A Strange and Wonderful Beast, Pt. II

In Which We Hunt the Jabberwock

Where we left off, I had isolated a bacterium that seems to be important for cholesterol metabolism, shown that it really does reduce cholesterol (in the chemical sense of the word “reduce”, although probably in the literal sense too), and that it’s a new genus deserving of its own name. I even reanalyzed some publicly available data, to show that the abundance of this bacterium in the gut is inversely associated with serum cholesterol levels in humans.

This is the point in the story where, if I had a PhD, I would publish all this as a paper, maybe do some animal studies, apply for a grant to run a human trial, and then sit on my hands and wait. But I never had the patience for a PhD, and certainly don’t have the patience for all that.

Y’see, this is my mom:

Pictured right, in case that wasn’t clear.

And while I was home for the holidays, I noticed something strange; a pale crescent at the edge of her iris, visible when she glanced down during one of our conversations.

And this freaked me out, because I had seen something like it before—but only once. Back when I was living in the suburbs outside DC, my landlord had a similar ring show up in his eye. I noticed it when I went to visit him in the hospital; I don’t know how long it had been there, he had been unwell for a while…but a few days later, he was dead.

So when I saw the same thing happening to dear old mom, I started frantically googling. As it turns out, it’s a known phenomenon. In the medical literature it’s called arcus senilis. At first, I thought maybe it was a depigmentation, a draining of color—but it’s actually a clouding-over.

Lipid deposits, accumulating in the cornea.

Cholesterol.

Now, like I said, at this point I had already isolated Astrobacillus and done the preliminary characterization work. I was still working for Seed, and for a while I’d been trying to get up the momentum within the company to develop it, but I wasn’t having much luck.

And in that moment, I had this terrible vision of a future where my mom has a stroke while this project is in development hell, and then a year later we find out that Astrobacillus works like gangbusters for reducing stroke risk, and I spend the rest of my life wondering what might have happened if I had moved faster, eventually going mad with regret and becoming a supervillain who calls himself…I don’t know, the Poopler or something.

“Y’know this was white when I bought it”

If I were a perfectly rational, evidence-driven person, seeing that little ring in mom’s eye wouldn’t have changed much. After all, I’ve known for years that she has high cholesterol; statins flare up her arthritis, so she’s been getting by on red wine and warfarin since her valve replacement. And the literature around arcus senilis suggests that it doesn’t actually mean you’re at greater risk for a cardiovascular event than anyone else with unmanaged high cholesterol.

But like all of us, my brain works in emotions and narratives, and there was something so horror-movie about that moment, or maybe fantasy-novel, you know? Young knight errant sallies forth to lift the curse upon the land, slay the jabberwock that’s been killing his countrymen…

…periodic reminder that heart disease is responsible for more deaths than all the cancers put together…

…and, having found a piece of the puzzle, returns home to discover that—in his absence—the beast has laid its mark upon his own mother, and the clock is ticking.

Better solve that puzzle quick, boy, the jabberwock grindles.

So we’re trying it!

I was test subject #1, of course—the strain came from my own microbiome (at the risk of sounding, uh, presidential, my lipid panel numbers are fantastic) so that was the logical place to start.

My best friend CJ, who happened to have high cholesterol and no coprostanol in his stool, bravely volunteered to be test subject #2. So far, it seems to be safe and well-tolerated, but the exciting thing is that—even though he last took the probiotic in the first half of May—he still had a coprostanol spot showing up in his poop as of the end of the month. It was a faint band, maybe 10% as dark as the cholesterol one, and another two weeks later it had vanished again—but even this is a pretty solid milestone in my book.

Still, we’ve got a ways to go to reach our goal here, which is engraftment: the bacterium becoming a part of his microbiome the way it’s part of mine, moving him indefinitely from “non-converter” status to “converter”. In theory, this shouldn’t be too hard, given that it’s apparently how things work in every healthy person: at some point early in life, a few cells of Astrobacillus find their way into your gut—likely from your parents’—and take root, reproducing faster than you can poop them out, equipping you with “bonus” genes for the rest of your life…or at least until you get unlucky with an antibiotic.

