is a difference in abundance, meaning Oxalobacter tends to make up a larger percentage of non-stone-formers’ microbiomes.

But feeding people Oxalobacter doesn’t seem to help, and there are a number of other bacteria that are strongly associated with the abundance of Oxalobacter in the gut: if you’ve got a lot of Oxalo, you’ve also got a lot of Ruminococcus and Oscillospira, for example.

One important fact, if we’re trying to make sense of this, is that oxalate isn’t just excreted in the urine; you’ve got special molecular transporters for it, and when these are working properly a lot of oxalate is actively secreted into the intestines. This suggests a model where Oxalobacter abundance is a consequence, rather than a cause.

Our bodies and our diets sculpt the microbiome. This might be why the low-oxalate diet seems, paradoxically, to increase urinary oxalate levels: if you starve out the bacteria that thrive on oxalate, you can’t count on them to clean it up when you eat a bowl of spinach salad. As it turns out, a 2005 study supports this: they found that, while a high-oxalate diet initially led to greater oxalate absorption, six weeks of that diet caused absorption rates to fall again, consistent with a microbial population of oxalate-eaters (Oxalobacter is by no means unique among bacteria in its ability to eat oxalate) growing to take advantage of the new food source.

But the microbiome sculpts our bodies right back, and the bacteria that thrive on oxalate might have a way of “asking” the body for what they need. Imagine Ruminococcus also thrives on oxalic acid, and can produce a molecule that signals your intestinal cells to excrete more oxalate whenever it’s hungry. You’d see an elevation in Oxalobacter abundance in people who don’t get kidney stones, even if it were really Ruminococcus running the show, because the Oxalobacter comes along for the ride.

While most research around stones has focused on the oxalic acid, the calcium bit of calcium oxalate is likely equally important, and it’s known that the microbiome has a lot of ways of influencing how the body handles calcium. I’ve talked about two of them, phytic acid and vitamin K, in previous posts. I’m trying not to become a “golden hammer” kind of person, but I’m intrigued by the vitamin K angle here for two reasons. One: a number of your body’s most important calcium-handling proteins are vitamin K-dependent; VK allows certain proteins to bind to calcium in a unique way, so finding a bunch of insoluble calcium where it shouldn’t be naturally puts vitamin K on my list of suspects. Two: I’ve found a couple of papers reporting decreased activity of vitamin K-dependent proteins in patients with kidney stones, and I’ve received a couple of anecdotal reports of vitamin K2 supplementation helping. (One person said “oxalates poured out of me” when they started taking K2, which I’ve been to afraid to follow up on, but should probably get around to.) If any readers suffer from kidney stones and would like to try out a small-scale placebo-controlled trial of vitamin K for prevention, sound off in the comments; if there’s enough interest I’ll coordinate something.

Lessons

The idea of Oxalobacter as a treatment for kidney stones goes back to the ‘80s, making it one of the first instances of people thinking about how to use bacteria (beyond those found in fermented foods) to improve health. It’s a humbling reminder about the difficulty and complexity of the problems we’re setting out to solve with microbiome science. A clean, simple story is alluring, but without a deeper understanding, you can end up chasing indicators rather than drivers, like cargo cult islanders setting up fake landing strips in hopes of getting supply drops.

That said, there IS a lot of what seems to be low-hanging fruit in the microbiome world: things like Faecalibacterium and certain Coprococcus species that are uniformly associated with good health outcomes, but aren’t available yet as a probiotic. It’s possible that these are just indicators, rather than drivers—but for now, maybe it’s worth just building the landing strip to find out.

🖖🏼💩