Functional gut disorders become clearer as models emerge

Functional gut disorders are troubling for both patients and physicians, according to gastroenterologist Nicholas Talley, MD, PhD, FACP.

“It's chronic, it's distressing, they can be disabling, and they're thought to be often psychological. … Patients think this; doctors think this,” he said. “It's still something that is confusing, and it's partly because we've lacked a disease model or models that we can hang our hat on and do something about.”

However, current research is beginning to provide such models to explain irritable bowel syndrome (IBS) and functional dyspepsia, according to Dr. Talley, a laureate professor and pro vice chancellor at the University of Newcastle in Australia and professor of epidemiology and medicine at Mayo Clinic in Rochester, Minn.

“The clues are coming together,” he told attendees at the annual meeting of the American College of Gastroenterology, held in Philadelphia last October.

Overlapping disorders

One major finding is that IBS and functional dyspepsia are connected. The latter condition is under-recognized in the U.S., Dr. Talley noted.

“It's better recognized in Asia, interestingly,” he said. “Functional dyspepsia is where people describe early satiety or fullness after they eat. It can be very unpleasant. Often they call it bloating but mean uncomfortable fullness after eating.” Some patients may also have epigastric pain or burning after eating or between meals.

About 10% of adults in the U.S., Canada, and the United Kingdom have symptoms meeting the criteria for functional dyspepsia, according to a survey published in the April 1, 2018, Lancet Gastroenterology and Hepatology.

Many of them also have IBS or will develop it, Dr. Talley added. “If you follow up, as we have done over a 10- to 20-year period, with subjects with functional dyspepsia from the general community, you can show that two in 10 of them will develop incident IBS,” he said. “This means these conditions must be intimately linked. They co-occur. They can progress to each other. This strongly suggests the etiology must be similar.”

One likely culprit is infection. For example, a study published in Gastroenterology in 2005 showed that patients who had Salmonella enteritis developed IBS and functional dyspepsia at much higher rates than average.

“Many patients cannot remember an acute gastroenteritis or acute infection leading to their symptoms, but they probably had one,” said Dr. Talley. “You can develop IBS [as a result], which we've known for over 60 years, but you can also develop dyspepsia, and if you're very unlucky, you get both.”

These complications of gastroenteritis might be explained by the development of inflammation that fails to completely clear in the intestines. Evidence of past bacterial gastroenteritis is suggested by the presence of cytolethal distending toxin B antibodies, which are produced in response to several bacteria that cause gastroenteritis. An autoimmune-type reaction to gut infections has led to an IBS-like phenotype in animal research, Dr. Talley reported.

“We now know that low-grade inflammation plays a role in at least subsets of cases with functional gut syndromes,” he said. Duodenal eosinophils may be responsible for some cases with dyspepsia, which would also explain the association between smoking and functional dyspepsia, because smokers with functional dyspepsia have higher duodenal eosinophil counts.

“I'm going to argue that immune activation is absolutely key to the pathogenesis in at least subsets of these cases with what we now call functional gut disorders,” said Dr. Talley. “For example, eosinophils degranulate next to the nerves and they can and do damage nerve structure, and they can change nerve function.” Eosinophilia may also occur because of exposure to dietary proteins, which may help explain nonceliac gluten sensitivity, also linked to duodenal eosinophils.

The good news is that this problem can potentially be treated. “Guess what? PPIs [proton-pump inhibitors] work in functional dyspepsia,” he said. A 2017 Cochrane review found that PPIs were effective for the condition, and Dr. Talley and colleagues have specifically found reductions in duodenal eosinophilia with PPI therapy.

“The responders to proton-pump inhibitors with [functional dyspepsia], they're the postprandial distress folks. That's the subgroup also most likely to have duodenal eosinophilia,” he said.

The gut's immune response may also, or alternatively, be driven by mast cells. “Mast cells are increased in the intestine in IBS,” said Dr. Talley. “This isn't everybody, though. It appears to be a subset of IBS.”

An approach to this problem may be cromoglycate, according to a study published in the October 1, 2017, United European Gastroenterology Journal, which found reductions in IBS diarrhea with the drug. “Something that actually will stabilize mast cells appears to potentially have some benefit in IBS … something to think about in at least some patients,” Dr. Talley said.

Another potential treatment is antihistamines, he said, citing a small study, published in Gastroenterology in 2016, that found reduced IBS symptoms with an H1 blocker. “In my hands, histamine blockade can be very useful for a subset of patients,” said Dr. Talley. “That remains to be proven by proper large randomized trials.”

