Precision Medicine: A Diagnosis of Inclusion in IBS

Following a discussion on the differential diagnosis of irritable bowel syndrome [IBS], experts consider how identification methods are becoming more accurate.

Mark Pimentel, MD: I do want to touch on methane a little, because 1 of the drugs we will talk about later is related to methane. Bill, do you want to make any comments on methane and its association with constipation? Because to be honest, 1 thing we’ve omitted from the discussion so far of pathophysiology is the microbiome in IBS [irritable bowel syndrome], because there’s a plethora of growing information on this topic, and methane is part of that story. And of course bile acids and other things are part of that story. But I want you to focus on methane for a moment.

William D. Chey, MD: Yeah. So this is 1 of the most fascinating new topics in the pathophysiology, diagnosis, and treatment of IBS, right? We have been talking about the potential role of breath testing, which is all around the microbiome, or where it lives. And what you’re referring to, Mark, is what might be living there. For bacterial overgrowth, for example, there are patients who have greater hydrogen production or methane production. Your group has done a great job showing us that methane tends to slow down motility and transit in the GI [gastrointestinal] tract, which has been associated with a greater likelihood of IBS-C, or IBS with constipation. It has potential treatment ramifications, in that methane bacterial overgrowth doesn’t seem to respond quite as well to rifaximin alone. So it is my understanding that your group has been able to show that the combination of rifaximin and neomycin seems to do better for those patients.

Mark Pimentel, MD: But the microbiome is growing, in terms of its relationship with IBS. Ali, do you want to comment on bile acids? And then, Brennan, I’m going to get you to wrap up this segment by explaining how we make a diagnosis of inclusion rather than a diagnosis of exclusion.

Ali Rezaie, MD: Yes. Bile acid malabsorption is another field that is growing in IBS. There are multiple factors that are involved in it. And interestingly enough, there is a role for the microbiome in it as well—the way microbiome interacts with bile acid. That’s a field that we’re learning more about, and hopefully it will lead to further therapies for patients who do have bile acid malabsorption.

Mark Pimentel, MD: What I’m hearing is: there are little buckets that are forming, and more data are needed. These buckets may help identify subgroups of IBS, and maybe we can really pinpoint, to your point earlier: If we know this, this therapy will work better. If we know this, this therapy will work better. And then ultimately the patient will be satisfied. Because it’s the lack of response by these patients to pharmacologic agents that drives a lot of the doctor shopping and expense.

Are we getting close to a diagnosis with inclusion for IBS? You know a lot about statistics and epidemiology. If you have 100 people coming through the door, chances are, if you were in Las Vegas, it’s an IBS patient if they have diarrhea. That’s more prevalent, versus IBD [irritable bowel disease]. So it’s a little fallacy to say that the Rome criteria, or just diagnostic criteria, are 90 %. Because just by the prevalence coming through the door, you’re going to hit the nail on the head by guessing. Can you comment on getting to that nirvana of a diagnosis of inclusion?

Brennan Spiegel, MD: Right. Behind all this is this idea of precision medicine, which is the notion that we can characterize patients more precisely, whether it’s through biomarkers—genetic, serological, whatever—or even psycho markers. Literally, just asking people questions and understanding how they’re feeling, what they’re feeling. These are all types of markers that we can use to maybe more precisely characterize any group of patients. In IBD, we used to talk about Crohn disease and UC [ulcerative colitis]. But now IBD-ologists talk about a whole spectrum—IBD1, and IBD2, and IBD3—or a whole sequence of different phenotypes and genotypes. And I think that’s where we’re headed now, finally, in IBS.

The diagnosis of inclusion with antibody, as we talked about earlier, suggests that there’s sort of a seropositive type of IBS. That’s really an interesting idea, and 1 that’s biologically sound and can be matched to a specific treatment paradigm potentially. We need to learn more about that. But I think in general what we’re seeing is a shift from the diagnosis of exclusion. We published a paper several years ago. Even the experts never really believed that. They just didn’t quite feel that was the case. But things have been changing now, and I think we’re starting to realize that we can make a diagnosis of inclusion. We’ll hear more about that as you and others continue to accumulate the research.

Mark Pimentel, MD: Do we need a summit on biomarkers? I feel like the IBD folks are much more organized. Perhaps maybe there’s more of them, so they can conglomerate better to put people into these new buckets that are evolving—the bile acid malabsorption bucket or the maldigestion bucket. For example, sucrose malabsorption. There are so many different buckets that are forming, but we don’t gather around them to try to weigh the evidence on all these different…

William D. Chey, MD: I have 1 comment: Rome IV criteria. Part of the Rome IV criteria was the development of something called the MDCP, which is the multidisciplinary clinical profile. And part of the MDCP, in anticipation of this happening, is focused on biomarkers. At the time we did Rome IV, there really wasn’t anything to put in that bucket. But we knew this was coming. I think there’s a misconception that the Rome criteria don’t embrace the notion of biomarkers. Rome totally embraces the notion of biomarkers. In fact, at a Board level, I can tell you that we’re already talked about the next phase being symptoms-plus. So the next evolution of the Rome criteria, I can tell you, will be not only symptoms. It will be symptoms and biomarkers, and not just biomarkers to exclude other diseases but biomarkers to help us to understand what the underlying pathophysiology is to go more toward a precision medicine route.

I think that’s coming. I think as part of Rome V—which believe it or not, people are starting to talk about because remember, it’s a 5-year process, starting in a few years—this is going to be a critical element. Certainly, it will be if I have anything to say about it.