More promising than “in theory”, it’s already been proven possible in animals. In a 1995 study, researchers put some rabbits on a high cholesterol diet,¹ and then fed them some live Eubacterium coprostanoligenes HL (the only coprostanol-producing bacterium currently available in public strain banks) for ten consecutive days. In the month that followed, the control rabbits—which were fed the same diet, but given heat-killed bacteria instead of live—had plasma cholesterol levels averaging 248 mg/dl, while the experimental group’s cholesterol was 183 mg/dl.

That’s huge—the kind of difference that’s not only statistically significant,² but what we’d call “clinically meaningful”. A drop of 65 mg/dL (AKA 1.68 mmol/L) is similar to the average effect of statins—and studies have shown that lowering your LDL by that much is enough to cut the risk of heart attack by about 60%, and stroke by 17%. Keep in mind that the probiotic was only dosed during the window labeled “Eubact” on the graph above (days 50-60), so clearly engraftment is possible—even when using a strain that originated from another species entirely.

Out of an abundance of caution, we’ve been scaling up the doses pretty slow in our first-in-humans work, and waiting a while between tries. The dose that we gave CJ in early May, which seemed to stick around for a few weeks in his gut, was about equivalent to the daily doses that were used in the rabbit study, scaled to a human’s weight. So this bodes well for the possibility that trying again, giving the same dose given multiple days in a row, could make a more permanent impact on his biology.

It might not be that simple, of course. For instance, CJ’s diet is a little weird, consisting almost entirely of cheeseburgers and coke. In some senses, this is a blessing; it eliminates a huge source of potential variance—there’s a reason lab rats are kept on a homogenous diet of pelleted “chow”. But it might turn out that the strain of Astrobacillus we’re working with needs pectin, or cellobiose, or one of the dozens of other things that are abundant in vegetable matter but not in burgers, to properly engraft: As best we can tell, cholesterol’s role in this creature’s metabolism is as an electron acceptor, the same role that oxygen plays in our metabolism. It might be that you need to eat something bitter once in a while, to stimulate the flow of bile (and thus cholesterol) into the gut. Or it might be that Astrobacillus doesn’t play nice with some organism which is present in his GI tract but absent in mine.

So now that we’ve got a little safety data,³ I’m recruiting for a broader study, which will involve looking at the fecal cholesterol/coprostanol ratio as well as examining the composition of the microbiome by sequencing. This will help us suss out the relationship between a person’s coprostanol-producer status, their microbiome composition, and their serum cholesterol. As we try dosing it into more people, we’ll find out if there are patterns which indicate likelihood of success. Maybe we’ll find that it’s easier to move the needle in people who already have a little coprostanol in their stool—that taking someone from 0% coprostanol/100% cholesterol to 10/90 is actually a lot harder than bringing someone whose baseline is 10/90 to 50/50. Maybe it’ll turn out that everyone who’s a total non-converter is also missing Collinsella or Coprococcus in their guts, suggesting that these people need a combination probiotic. As mentioned last post, though, there’s a pretty strong inverse relationship between the abundance of this bacterium in your gut and your serum cholesterol, so it might be as simple as “more is better”.

In any case, it’s an exciting time, and it’s going to be a busy couple of months. If you’re interested in helping alpha-test this (or just contributing to the dataset) and you haven’t already signed up, you can do so here.

—🖖🏼💩

1. Rabbits are a good model animal to use for a study like this, because—although their livers produce cholesterol much like ours—their diets ordinarily contain none.

2. The wild thing is that this study was run in a total of six rabbits: three experimental and three control. If you don’t know your statistics, that kind of thing might make you go “wait a minute, that might just be a fluke”…but this is the point of a p-value, which takes into account the variance within groups. To get a p-value less than 0.001 with an n of 6, your effect size has to be MASSIVE.

3. My brother Michael—who has high cholesterol and low-but-nonzero fecal coprostanol—also tried some a few weeks ago, and he’s suffered no ill effects.