Robert Terkeltaub, MD, on the Impact of the Gut Microbiome in Gout

In part 1 of this video, Dr Robert Terkeltaub reviews how certain mechanisms by which the gut microbiome and genetic variants can affect the disease course of gout.

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

Gout & Hyperuricemia: Clinical Role of the Gut Microbiome and ABCG2-Mediated Intestinal Urate Handling

• The gut is a central “transport hub” for purine and urate metabolism, integrating dietary inputs, endogenous purines, and ABCG2-mediated urate transport into the intestine, with ~1/3 of urate excretion intestinal vs ~2/3 renal in normal physiology; reduced renal function (present in ≥90% of gout) shifts burden to the gut, making intestinal urate elimination critical, especially in Stage 4 chronic kidney disease, where it becomes the primary pathway.
• The gut microbiome is essential to maintain normal serum urate despite intact renal function. The microbiome microbiota provide metabolic capacity absent in humans, who lack uricase, including purine/urate degradation and butyrate production, with butyrate supporting intestinal barrier integrity and suppressing systemic inflammation.
• ABCG2 variants are common in East Asian and some Hispanic populations with up to 50–75% prevalence in certain groups. These variants can impair intestinal urate transport, contributing to early-onset and severe gout. Gut dysbiosis reduces anti-inflammatory butyrate and urate degradation, increases reabsorption into circulation, and may worsen comorbidities (e.g., atherosclerosis), reinforcing the gut’s role in hyperuricemia pathophysiology.

Please check in for Part 2 of this video discussion on the gut microbiome in gout--coming soon.

Hi, I'm Bob Terkeltaub. I'm a professor of medicine, emeritus professor at University of California San Diego. I'm a rheumatologist and my main interests have been inflammation, gouty arthritis, and calcifying diseases. And I'm here today to talk about the gut microbiome in gout.

And you may wonder why the gut, why the microbiome? Because with gout we think about inflammatory arthritis, we think about the serum urate, we think about how the kidneys handle urate, we think about how urate is produced. We think about the diet. Well, I mean I'll have to convince you that there's lots of reasons to think about the gut in gout and the gut's microbiome and gout.

So we start by trying to frame this as to why the gut is important in gout. And the gut is like Grand Central Station in hyperuricemia and gout and it's a transport hub for purines and urate. It's where the diet and the microbiome and the endogenous purines from gut enterocyte lining cell turnover and urate biology where the transporter ABCG2, which imports urate into the gut, where they all meet and where urate and purines are processed. And that's not just dietary purines and urate, as I mentioned.

Then it's also the exit pathway by fecal excretion for urate and it's also a factory for butyrate generation. We like butyrate; it's anti-inflammatory. It's something that's a really nice element in yogurt and cheese. And butyrate is made by teams of microbial strains in the gut and it gets into the circulation and suppresses inflammation by a variety of mechanisms but also helps keep our intestinal barrier in good shape so that LPS and other nasties don't get into our circulation and promote inflammation.

So there's a lot going on in the gut in hyperuricemia and gout. And one strain of investigation has reinforced that there's a multiorgan regulatory circuit that almost functions like artificial intelligence. There's remote sensing. So when the kidneys, the gut, the liver, the brain, and the circulation all talk to each other in ways that are subliminal, really they're talking to each other about information from what the diet has provided in terms of sugar, purines, fat, what is going on in terms of the microbial metabolism of a variety of amino acids, including tryptophan, including phenylalanine and others in the gut. And then the gut microbiome content is also part of this sensing network. And the gut and renal urate transporters are a big part of this sensing network. So when we have less kidney function, the gut actually increases its workload, increases its ABCG2 expression and imports more urate into the gut normally where it can take on some of the roles of the kidney.

And that's basically the crux of this multiorgan remote sensing regulatory circuit that's going on in human beings that can be disrupted by any one of the elements of this network.

So why am I interested in the gut and the gut microbiome? Why should we be interested in the gut and the gut microbiome in hyperuricemia and gout? Well, the obvious reason starts with the fact that humans lack the enzyme uricase, which degrades urate to a much more soluble compound, allantoin, which is more readily excreted by the kidney. And so human uricase is a pseudogene, it's not expressed. And then the microbiome has about 9 million genes. Humans only have about 20,000 genes. So humans lack uricase as I said, but also the microbiome has tons and tons and tons of very interesting genes that affect purine metabolism and inflammation that humans don't express. So the microbiome can be the perfect complement to what the enzymes are and other mechanisms that humans express to deal with urate biology and inflammation.