Additional potential culprits

This model assumes that symptoms of IBS and functional dyspepsia result from an initial infection causing persistent inflammation, but some patients' symptoms may be caused by chronic infections, according to Dr. Talley.

“There's some evidence chronic infections also play a role in functional gut syndromes,” he said. For example, ecological analysis has revealed that countries with higher percentages of Cryptosporidium in the water have higher rates of dyspepsia.

Dr. Talley's own research, conducted in Australia and published in Neurogastroenterology & Motility in 2015, has revealed an association between childhood pets and functional gut disorders. “We found herbivore pets, such as rabbits or horses or whatever, that was linked to functional dyspepsia and IBS,” he said. “If you touch a horse and touch your mouth, you're likely to become infested. They're full of parasites!”

Helicobacter pylori has also been linked to functional dyspepsia, to the extent that guidelines recommend testing and treating for it in patients with the disorder. “There's some debate is it really this, or are they just changing the microbiome with anti-[Helicobacter pylori] therapy?” noted Dr. Talley. “By the way, these folks are less likely to have postprandial distress. … The group that appears to respond to H. pylori therapy is the epigastric pain group.”

Speaking of the microbiome, it definitely seems involved in functional gut disorders, but the specifics are still unclear, according to Dr. Talley. “The data, I would argue, are very interesting, but they're all over the place,” he said. “It's incredibly complex, incredibly interesting, going to be very, very important.”

Despite the limited understanding of the microbiome, therapies are already targeting it. “We can modulate the microbiome,” he said. “Rifaximin, the only drug that changes the natural history of IBS, you give it for 10 days, two weeks, and those who respond stay symptom-free for a period of time well after you stop therapy. This is fascinating.”

Rifaximin may also work for functional dyspepsia, but more research is needed in this area, according to Dr. Talley. “We have no idea about what rifaximin hits, which is a tragedy and it's got to be fixed. It's insane that we give a therapy to people and we don't really have any idea who we should give it to and not give it to.”

Some patients may require entirely different therapies because their symptoms, although similar, are caused by entirely separate conditions. “There's a genetic IBS. There's actually a real mutation. This is a sodium-channel gene,” said Dr. Talley. “You can reverse the sodium-channel deficit with drug therapy.” This mutation may be responsible for 2% of IBS cases, and was discovered thanks to research on patients with the long QT syndrome and unexplained gut symptoms, he explained.

At least one other diagnosis should be split off from IBS, according to Dr. Talley. “The data are becoming more compelling for bile salt-induced IBS. It's not IBS; it's bile salt diarrhea, which manifests as IBS,” he said, noting that it could be the cause of up to 20% of IBS diarrhea cases and it responds to specific treatment.

Brain and gut

A deeper understanding of the association between functional gut disorders and psychological problems could also lead to a better classification of IBS patients.

Some psychological distress may be explained by the models of IBS already described. “Increased [tumor necrosis factor] levels are linked to increased anxiety in IBS,” said Dr. Talley. “The intestinal inflammatory response or the immune activation response may drive extraintestinal gut symptoms, including anxiety.”

However, other IBS patients seem to have a different set of problems. “The epidemiological and some of the pathophysiological studies suggest that there are two pathways,” said Dr. Talley. “They are somewhat distinct, and the management might be quite separate.”

In one pathway, patients have psychological distress first, then develop gut symptoms. “There's another subset where they get their gut symptoms, the classic functional bowel syndromes, and then they get incident, new-onset, psychological distress. And I think that's more likely to be driven by gut-to-brain mechanisms,” he said.

One theory is that cases that start in the brain and then move to the gut relate to corticotropin-releasing hormone and its effects on the gut, while those starting in the gut may relate in some cases to cytokine release altering the brain, Dr. Talley speculated.

“There's likely a gut-brain pathway, there's a brain-gut pathway, and I think that's very exciting,” he said. “Management might be distinct for those with brain-gut disease, perhaps psychological therapies, versus gut-brain.”

Figuring out how to manage all patients based on the specific causes of their symptoms should be the goal of research on functional gut disorders, urged Dr. Talley. “We want to classify people properly. This will require a lot more science, but we're getting closer [to] where we can subset and perhaps target therapy in new ways that may lead even to cure in the near future,” he said.

And perhaps, during that process, the diseases can get new names. “‘Functional’ as a term I think has really done us a disservice. … It still has really negative connotations for patients so we need a new name,” he said. “We also need to come up with a model of these diseases that allows us to understand, to explain them, and indeed to hopefully manage them more effectively.”