Dr Terkteltaub continues his observations on the role of the gut microbiome in gout, including the critical importance of fiber and how clindamycin is implicated in gout flares.

Robert Terkeltaub, MD, is Professor Emeritus of Medicine at the University of California San Diego.

Gut Microbiome Dysbiosis, Dietary Fiber, and Gout Risk

• Gout microbiome studies, conducted mainly in China, found reduced microbial diversity, urate-degrading strains and genes, and butyrate-producing bacteria, with lower fecal and serum butyrate.

• Cohort data showed cereal- and legume-derived fiber intake was associated with approximately 30% lower incident gout risk when comparing the highest versus lowest consumption quintiles.

• Canadian target trial emulation found recent clindamycin exposure, versus trimethoprim, was associated with 60% more gout flares among patients without chronic kidney disease (CKD) and 370% more among those with CKD.

I think the things that rheumatologists should know is really that most of this large mass of organisms in the gut sit in the deeply anaerobic environment of the colon and terminal ileum. And there's four major phyla. They're major producers of butyrate. And there's purine-degrading bacteria that are predominantly in that particular phylum as well. They chew up uric acid directly, but in all the 4 phylum of gut bacteria, you can find purine-degrading bacteria. And so patients with gout, the dysbiosis has been studied almost exclusively in China. The key findings are that the microbiome is less diverse, but diversity is something very common in the microbiome. So we're not sure how to unpack that exactly, but we want the microbiome to be diverse for health.

And then there's a decrease in urate degrading microbiome strains and those genes. There's depletion of butyrate-producing bacterial strains and genes. When you deplete these major players, they're linked to decreases in fecal and serum butyrate in patients with gout. And again, this work has come from China. So the diet is different and the genetics of gout are different in that population. And we're waiting for a lot of this work to emerge in North America, which it is, but slowly.

And then what's really odd is that when people get on urate-lowering therapy and their gout gets a lot better, that the microbiome dysbiosis in gout can be restored to the direction of normal. But this is actually very common in diseases where there's gut dysbiosis. When you get back to normal physiology, somehow, we don't understand the how part of it totally, there's restoration to the normal gut-gut microbiome and normal relationships with the host. Most butyrate made by anaerobic bacterial consortia, teams of bacteria, and they ferment dietary fiber and complex carbohydrates in the colon.

Now that's a problem because the American diet, the European diet, very poor in fiber. And that's why you see so many commercials for Metamucil and other things because it's a major public health problem and so extends way beyond gout. But there's going to be naturally less butyrate made if you're providing less substrate for fermentation.

So the Big Bang really in this field was in 2023. And what was defined there by Dylan Dodd's lab and Federico Ray's lab, were that there's high capacity, multiple high capacity urate-consuming, urate-degrading strains. These strains don't have uricase. They have what's called the uric acid gene cluster, which is a very highly conserved urate- and purine-consuming bacterial gene cluster. It's not something that's present in human beings. And it does some really odd things. It takes uric acid and converts it back to xanthan in a high-capacity way. And then it also generates butyrate.

And so what is important about that discovery was they did a lot of experiments in mice and they did experiments in germ-free conditions, but they made the mice uricase-deficient to try to model human disease, and they found that several things happened. One, when you gave antibiotics that targeted anaerobic organisms, there was a massive rise in the serum urate. And so basically when you gave back purine-degrading bacteria, you compensated for the loss of uricase and the serum urate would normalize. The second thing is that they looked in Stanford at a cohort of their patients over many, many years. Patients who had gotten clindamycin, which as you know is used and overused actually to target anaerobes versus trimethoprim sulfamethoxazole. And they found that there was a markedly increased risk over years of developing gout in people who had been exposed to the clindamycin.

And it's been linked to modulation of inflammation and obesity in the Western diet. And what's important about the Bacillota phylum as well is that the members of that phylum are very susceptible to antibiotics and other disruptions affecting the gut. And there's a lot of surgical disruptions to the gut, but vastly more overuse of a broad spectrum antibiotics in dentistry and in other things, particularly clindamycin and dentistry is a stunning example of that. So this becomes a really important problem and something that we have to think about as clinicians.

I think we have to be more practical and think about what we can do at the population level and what we can do, what we can tell our patients as to what they can do and what we can ask them to do to get as much as they can out of their microbiome.

And there is a major problem in the developed countries of a microbiome loop that promotes gout. And it starts with the decrease in fermentable dietary fiber. And these include the cereals and barley and includes legumes, especially things like onions and artichokes, which gets more exotic as we go. These are the really fermentable fiber content items in our diet and also some fruits. And basically our diet is poor in fiber. There's a lot of excess prescribing of clindamycin, Augmentin, broad-spectrum antibiotics in United States and Europe. And when you give these broad spectrum antibiotics, the gut microbiome anaerobes take a huge hit. And to recover, they need to have a lot of fiber in the diet to provide a source of energy that they can use to survive. So that's a really serious public health loop for all the diseases that involve low fiber, including many gastrointestinal diseases, obviously.

And then a tremendous proportion of our patients with gout have chronic kidney disease. So they're relying more on their gut to handle urate. And then their gut microbiome is depleted of purine-degrading bacteria, butyrate-generating anaerobes. So this is a vicious cycle here that we can attack by advocating for much less unnecessary use of broad-spectrum antibiotics and for advocating that our patients, especially the patients that have CKD, should maintain really good dietary fiber intake.

And the study of fiber by Sharan Rai of patients with incident gout, but no history of gout at baseline, in huge numbers of patients in the cohorts showed that fiber from cereals and legumes were inversely associated with gout, the intake of these fibers. And the decreased risk of incident gout was about 30% decreased risk. When you compare the extreme quintiles, the high fiber consumers to the lowest fiber consumers, a 30% decrease in the risk over time of getting gout. So again, that is a very significant finding for public health and related to how we talk to our gout patients.

So Natalie McCormick did a target clinical trial emulation study and looked at in this Canadian population, patients who had received clindamycin versus trimethoprim. And this is also an attempt to confirm what Dylan Dodd had seen in his study of the Stanford cohort looking at the diagnosis of incident gout. But here, what Natalie did was she looked at what happened with patients with gout who developed gout flares. And were there more gout flares when people had recently gotten clindamycin specifically? And oh my God, there were. I mean, it was 60% more in patients without CKD, and it was 370% more in patients with CKD. So the clinical implications of all this material are becoming really more clear when you do these cohort studies.