And so this is potentially a rich source of compounds for new drugs. But what we have in the gut is basically a pharmaceutical factory that is attempting in physiology to stay relevant by compensating for things that humans lack in terms of the enzymatic and other architecture of urate handling and inflammation. And so the relationship of the gut organisms to human gut cells and to the human system is really a mutually beneficial one. And that's why we have these commensal organisms in our gut.

And then there's the mass effect. So the ratio of bacteria to enterocytes, there’s about 40 trillion bacteria and about 30 trillion enterocytes, so there's a hell of a lot of mass of these bacteria that have all these useful genes that can help us in handling urate and purines and keeping gout at bay.

And then the recent research, I mean things really have only started in this area about 15 years ago, and then there was a big explosion of research by Dylan Dodd at Stanford and Federico Rey at the University of Wisconsin in Madison in 2023, where they simultaneously and independently published landmark research papers that showed that the gut microbiome maintains normal serum urate in mice that are made deficient in uricase to model basically the human state. And that happens when renal function is normal. And so the kidneys can take on their normal role of handling urate, excreting urate, but basically the gut microbiome is essential to maintain a normal serum urate in this preclinical modeling state.

And the recognition over the last few decades that the gut microbiome is, as I mentioned, a butyrate factory and that butyrate suppresses systemic inflammation and most of the action is happening in the colon and the terminal ileum, which are deeply anaerobic. And there's multiple anaerobes that break down butyrate there. And some of these anaerobes, a lot of them actually, also break down urate and purines and are important organisms that we'll talk about.

But we know that gout is a disease that's associated very commonly with common comorbidities in the United States. Obesity, metabolic syndrome, chronic kidney disease, hyperlipidemia, and also atherosclerosis.  And the gut microbiome effects on purine consumption, on urate consumption, have also been identified to limit some gout comorbidity with atherosclerosis being a very important one in preclinical studies. And then last but not least in terms of the reason I got interested in this is that the patients with gout have what we call dysbiosis in the gut. And that compromises the butyrate factory functions that are anti-inflammatory and also impacts on how the gut handles purine and urates.

So why is this relevant in the clinic? It's very relevant, but particularly so because in a normal situation about two-thirds of our urate elimination is renal and one-third is intestinal. When you have decreased renal urate elimination, which is the state in at least 90% of gout, it drives hyperuricemia. And when you have decreased renal urate elimination because your GFR goes down or because of genetics and different renal urate transporters that don't function in a physiologic way, when your renal urate elimination decreases, it places progressively more burden on the intestinal elimination of urate such that when patients reach a Stage 4 chronic kidney disease, the main mechanism to get rid of urate is in the gut. And there's unfortunately limits in what the gut urate elimination is, but when people have dysbiosis, the limits are even more severe.

There are common problems that are hereditary with a common gene variant of ABCG2, present very commonly in patients of South Asian, East Asian extraction, also in Mexican-Americans to a lesser degree. Half the patients who are Han Chinese extraction with gout, same for Japanese, Thai, Korean, they have impaired ABCG2 stability and they have decreased ABCG 2. And in Filipino patients it's about three-quarters of the gout patients that we see. And so people start off with impaired ABCG2.

A lot of the patients that we see in the clinic that have early onset gout, meaning before age 40, and/or tophaceous gout, they have a renal uric acid overload because their gut isn't eliminating enough urate and they have more severe early phenotypic gout. And so we see a lot of these patients in the clinic and especially in San Diego, and in my practice where I've taken care of a lot of patients who are of East Asian extraction.

And then the gut urate transport goes in both directions. So the urate comes into the gut via ABCG2, and if the microbiome population is not right to degrade all the urate properly, the urate can diffuse back into the circulation.

These are all important reasons why in the clinic, when you look at a patient that walks in the door and you look at their ancestry and you look at their family history of gout, you look at their kidney function, you look at the age of onset of gout, and their inflammatory burden. These are all reasons why the gut microbiome and the gut are really important clinically for rheumatologists. And so we can construct a formula. The serum urate is regulated in part by the rate of gut urate consumption and purine consumption versus the reabsorption back into the circulation. So it's not just related by how much urate we reabsorb in the kidneys and excrete in the kidneys or how much we make or intake in the diet of purines. The gut really is part of the whole equation as to why people get hyperuricemia and why they get problematic gout.